Datasets:

farleyknight

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big_patent_10_percent

like 1

a basket - shaped strainer 10 is supported by a pivot 12a within a bowl 12 for rotation about the vertical axis 14 . the strainer 10 has perforated sides and bottom and has an open top . the side perforations are by means of vertical slits some of which are shown at 10a . the bottom perforations are similar radially arranged slots two of which are visible at 10b . the strainer has a cover 16 fitting frictionally at the open top of the strainer . the fit is such that when the cover 16 is rotated about the vertical axis 14 the strainer 10 rotates with it but the cover 16 can be easily lifted by hand from the strainer 10 . the cover 16 is also perforated , having circumferential segmental slits defined between circular segments 16a extending between radial ribs ( which are not visible in the shown views ). the strainer cover 16 has a central keyhole 16b which is rectangular in cross - section and flares in the up direction so as to easily receive a strainer - driving pin 18 which has a tapered lower end also of rectangular cross - section . the fit of the pin 18 in the hole 16b prevents relative rotation between the strainer cover 16 and the pin 18 but permits easy withdrawal of the pin 18 from the hole 16b . the pin 18 is journaled for rotation about the vertical axis 14 within a hole 20a centrally located in a bowl cover 20 which fits over the bowl 12 . the pin 18 has a part extending above the lowermost portion 20b of the cover 20 , and a driven gear 22 is affixed to that part of the pin 18 to rotate coaxially therewith . an idler gear 24 is journaled on a pin 20c extending up from the portion 20b of the cover 20 and meshes with the driven gear 22 . a planetary gear 26 is supported for rotation about the vertical axis 14 between a pair of coaxial circular flanges 20d and 20e extending upwardly from the portion 20b of the bowl cover 20 , and meshes with the idler gear 24 . the three gears are mounted in a substantially coplanar relationship so as to minimize the height of the step - up transmission which they form . the planetary gear 26 has an integral dome 26a extending upwardly and terminating in a key block 26b which fits in a similarly shaped key slot 28a of a turning cover 28 . the key block 26b has a pair of spring latches 26c and 26d which extend upwardly from it and snap - fit at the key slot 28a when the cover 28 is forced down on the dome 26 . this snap - fit prevents separation of the turning cover 28 from the dome 26 except by squeezing the latches 26c and 26d toward each other such that their hooks 26e &# 39 ; and 26d &# 39 ; clear the key slot 28a . a cap 30 fits over a central opening 28b of the turning cover 28 and has an opening 30a which faces downwardly and fits frictionally over a pin 26e which extends up from the dome 26 . the turning cover 28 is supported by circular bearing flange 20f within a circular depression 20g at the top of the bowl cover 20 . an offset turning handle is made up of a pin 32 which extends up from the turning cover 28 and a sleeve 34 which has a central opening 34a shaped to receive the pin 32 in a snap - in lock formed by a notch at 34b and has a mating collar at 32a . a transmission cover 36 fits over the dome 26a permitting the key slot 26b to protrude upwardly therefrom through a central opening 36a . the transmission cover 36 snap - fits in the bowl cover 20 by means of four spring loaded projections 36a which fit within suitably shaped and disposed openings 20j in the bowl cover 20 . the bowl cover 20 has a peripheral groove 20h and a downwardly extending skirt 20i . when the cover 20 is being put on the bowl 12 the skirt 20i forces radially outwardly a pair of cover - retaining latches one of which is generally indicated at 38 . the latches 38 are resilient and are biased such that when the cover is in its position to close the bowl 12 the hook 38a of each latch 38 snaps in place in the groove 20h . referring to fig3 - 5 the latch 38 comprises , in addition to the hook 38a , an upwardly extending resilient strip 38b which fits within a loop 40 integrally formed with the bowl 12 . as best seen at fig4 the space between the loop 40 and the sidewall of the bowl 12 tapers upwardly so that the latch 38 can be inserted into the loop 40 in the upward direction until the latch is wedged within the loop and a projection 38c snaps upwardly against the upper surface of the loop to lock the latch within the loop . all of the parts of the appliance , including the gears , are molded of inexpensive plastic material and can be easily assembled by hand , without the use of any tools . specifically , the cover is assembled by pushing the driving pin 18 through the opening 20a in the cover 20 until the gear 22 rests on the part 20b of the cover , the idler gear 24 is placed on the pin 20c to mesh with the gear 22 and the planetary gear 26 is put in its place to mesh with the idler gear . the transmission cover 36 is then snapped into the cover 20 by having its projections 36a snap - fit into the corresponding holes 20j in the cover 20 . the turning cover 28 is snap - fitted onto the dome 26a of the planetary gear and the cap 30 is friction - fitted down onto the pin 26e of the key block 26b . the sleeve 34 is then snapped onto the pin 32 to form the crank handle . the cover - retaining latches 38 are snap - fitted up through the loops 40 as described , and the appliance is ready for use . in use , the material to be dried is put in the strainer and the strainer is put in the bowl with its bottom central recess 10c resting on the pivot l2a . the strainer cover 16 is fitted by hand at the top of the strainer , and the bowl cover 20 is put on top of the bowl such that its driving pin 18 fits within the keyhole 16b of the strainer cover 16 and the cover - retaining latches 38 snap in place in the peripheral groove 20h of the cover 20 . the turning cover is manually rotated about the axis 14 by means of the crank handle sleeve 34 , which freely rotates about the pin 32 , and thus rotates the strainer 10 at a higher speed to extract moisture from the vegetables in it mainly by centrifugal force . this moisture runs down the inside of the sidewall of the bowl 12 and collects in the clearing between the bottom of the bowl and the strainer 10 . the rotational motion is transmitted from the turning cover to the planetary gear through the keyed connection between the dome and the turning cover . the planetary gear rotates the idler gear , which in turn rotates the driven gear and thereby the driving pin . the driving pin 18 in turn rotates the strainer cover 16 and the strainer cover 16 rotates the strainer 10 through the frictional fit therewith . the appliance can be easily picked up by the cover 20 or the skirt 20i thereof and moved about as desired . it is opened by grasping the top end of the cover - retaining latches 38 and bending the latches outwardly , to move the hooks 38a away from the cover 20 until they clear the cover , while simultaneously lifting the cover 20 . lifting of the cover 20 does not remove the strainer cover 16 since the driving pin 18 easily withdraws from the keyhole 16b of the strainer cover 16 . the strainer bowl 10 can be picked up from the bowl 12 with the strainer cover 16 still on it , or the strainer cover 16 can be picked up first . the entire appliance can be washed with no adverse effects on any of the moving parts , and the appliance can be disassembled if desired without the need for any tools or with minimal tools . directional terms used as &# 34 ; up &# 34 ;, &# 34 ; down &# 34 ;, &# 34 ; vertical &# 34 ; and the like apply to the view illustrated in fig2 ; it should be clear that in use or in the course of assembly or disassembly the appliance can be oriented differently .

an appliance which is made solely of snap - in molded plastic components includes a strainer for holding the vegetables which is rotated within a covered bowl by a hand crank transmitting the rotational motion through a step - up transmission having a planetary gear and through a frictional fit between a strainer and an easily removable strainer cover .

referring particularly to fig1 of the drawings , this invention is illustrated as applied to a vacuum cleaner indicated generally at 11 and comprising a housing including a head portion 12 pivotally connected to a body portion 13 . wheels 14 may be rotationally supported on or adjacent the pivotal connection between the head and body portions . a motor blower 15 is arranged in the head portion together with a nozzle 16 which may be fitted with a driven brush 17 . a flexible tube 18 extends from the motor blower 15 in the head portion 12 along a trough 19 formed in the rear of the body portion 13 and provides a conduit to an exhaust fitting 20 providing a terminus to the air conduit from the vacuum cleaner nozzle 16 . the exhaust fitting 20 is preferably fitted with a flexible gasket 22 . retaining fingers 23 extending from the rear of the vacuum cleaner body portion 13 provide storage for coils of the power cord 24 for the motor blower . the body portion 13 of the vacuum cleaner housing is adapted to be closed by a cover 30 having the form of a shallow tray . the tray - like cover 30 is provided with a bent wire dirt bag retainer 32 shaped so as to embrace and locate a collar portion 33 of a disposable dirt collecting bag 34 in registry with the exhaust fitting 20 in effective position to separate and collect dirt from air delivered into the bag from the conduit . the free extremity of the cleaner body portion 13 and the cover 30 are formed with aligned recesses 35 and 36 , respectively , adapted to accommodate means for supporting a handle indicated generally at 50 on the vacuum cleaner . preferably , the handle is supported on the cleaner body by a u - shaped bracket 41 which , as best shown in fig3 and 5 , has a base 42 secured to the cleaner body by any suitable means , such as a staking 43 , or use of a rivet or other fastening device . the bracket 41 is formed with a pair of bracket arms 44 in which bearing projections 47 formed on the handle 50 are journaled . the handle 50 may be pivoted relatively to the vacuum cleaner housing selectively into either of two positions , each suitable for a different mode of vacuum cleaner operation . fig1 and 3 illustrate the extended position of the handle relatively to the cleaner housing suiting the cleaner for upright floor supported vacuum cleaning operation , while fig2 and 6 illustrate the retracted position of the handle suitable for hand carried vacuum cleaning operation . the preferred construction of the handle 50 and the means for accommodating the handle in two different positions without appreciable limitation on the size and configuration of the vacuum cleaner housing will now be described . preferably , the handle 50 is formed with two telescopically and rotationally interrelated parts 51 and 52 , part 51 being that formed with the bearing projections 47 . the part 52 , which is formed at one extremity with a hand grip 53 , is slidable lengthwise within the handle part 51 and at the extremity opposite the hand grip carries a latch button 54 loaded by a spring 45 , which latch button is engageable with a latch aperture 55 near the free extremity of the handle portion 51 to lock the handle parts in extended position , or with a latch aperture 56 near the pivoted extremity of the handle portion 51 to lock the handle parts in retracted position depending upon the relative rotational position of the handle parts . in the retracted postion of the handle parts , as shown in fig5 a projection 57 on handle part 52 seats in a socket 58 in the cover 30 to constrain the handle in position for supporting the cleaner in a hand carried vacuum cleaning operation . a major portion of both handle parts 51 and 52 are formed with rectangular configuration as shown in the perspective view of fig2 and telescopically related . the extremity of the handle part 52 opposite the hand grip 53 is formed with a cylindrical cross sectional shape 62 to accommodate rotational movement of the handle parts when the latch button 54 is depressed into the aperture 55 . when so depressed , the latch button 54 may be accommodated in an undercut 46 in the hollow interior 60 to prevent complete separation of the handle parts 51 and 52 . fig1 and 3 illustrate a latch device effective to constrain the handle in the extended position relatively to the cleaner housing rendering the cleaner suitable for upright floor supported vacuum cleaning operation . this latch device comprises a flexible latch element 70 secured inside the handle portion 51 and arranged protruding from the handle , as illustrated in fig1 and 3 , to engage beneath a shoulder 71 on the cleaner body portion 13 to retain the handle in the postion shown in fig1 and 3 . a release button 72 carried by the latch element 70 within the handle portion 51 is accessible to an operator through an aperture 73 in the handle permitting the latch element 70 to be shifted out of engagement beneath the shoulder 71 freeing the handle for pivotal movement out of the extended position . fig5 best illustrates the latch device effective to constrain the handle in the retracted position relatively to the cleaner housing rendering the cleaner suitable for hand carried vacuum cleaning operation in the form illustrated in fig2 . as described above , and with particular reference to fig5 when the handle part 52 is rotated 180 ° from the position relative to the handle part 51 shown in fig1 and 3 and the handle 50 is rotated about the bearing projections 47 into retracted position adjacent the cleaner housing , the handle part 52 , upon telescopic insertion into handle part 51 , shifts a projection 57 on handle part 52 into a cover socket 58 substantially simultaneously with the reception of the latch button 55 into the aperture 56 in the handle part 51 . to remove any looseness in the interlocking relation between the handle and the cleaner housing , a resilient tab 80 is formed to extend from the handle part 52 adjacent to the projection 57 . the tab 80 engages the cover 30 in the interlocked position of the projection within the socket 58 and , in being deflected thereby , the resilient tab 80 imposes a light force between the handle 50 and the cleaner housing to remove any slack therebetween . with reference to fig6 the pivotal connection between the cleaner head portion 12 and body portion 13 is illustrated . indicated at 90 is an axle stud for one of the cleaner wheels 14 , which axle studs are journaled in extensions 91 from the cleaner head portion 12 . the studs 90 also extend laterally inward from the extensions 91 and are embraced by the body portion 13 of the cleaner to provide the pivotal connection between the cleaner housing parts 11 and 12 . as shown in fig6 the housing parts 11 and 12 are formed with interchanging stop surfaces 92 and 93 , respectively , adjacent pivotal connections therebetween . the stop surfaces are adapted to abut defining one extreme limit of the angular range of pivotal movement between the body and head portion of the cleaner housing in which , as shown in fig2 and 6 , the undersides of the head and body portions 11 and 12 are substantially coplanar . as shown in fig2 and 6 , the handle , when shifted into retracted position , brings the hand grip 53 into engagement with a raised abutment projection 100 formed on the upper surface of the head portion 12 of the cleaner . as the handle parts 51 and 52 are shifted telescopically into the retracted position , the hand grip 53 acts as a cam means in engaging the projection and urging the stop surfaces 92 and 93 into engagement . engagement of the latch button 54 into the aperture 56 of handle part 51 locks the cleaner head and body portions in this extreme position of angular relation shown in fig2 and 6 . as shown in fig2 the head portion 12 of the cleaner housing is formed in the upper surface with an opening into the nozzle 16 which can be closed by a hinged cover plate 111 . when the cover plate 111 is swung up , as shown in fig6 the opening is exposed to accommodate an adapter 112 carried by one extremity of a flexible hose 113 to the opposite extremity of which various cleaning implements such as a brush 114 or the like may be carried . the adapter 112 is shaped , as shown in fig6 to block off the nozzle 16 passageway to the motor blower when the adapter is fully inserted into the opening 110 so that air will be drawn by the blower instead of through the flexible hose 113 . when the flexible hose 113 is utilized , the cleaner is adapted for use in the mode of a cannister cleaner and particularly adapted for off - the - floor cleaning operations in the course of which the cleaner housing is apt to be drawn along by forces imparted thereto by the flexible hose 113 . in the form of the cleaner of this invention , as shown in fig2 and 6 , the compact configuration of cleaner parts and the low silouette provided by the retracted postion of the handle 50 provides a stability to the cleaner housing which resists tipping and overturning to which the cleaner would be prone in the upright mode shown in fig1 .

a vacuum cleaner having pivotally interconnected body and nozzle head portions and a handle which is extendable for upright floor cleaning operation or retractable for hand carried or cannister type vacuuming operation , in which the handle in retracted position fixes the cleaner body and nozzle head portions against pivotal movement .

fig1 shows a cylinder ( 3 ) with an opening ( 4 ) including a roll of adhesive paper ( 1 ) and a winding shaft ( 9 a ). the paper drawn from the roll ( 1 ) gets out of the cylinder ( 3 ) through the opening ( 4 ), laid along the round of said cylinder to be wound on the winding shaft ( 9 a ) put in said cylinder through the opposite side of said opening ( 4 ). the cylinder ( 3 ) is closed with two end plates ( 5 ) and ( 6 ) at both ends , the end plate ( 5 ) having a center hole ( 7 ) to insert a center shaft ( 10 ) and two supporting holes ; ( 8 b ) for sustaining an unwinding shaft ( 8 a ) with the roll of adhesive paper and ( 9 b ) for sustaining the winding shaft ( 9 a ), the end plate ( 6 ) having a center hole ( 11 ) with a stopper ( 12 ) and two supporting holes ; ( 8 c ) for sustaining the unwinding shaft ( 8 a ) and ( 9 c ) for sustaining the winding shaft ( 9 a ), the stopper ( 12 ) to be fit with a stopper channel ( 15 ) on the top of the center shaft ( 10 ) to prevent slip - off . on an end of the unwinding shaft ( 8 a ), socket holes ( 16 b ) are equipped , which are fit with projections ( 16 a ) put on an unwinding gear shaft ( 13 ) shown in fig2 . also on an end of the winding shaft ( 9 a ), socket holes ( 17 b ) are equipped , which are fit with projections ( 17 a ) put on a winding gear shaft ( 14 ) shown in fig2 . in a gear box ( 2 ), the center shaft ( 10 ) is equipped with a one - way bearing ( 18 ) joined with a driving gear ( 19 ) to enable the shaft rotation only in the arrow direction . the winding gear shaft ( 14 ) is equipped with a winding gear ( 20 ) engaging with said driving gear ( 19 ). the unwinding gear shaft ( 13 ) is equipped with a ratchet gear to prevent reverse rotation . an arm with backstop claw ( 22 ) is equipped on the center shaft ( 10 ) at the arm &# 39 ; s fulcrum , each end of the arm being pressed on the winding gear ( 20 ) and the ratchet gear ( 21 ) respectively using a spring ( 23 ) to prevent slip or reverse rotation of them . in this status , the winding gear ( 20 ) can &# 39 ; t rotate by itself or the ratchet gear ( 21 ) can &# 39 ; t rotate reverse but can advance only in the arrow direction . on the end of the unwinding gear shaft ( 13 ), the projections ( 16 a ) are equipped to fit in the socket holes on the unwinding shaft ( 8 a ). on the end of the winding gear shaft ( 14 ), the projections ( 17 a ) are equipped to fit in the socket on the winding shaft ( 9 a ). to prepare the operation of this cleaner , the cylinder ( fig1 ) should be held and the center shaft ( 10 ) should be inserted into the cylinder through the center holes ( 7 ) and ( 11 ) to fit with the stopper at the stopper channel ( 15 ). at the same time , the projections ( 16 a ) and ( 17 a ) should be fit with the socket holes ( 16 b ) and ( 17 b ) respectively to join the unwinding shaft ( 8 a ) and the winding shaft ( 9 a ) with the unwinding gear shaft ( 13 ) and the winding gear shaft ( 14 ). this is the end of preparation before operation . fig3 shows the sectional view of combination of the cylinder ( fig1 ) and the body ( fig2 ). when the handle ( 25 ) is held and the cylinder is moved back and forth pressing onto the floor , the one - way bearing ( 18 ) slips around the center shaft ( 10 ) on the forth way together with the driving gear ( 19 ) but the winding gear ( 20 ) engaged with the driving gear doesn &# 39 ; t rotate . thus said cylinder and said body ( gear box ) turn on said center shaft without rotation of the winding shaft ( 9 a ) or the roll of adhesive paper ( 1 ) to attract dust . in other words , the center shaft turns against the cylinder and the gear box . on the back way , said one - way bearing ( 18 ) fixed on said center shaft is locked . then said driving gear ( 19 ) is also stopped . however the winding gear ( 20 ) fixed on the winding gear shaft ( 14 ) starts the planet motion around said driving gear ( 19 ) as said cylinder continues rolling on the floor . then the top of the arm with backstop claw biting the winding gear ( 20 ) is forced up with the motion , the opposite top of the arm also being forced up against the ratchet gear ( 21 ). the lock of the unwinding shaft ( 8 a ) and the winding shaft ( 9 a ) is released to wind the adhesive paper . when the back motion of the cylinder stops , both tops of said arm again bite said winding gear ( 20 ) and said ratchet gear ( 21 ) respectively to lock them . the winding adhesive cleaner according to the invention described above realizes a new ideal feeding system that adhesive paper laid on the cylinder ( 3 ) is wound up into the cylinder at the most dirtied part after running around the cylinder and that the fresh adhesive face is always fed at the same time . if the cleaner is lifted up unexpectedly when it is sticking on the floor , adhesive paper isn &# 39 ; t drawn out to loosen because the unwinding shaft ( 8 a ) and the winding shaft ( 9 a ) are both locked at the same time when the cleaner is stopped . even if adhesive paper is slackened a little , it will be dissolved through rotation of the cylinder . the cylinder can also be turned hanging a finger in a winding hole ( 24 ) to dissolve slackened paper or even to prepare fresh adhesive face all round of the cylinder . when all of fresh adhesive face is consumed , the cylinder ( fig1 ) is taken off from the center shaft ( 10 ) to throw away . a winding adhesive cleaner according to the invention has the effects as follows : ( 1 ) adhesive face is continuously changed without removing dirtied face or suspending cleaning operation ; ( 2 ) operation without touching dirty adhesive face directly with fingers is very sanitary ; ( 3 ) cleaning time is remarkably shortened and fatigue for cleaning is reduced ; ( 5 ) through above effects , cleaning mind is encouraged to achieve clean life environment .

a winding adhesive cleaner according to the invention comprises a body equipped with a gear box and an attachable cylinder equipped a rolled strip of adhesive paper . adhesive face on the cleaner is continuously changed without removing dirtied face or suspending cleaning operation . and cleaning operation can be very sanitary because it is unnecessary to touch dirty adhesive face directly with fingers . furthermore , the cylinder after consumed can be thrown away as a combustible waste .

the closed wound orthopaedic drainage and autotransfusion system 10 of this invention includes a universal y - connector 12 for connection to the closed wound drain 14 . extending from the y - connector 12 is a suitable length of patient drainage tube 16 having a pinch clamp 18 for controlling or stopping liquid flow and a sterile self sealing injection port 20 through which an acd - a anticoagulant or any other prescribed anticoagulant may be added to the system if desired by the surgeon . a luer lock type of connector 22 may be included to connect tube 16 to tube 24 anchored or fixed to and in fluid communication with the interior of transparent rigid container 26 . pinch clamp 28 is associated with tube 24 to control or stop liquid flow . the transparent rigid container 26 includes an upwardly extending apertured lug 30 that receives strap 32 for suspending or hanging the assembly 10 from a bed rail or iv pole . an internal pre - filter 34 is mounted on and extends interiorly of the container 26 and filters the autologous shed blood flowing into the container from tube 24 . in accordance with a successful embodiment of assembly 10 , the filter 34 may possess 260 micron porosity . suction is supplied to the interior of container 26 through fixed tube 36 and the liquid collected in the container is adapted to be transferred through fixed transfer tube 38 as will be explained in detail shortly . suction is supplied to the interior of the container 26 by an evacuator or suction reservoir 40 which is adapted to be releasably connected to the side of container 26 by a velcro ® brand hook and loop fastener 42 or any other suitable fastener . the suction reservoir 40 includes a pair of spaced circular plates 44 and 46 connected by a resilient sleeve 48 and adapted to be urged in their spaced apart relationship by internal springs 50 . a fixed inlet tube 52 is adapted to be coupled with tube 36 by a luer lock connector 54 . a valve controlled outlet 56 is adapted to purge the suction reservoir 40 of air upon collapsing the resilient sleeve 48 by manually squeezing the plates 44 and 46 together . a one - way outlet umbrella valve 58 is adapted to be detached from the outlet 56 and coupled thereto by means of opening 60 on strap or tether 62 to permit disposal of exudate collected in the reservoir 40 into a bag when and if the reservoir is connected directly to the wound . the umbrella valve 58 includes a flexible disc 64 covering openings 66 for sealing the reservoir interior from the ambient . when the reservoir 40 is collapsed the flexible disc 64 flexes outwardly to permit air within the reservoir to vent through the openings 66 . when the valve 58 is disassociated from the outlet 56 , the latter may be sealed off by attached plug 68 to seal the interior of the reservoir 46 from the ambient . the tube 36 has a pinch clamp 70 associated therewith and an interposed filter 72 which according to a successful embodiment may be a 1 . 2 micron hydrophobic bacteria air filter . a transfer button 74 serving as a vent valve is also interposed in tube 36 and when depressed releases suction in the system or in the suction reservoir 40 and consequently the container 26 . the inlet of a blood transfusion bag 76 is connected to the container 26 by the tube 38 and may be suspended from the reservoir 40 by a velcro ® brand hook and loop fastener 78 or any other suitable fastener . the tube 38 may also possess a pinch clamp 80 . the top of the bag 76 is provided with a hole 82 to facilitate suspending the bag from an iv pole during reinfusion . in this regard , a standard blood administration set 84 may be coupled with the bag 76 by initially removing the protective cover or plug 85 of the spike port 86 having a puncturable membrane 87 closing the bag outlet by means of an interposed standard blood transfusion filter 88 with a membrane puncturing trocar or needle and which typically is a 20 - 40 micron microaggregate blood filter . the administration set 84 will typically include a drip chamber and flow control clamp as well as the usual needle and trocar or adaptor to its ends . in using the closed wound orthopaedic drainage and autotransfusion system 10 , it is initially removed from its protective pouch ( not shown ) using sterile techniques . the pinch clamp 80 located on tube 38 between collection container 26 and the blood reinfusion bag 76 is closed to prevent fluid from entering the bag prior to blood transfer . using an aseptic technique , the universal y - connector 12 located at the end of the patient drainage tube 16 is connected to the appropriate size wound drain 14 . if anticoagulant is to be used , it can be injected into the system 10 prior to blood collection through the injection port 20 . in practice , 25 - 35 ml of acd - a can be added for every 250 ml of blood collected . this is consistent with the 1 : 7 to 1 : 10 anticoagulant / blood ratio . in this regard , pinch clamp 18 or the patient drainage tube 16 between the injection port 20 and patient is closed . the desired amount of acd - a anticoagulant is aspirated into a syringe , and then injected through the injection port 20 which should be elevated above the container 26 . the pinch clamp 18 is opened to begin collection of autologous shed blood . the container 26 should be periodically agitated during collection to help insure the proper mixture of anticoagulant and blood . if gravity collection is desired , the suction reservoir 40 is not compressed . if suction drainage is desired , the tethered one - way umbrella valve 58 is coupled with the outlet port 56 . the plates 44 and 46 of the reservoir 40 are compressed which will create a negative pressure in the container 26 . it may be necessary to repeat this step periodically as the collection continues . during transportation it will prove beneficial not to wet filter 72 , otherwise drainage will automatically be shut off . in order to prevent this occurring , the pinch clamp 70 is closed and the system 10 is placed on the bed during transportation . loss of blood into the suction reservoir 40 is thus prevented by closing pinch clamp 70 . should the filter 72 become wet either through overfilling , malpositioning or not closing the pinch clamp 70 , prior to placing the container 26 on its side , drainage will automatically be shut off as stated . in order to resume drainage , the container 26 is placed in an upright position and the transfer button 74 is pressed or depressed to release or vent the negative pressure in the suction reservoir 40 . clearing of the tube 36 from the container 26 to the filter 72 may be facilitated by tapping the housing of the filter 72 with the transfer button 74 depressed . after the filter is cleared of fluid , the system 10 may be recharged by compressing the plates 44 and 46 of suction reservoir 40 . when the container 26 is full or it is desired to reinfuse the collected blood , the transfer tube 38 is uncoiled , if previously coiled , and the blood bag 76 is positioned below the collection container 26 . the pinch clamp 18 on the patient drainage tube 16 is closed and the pinch clamp 80 on the transfer tube 38 is opened . the transfer button 74 is depressed and held in this position until all the blood has drained from the container 26 into the blood bag 76 . the pinch clamp 80 on the transfer tube 38 is then closed and the pinch clamp 18 on the patient tube is opened followed by compression of the plates 44 and 46 of the reservoir 40 to continue collection under suction . the initial quantity of blood collected may be reinfused by initially removing the protective cover of the spike port 86 from the blood bag 76 . a standard blood filter 88 is inserted into the spike port 86 . a standard blood administration set 84 is coupled with the filter 88 if not already combined . the bag 76 is then suspended from an iv pole . the blood filter 88 and fluid administration set 84 are primed in usual fashion and air is purged from the administration set 84 . the administration set 84 may now be attached to the patient access and blood will be reinfused by gravity . before the drip chamber of the administration set 84 empties , the clamp on the administration set 84 should be closed . in this event additional quantities of the patient &# 39 ; s blood will be reinfused , the blood bag 76 may be left hanging on the iv pole until blood is ready to transfer from the container 26 . in the event , the clamp on the blood administration set 84 should be closed and the blood bag 76 should be lowered below the container 26 . the above described transfer procedure may now be performed . when it is determined not to collect the patient &# 39 ; s blood any longer for autotransfusion , but to continue to drain the wound , the clamps 80 and 18 on the respective blood transfer tube 38 and patient drainage tube 16 are closed . the suction reservoir 40 is removed from the container 26 and the one way valve 58 is removed from the port 56 . the reservoir is disconnected from the container 26 at the luer lock connector 54 , and the container 26 is disconnected from the patient tube 16 at the luer lock connector 22 . the suction reservoir is then connected directly to the patient drainage tube 16 by connecting the mating luer lock connector halves . the reservoir plates 44 and 46 are compressed towards one another and the port 56 is closed by the tethered one way valve 58 . the container 26 and bag 76 may then be properly discarded . when it is desired to empty the suction reservoir 40 that is connected directly to the patient drainage tube 16 , the clamp 18 is closed and the port 56 is opened by removing the tethered one way valve 58 . the reservoir 40 is turned over and the plates 44 and 46 of the reservoir 40 are compressed until the contained fluid is removed . for continued drainage , the plates 44 and 46 of the reservoir 40 are compressed and the port 56 is closed by the tethered one way valve 58 . the clamp 18 on the patient drainage tube 16 may now be released or opened to resume the collection process . thus , the several aforenoted objects and advantages are most effectively attained . although a single somewhat preferred embodiment of the invention has been disclosed and described in detail herein , it should be understood that this invention is in no sense limited thereby , but its scope is to be determined by that of the appended claims .

a detachable suction reservoir provides suction to a drainage and autotransfusion system coupled with a closed wound drain to facilitate drainage of blood from the wound into a substantially rigid collection container . this blood is adapted to be transferred into a blood bag which in turn may be coupled with an administration set for reinfusion . while blood is reinfusing , blood collection into the container continues . following autotransfusion , the suction reservoir can be converted to a suction device for blood collection directly from the closed wound drain .

the pacifier of the present invention is capable of being formed in a variety of ways ; however , the invention will be described in terms of forming the pacifier by injection molding . the composite integrally formed pacifier 2 of the present invention , as best seen in fig1 consists of a rigid shield 4 , a ring section 6 and a nipple section 8 . the shield member 4 is provided with ventilation holes 10 which are customarily found on pacifier shields . the shield 4 of the present invention is also typically configured and can take any suitable shape . however , for illustrative purposes the shield 4 is shown as a circular shield of essentially 45 millimeters ( 1 . 75 inches ) in diameter and of about a 0 . 1 inch thickness . the material used is preferably rigid polypropylene . other materials which provide the smooth surface characteristics and sufficient rigidity and which will maintain dimentional integrity after boiling can also be used for the shield material . as best seen in fig2 and 3 , the shield member 4 is also provided with a centrally disposed shoulder or recess 12 . an array or a plurality of holes 14 are located around the edge of the shoulder 12 . a centrally disposed opening 16 is also provided to afford the maximum captivity of the shield 4 by the material of the handle 6 and nipple 8 . as best seen in fig4 a cavity 20 for injection molding is shown with the shield 4 located intermediately . the remainder of the mold cavity is configured in the form of the ring and nipple member of the pacifier . an interference member 22 is located to direct the flow of the nipple and ring material adjacent the shoulder opening 16 in the insert . the nipple 8 and handle 6 are formed by flowing the nipple and handle material , typically elastomeric polyvinyl chloride , through the mold such that the material passes through the holes 14 in the shoulder 12 and in the opening 16 around the centrally disposed interference member 22 to capture the shield 4 thus providing an integrally formed one - piece pacifier 4 . it has been found that a shield 4 will provide the necessary rigidity and resiliency to inhibit a child from swallowing the pacifier if the shield 4 is sized in an outside diameter of approximately 45 to 46 millimeters . practice has also taught that a shield 4 of rigid polypropylene of the present invention sized 45 millimeters ( 1 . 75 inches ) of approximately 2 . 5 millimeter thickness will obtain the desired result and pass the requirements for pacifiers as reported in the federal register , volume 42 , no . 126 , thursday , june 30 , 1977 , part 1511 . the test requires that a pacifier will resist passing through an opening having a diameter of 42 . 7 millimeters ( 1 . 68 inches ) when the pacifier 2 of this invention is urged through the opening at a force not exceeding two pounds ( 8 . 9 newtons ) within a period of five seconds and maintained at two pounds for an additional ten seconds . the test also includes &# 34 ; heat cycle deterioration &# 34 ; testing wherein the pacifier 2 is submerged in boiling water for five minutes , removed from the boiling water and cooled to room temperature ( 60 ° to 80 ° f .) for five minutes . after six cycles of the boiling / cooling procedure , the pacifier 2 is again urged through the 42 . 7 millimeter opening with a force attaining two pounds within five seconds and being maintained at two pounds for an additional ten seconds .

a pacifier having a rigid safety shield formed of non - resilient material integrally formed with a nipple and ring of soft conventional rubber - like pacifier material .

in describing embodiments of the present invention , specific terminology is employed for the sake of clarity . however , the invention is not intended to be limited to the specific terminology so selected . it is to be understood that each specific element includes all technical equivalents , which operate in a similar manner to accomplish a similar purpose . the above - described embodiments of the invention may be modified or varied , and elements added or omitted , without departing from the invention , as appreciated by those skilled in the art in light of the above teachings . each reference cited herein is incorporated by reference as if each were individually incorporated by reference . the formulation of the present invention is a palatable , oral formulation of prednisolone acetate . prednisolone acetate has been used in ophthalmic and parenteral medicinal products , but has not previously been used in oral liquid preparations . prednisolone acetate is practically insoluble in water . the low solubility presents a formulary challenge during product development of an aqueous liquid oral preparation . however , the use of the acetate form provides a taste advantage because the active does not dissolve in the aqueous environment of the mouth , and therefore prevents the interaction of the bitter - tasting molecules of the prednisolone with the taste buds . the present invention is an aqueous suspension having a thickening component and a vehicle , or carrier , component and may include other pharmaceutically acceptable excipients . the vehicle is pharmaceutically acceptable , aqueous and suspension - stabilizing . prednisolone acetate is evenly dispersed in the semi - solid aqueous vehicle . the suspension has a homogeneity so that the active ingredient is uniformly dispersed but undissovled in the vehicle . the formulation consists of mutually compatible components at room temperature . the suspension has a crystalline stability in that the prednisolone particles stay within a target particle size range over time . the vehicle component serves as the external phase of the suspensions . the vehicle may be comprised of water , glycerin , propylene glycol and mixtures thereof . the vehicle component may contain glycerin up to about 50 %. the vehicle may also comprise propylene glycol up to about 20 % or from about 3 % to about 10 %. purified water comprises the bulk of the vehicle component comprising from about 29 % to about 64 % of the formulation . purified water makes up the bulk of the vehicle component , comprising from about 29 % to 64 % ( w / w ) of the formulation . water concentration can be less than about 50 % ( w / w ) or even less than about 43 % ( w / w ). thickening agents are pharmaceutically acceptable excipients that add a desired viscosity and flow to a formulation . carbomers are synthetic high molecular weight polymers of acrylic acid . in one embodiment , carbomer 943p ( carbopol 974p ) has been found to be a suitable thickening , or gelling agent , providing good sensory appeal and texture . the rheology of the carbomer provides for a high yield value , low shear thinning quality , in non - thixotropic liquid formulations . the viscosity of the carbomer gel is ph dependent . carbomer gels exhibit maximum viscosity at about ph 7 . 0 . more acidic or basic ph &# 39 ; s will cause the carbomer to lose viscosity . however , prednisolone acetate is most stable at slightly acidic ph &# 39 ; s , and will degrade to undesirable breakdown products at the higher ph . at neutral ph &# 39 ; s , prednisolone acetate will undergo oxidation and hydrolysis and form undesirable and less active degradation products . at a ph of 4 . 6 to 5 . 4 , prednisolone acetate is stable in the formulation and the carbomer may retain its viscosity . the carbomer comprises up to about 1 % ( w / w ) of the inventive formulation . in particular , we have found that the carbomer of the inventive formulation should be between about 0 . 40 % to about 0 . 50 %, more particularly , about 0 . 40 % to about 0 . 48 %. the oral formulation of prednisolone acetate is a spill - resistant formulation . spill resistant oral formulations are more extensively described in , for example , u . s . pat . nos . 6 , 071 , 253 , and 6 , 102 , 254 , herein incorporated by reference . the pharmaceutical suspension comprising of the invention has prednisolone acetate uniformly dispersed in an aqueous vehicle , the active ingredient remaining in suspension without agitation during the product shelf - life . the shelf life may be up to about six , twelve , eighteen , twenty - four months , thirty months , or thirty - six months . the suspension has antimicrobial activity , is pharmaceutically effective and meets applicable regulatory requirements as would be understood by a person of ordinary skill . the viscosity may be about 5 , 000 to about 15 , 000 cps , about 5 , 000 to about 14 , 800 cps , about 9 , 000 to about 11 , 000 cps , or about 9 , 500 to about 10 , 500 cps . in inventive pharmaceutical suspensions there is no crystalline growth during a heat - cool study for three days at a temperature range of about 8 ° c . to about 45 ° c . the active ingredient particles may be crystals that neither dissolve or grow substantially when the sample is heated e . g . to 45 ° c . and cooled to room temperature repeatedly . the formulation is dosed by volume , and specific gravity values were used to estimate the prednisolone acetate concentration in the composition . the 5 mg / ml dose was calculated , based on specific gravity to be 0 . 097 % ( w / w ), which is equivalent to 0 . 087 % ( w / w ) of the prednisolone base form . the 15 mg / ml dose was calculated to be about 0 . 293 % ( w / w ), which is equivalent to 0 . 262 % of prednisolone base form . the particle size of the active pharmaceutical ingredient may have important effects on the bioavailability of a formulation . smaller particle sizes have increased surface area and will dissolve faster than larger particles . however , decreasing the particle size may cause some agglomeration of the particles , and the increased surface area can result in faster degradation of the compound due to oxidation and hydrolysis . in the inventive formulation , a fine particle size was found to achieve the desired bioavailabilty . the prednisolone acetate of the inventive formulation has a median particle size of approximately from about 1 μm to about 30 μm , more preferably about 5 μm to about 20 μm , most preferably from about 6 μm to about 8 μm . the particle size may be achieved using such methods air - jet milling , ball milling , mortar milling or any other method known in the art for decreasing particle size . for example , the prednisolone acetate particles of the disclosed formulation were micronized using a stainless steel , air - jet mill with a grinding chamber diameter of four inches ( sturtevant , hanover , mass ., u . s . a ., model no . sdm - 4 .) the size of the particles may be measured using a light scattering device , sedimentation methods , centrifugal force measurements , or any method known to one skilled in the art . by means of an example , the matersizer 2000 manufactured by malvern instruments , ltd ., malvern u . k ., may be used to measure the particle size . pharmaceutical excipients are pharmaceutically acceptable ingredients that are essential constituents of virtually all pharmaceutical products . excipients serve many purposes in the formulation process . the inventive pharmaceutical suspensions may comprise at least one additional component selected from the group consisting of excipients , surface active agents , dispersing agents , sweetening agents , flavoring agents , coloring agents , preservatives , oily vehicles , solvents , suspending agents , dispersing agents , wetting agents , emulsifying agents , demulcents , buffers , salts , spreading agents , antioxidants , antibiotics , antifungal agents and stabilizing agents . spreading agents may be added to the vehicle component . polyols , such as malitol , mannitol , polyethylene glycol and sorbitol may be added to the vehicle components to adjust the spreadability in the spoon bowl upon pouring . the present embodiment may contain sorbitol , in a concentration of less than 5 %. the suspensions of the present invention may also contain edetate disodium ( edta ). edta is a chelating agent that forms a stable water - soluble complex with alkaline earth and heavy metal ions . it is useful as an antioxidant synergist , sequestering metal ions that might otherwise catalyze autoxidation reactions . edta may also have synergistic effects as an antimicrobial when used in combination with other preservatives ( handbook of pharmaceutical excipients 4 th ed .). the suspension formulations may require a crystal conditioning surfactant , i . e . a wetting agent . the hydrophobic properties of prednisolone acetate may benefit from a wetting agent to disperse the steroid in the formulation . a concentration of from about 0 . 05 % to about 0 . 5 % poloxamer 188 was found to be effective at wetting the prednisolone acetate without excessive foaming and dispersion of the suspension . the present formulation is an improvement over previously described prednisolone suspensions because the ingredient remains suspended indefinitely , without agitation ; that is without stirring or shaking . the dispensed dose is always uniform over the shelf life of the product . the formulation of the invention can not be shaken easily , so the particles remain suspended without shaking . the suspension has antimicrobial activity . propylparaben ( up to about 0 . 04 %) and butylparaben ( 0 . 018 % to about 0 . 18 %) are suitable . other antimicrobial excipients may also be used . these suspensions are alcohol - free . the organoleptic ingredients improve the taste and appearance and do not negatively affect the suspension stability . the organoleptic agents in the following examples include coloring and flavoring agents , sweeteners and masking agents . mutual compatibility of the components means that the components do not separate in preparation and storage for up to the equivalent of two years at room temperature ( as indicated by three month intervals of accelerated stability testing at 40 ° centigrade and at 75 % relative humidity ). storage stability means that the materials do not lose their desirable properties during storage for the same period . preferred compositions do not exhibit a drop in viscosity of more than 50 % or an increase in viscosity of more than 100 % during that period . the following examples further illustrate the invention , but should not be construed as limiting the invention in any manner . the prednisolone acetate oral suspension was formulated to contain the following ingredients : comparison of different prednisolone actives for sensory evaluation : a small sample of volunteers compared the different formulations of prednisolone for taste and flavor . results are given in table 2 . stability testing was performed on 1 . 0 kg portions of a 5 . 0 kg experimental batch of 5 mg / 5 ml prednisolone acetate . naoh was added to the portions to give various ph values ( batch a - e ) and packaged in 4 ounce amber petg bottles . the samples were left at the environmentally stressed conditions of 40 ° centigrade or 50 ° centigrade for one month . hplc methods were used to measure the percent of prednisolone acetate retained in the bottle . the control sample used was a 5 mg / 5 ml prednisolone acetate suspension exposed at room temperature and sampled after 4 months . the data is summarized in table 3 . as demonstrated by the results shown in table 3 , in the ph range of 5 . 0 to 6 . 2 , the micronized prednisolone acetate is more stable at the lower ph values . dissolution tests are a qualitative tool that provides information about the biological availability of a drug formulation . experimentally , suspension formulations are considered to disintegrate equivalently to tablet formulations , therefore dissolution testing is done comparing suspensions to tablets . a standard dissolution test ( usp apparatus 2 ( paddle )) was followed to compare the prednisolone acetate suspension to a commercially available 5 mg tablet of prednisolone . the dissolution curves of the suspensions were very similar to the dissolution curve for the tablet following a 15 minute period . twenty three volunteers ( male and female non - or ex - smokers ) were orally administered a single 5 mg dose of prednisolone in the morning after a ten hour overnight fast . the study design was a randomized , 6 - sequence , 3 - period , crossover design . either 5 ml . of a 5 mg / ml prednisolone acetate suspension , or one 5 mg tablet of a commercially available product , was administered . blood samples were taken at determined intervals . pharmacokinetic parameters used to evaluate and compare the relative bioavailability , and therefore bioequivalence , of the two formulations of prednisolone after a single oral dose administration under fasting conditions were c max , auc t , aug ∞ , k el and t 1 / 2el . c max — maximum concentration . auc t — area under the concentration - time curve using the trapezoidal method to the last measurable concentration ; auc ∞ — area under the concentration - time curve extrapolated to infinity ; k el — elimination rate constant ; t 1 / 2el — terminal half - life . bioequivalence was determined using the 90 % confidence interval for the exponential of the difference between the tablet and the suspension . the test met the 80 . 00 - 125 % confidence interval limits with a statistical power of at least 80 %. in describing embodiments of the present invention , specific terminology is employed for the sake of clarity . however , the invention is not intended to be limited to the specific terminology so selected . it is to be understood that each specific element includes all technical equivalents , which operate in a similar manner to accomplish a similar purpose . the above - described embodiments of the invention may be modified or varied , and elements added or omitted , without departing from the invention , as appreciated by those skilled in the art in light of the above teachings . each reference cited herein is incorporated by reference as if each were individually incorporated by reference .

the present invention relates to novel oral suspension formulation comprising prednisolone acetate , a pharmaceutically acceptable vehicle and a thickening agent . the present invention further provides a method of treating patients in need of prednisolone with the novel formulation .

referring in detail to the drawings , the suction catheter 2 comprises a proximal end 4 , a distal end 6 having a whistle tip 8 and side port 10 , a central portion 12 integrally uniting the proximal end 4 with the distal end 6 and a suction control valve 14 attached to the proximal end 4 . the valve 14 comprises a flexible tubular member 16 having a lumen 18 larger than the lumen 19 of the catheter 2 . the proximal end 4 of the catheter is joined to the distal end 20 of the member 16 by the hub 22 , preferably by cementing the proximal end 4 to the bore 24 of the hub 22 and the distal end 20 of member 16 to the proximal taper 26 of hub 22 . the hub 22 may be provided with a rib 27 to limit the distance the end 26 extends into the end 20 of member 16 . the rigid connector member 28 with a lumen 30 smaller than the lumen 18 of member 16 has its distal end 32 fitted into the proximal end 34 of member 16 leaving the tapered proximal end 36 free for connection with a vacuum hose or other vacuum source ( not shown ). the distal end 32 of connector member 28 has an integral nipple 38 and a rib 39 may be provided to limit the distance the end 32 extends into the end 34 of member 16 . the valve member 40 comprises a proximal tubular portion 42 having a lumen 44 larger than the lumen 30 of connector member 28 , but smaller than the lumen 18 of member 16 , and a closed distal end portion 46 integral with the proximal portion 42 . the free end 48 of valve member 40 is fitted over the nipple 38 and the two are preferably cemented together . the closed distal portion 46 of valve member 30 is of chisel point design having a v - shaped ( inverted ) lateral cross - section 50 ( see fig2 and 5 ) and a u - shaped ( inverted ) anterior cross - section 52 ( see fig7 ). the lateral cross - section 50 has a median slit 54 through it . preferably , the lateral cross - section 50 tapers down in thickness from the apex 56 to the base , i . e ., the distal portion 46 is radiused to thicken in the center . in the embodiments shown in fig5 - 7 , the tip or apex 56 is also radiused . in another embodiment , as shown in fig8 the tip 56a of valve member 40a is straight ( square ). the tubular member 16 has diametrically opposed longitudinal ribs 60 on the outer surface 62 to serve as indicators for the application of pressure as indicated by the arrows in fig3 a . other types of protrusions , e . g ., beads , spots , etc . can be used instead of ribs . the various parts of the new control valves and catheters can be produced from any suitable materials and by a suitable method known to the art . advantageously , the catheter 2 and member 16 are formed of plasticized polyvinyl chloride by extrusion , but other materials , e . g ., polyolefins , rubber , silicone rubber , etc . and other methods , e . g ., dip casting , molding , etc . may be used . advantageously , the catheter 2 and member 16 are made of transparent material to provide see through ability . the hub 22 and connector member 28 should be formed of rigid material , e . g ., nylon , polyethylene , pvc , hard rubber , etc ., advantageously by injection molding , although other materials or methods may be used . the valve member 40 can be made of resilient material , e . g ., silicone rubber , plasticized pvc , natural rubber , etc . and may be formed by contour molding , plastisol casting , blow molding , injection molding , etc . since the control valve 14 completely seals off the catheter 2 when in the closed position ( see fig2 ), it is possible when suctioning , if the ports 8 and 10 were to be occluded by tissue and the valve was closed by the user , that vacuum would remain in the catheter 2 and therefore &# 34 ; hold &# 34 ; the occluding tissue . if the user were to withdraw the catheter while the tip was holding tissue , damage to it could occur . in order to prevent this , a preferred form of the new catheters includes vent means in the distal end to automatically release vacuum in the catheter on the closing of the control valve . a preferred form of such new catheter is shown in fig9 . the catheter 70 has a side - entering port 72 in the distal end portion 74 . in addition to the primary lumen 76 , there is a secondary lumen 78 within the catheter wall 80 . this lumen 78 opens at its distal end 82 into the port 72 and at its proximal end 84 it opens through the outer surface 86 of the catheter wall 80 proximal of the port 72 , e . g ., about 10 cm . from the port 72 . alternatively , the opening 84 for the secondary lumen 78 could be in the vicinity of the catheter proximal end 88 so that it would vent outside the body of the patient . it is preferred , however , to have the opening 84 located so that it will be within the body of the patient when the catheter 70 is fully installed . the opening 84 to secondary lumen 78 would permit venting of the catheter within the trachea or one of the principal bronchi of the patient . the catheter of fig9 is equipped with a control valve 14 as described for the catheter 2 . upon closing of the valve 14 , any vacuum remaining in the catheter 70 will be released by the venting action of the secondary lumen 78 . an alternative form of venting means is shown in fig1 . here , the catheter 90 has tiny holes 92 , e . g ., holes 0 . 1 to 1 mm . diameter , through wall 94 . such holes will be positioned proximal of the catheter distal end similar to the positioning of openings 84 as described above . hence , upon closing of the control valve 14 of the catheter , the lumen 96 of catheter 90 will be vented to ambient atmosphere and any residual vacuum created by occlusion of the distal end openings of the catheter will be released . the control valves of the invention may be marketed as separate items for attachment to suction catheters . however , since the catheters are primarily designed to be disposable after a single use , the catheters and control valves are advantageously made and sold as single units . they may be made by automatic assemble methods in all the sizes and lengths required by the medical profession . the catheters are advantageously packaged in paper or plastic envelopes that permit them to be sterilized after packaging such as by exposure to ethylene oxide gas or gamma rays . if desired , the catheters may have a frosted slip surface ( see u . s . pat . no . 3 , 508 , 554 ). the catheters 2 and 70 of fig1 and 9 have been shown as having a so - called whistle tip . the invention can be applied to suction catheters having any other type of tip found useful in the trade , e . g ., closed end tips with side entering ports , squared - off tips with rounded edges or other acceptable tip structures . the new control valves and catheters can operate effectively with vacuums from about 50 to 500 mm . hg . the catheters will have zero negative pressure with the control valves in the normally closed position . since the control valves have no open ports , they prevent soiling of a user &# 39 ; s hand and also conserve vacuum potential . the pinch technique for operation is easily used and permits one hand manipulation . moreover , the new suction catheters operate without the noise disturbances of the conventional open port control types .

suction catheters are provided with improved suction control valves that have no open ports and that are normally closed providing advantages over the conventional control valves that are normally open . the valve comprises a resilient member having a distal end of chisel point design that is slit at the tip enabling the slit to be pinched open through an enveloping sheath to apply suction to the catheter and return to a closed position upon release of pinch pressure . the catheter may include vents to release vacuum if its distal end openings become occluded .

reference will now be made in detail to the present preferred embodiment of the invention , an example of which is illustrated in the accompanying drawings . while the invention will be described in connection with a preferred embodiment , it will be understood that it is not intended to limit the invention to that embodiment . on the contrary , it is intended to cover all alternatives , modifications , and equivalents as may be included within the spirit and scope of the invention defined in the appended claims . while the following description will seek to improve understanding of the invention by describing the various components and elements , it should be considered that certain apparatus may be sufficiently and adequately explained by the accompanying drawings , which are fully incorporated herein , and not require further description . all such apparatus should be considered as part of the specification of the invention for all purposes . making reference first in fig1 it can be seen that the adhesive blotting apparatus according to the present invention ( 10 ) comprises an adhesive ( 11 ) so that drool or spittle which may be expelled from a person &# 39 ; s mouth during sleep will flow down to the blotting apparatus ( 12 ) so that it may be captured and absorbed by a blotting material . making reference now to fig2 it can be seen that the device , once positioned properly in the vicinity of a person &# 39 ; s mouth ( 20 ), will be able to receive whatever fluids . such as drool or spittle ( 30 ) that may pass from a person &# 39 ; s mouth ( 20 ) during sleeping hours . it is assumed , for the purpose of this invention , that most persons will sleep on their back or side . if a person was sleeping on their stomach with their face down , it is likely and probable that such escaping fluids would be absorbed by the bedding material and this apparatus would not be useful . it can be seen that it be that such will indeed be in a proper position to the fluids and will stay in place such as to be capable of absorbing and maintaining a reasonable amount of such rule fluid unless such amounts to a flow which would be indicative of a more serious medical issue . it should be noted that the adhesive may be selected from the variety of adhesive materials which are adapted to be placed upon a person to capture and then remove a minor amount of drool or spittle with as little discomfort as possible . a few comments should be made about the materials selected for use with the apparatus . there are a variety of adhesives for the skin . these range from the type used for simple band - aids to the type used for more heavy - duty adhesions , such as to hold gauze strips in place . the apparatus could be made with any of these adhesives and would be selected by each person so as to provide the minimal amount of adhesion to keep the apparatus in place overnight while minimizing the discomfort associated with the overnight adhesion to the face as well as the removal in the morning . similarly , the blotting material can be selected from a variety of materials ranging from cloth to synthetic material and should be selected so as to reliably block and contain the amount of fluid associated with each individual person . some people may release considerably more drool and spittle than others and this should be taken into consideration when selecting each version of this apparatus . making reference now to fig3 , it can be seen that the apparatus could be manufactured of a desired shape to fit completely around the mouth and under the nose . this would accommodate a person who released fluid from both the nose and the mouth during the night . of course , such a shape could also be sized so as to fit persons of various sizes and physiques . the variety of sizes and shapes are endless depending upon the needs and size of each individual person . the apparatus could be manufactured in these various sizes and shapes as desired . making reference now to fig4 , it can also be seen that the apparatus could also be made with a covering sheet ( 40 ) so as to in close or completely capture the fluid released by the nose or mouth . this would be an alternate embodiment of the basic invention which is keeping in the spirit and scope of the original invention . finally , making reference to fig5 , it can further be seen that the basic apparatus could be manufactured in a sheet ( 50 ) so that each individual consumer could fashion and apparatus tailored to their individual needs by simply cutting a desired size and shape from the sheet with a scissors . because of the abdomen and start over that area because of the way these of the materials selected and because such materials will be placed upon a person &# 39 ; s skin and used to absorb bodily fluids is not anticipated that such apparatus would ever be reused . accordingly , the these materials together with the simple construction and design make it possible for a person to fly a new one every night and then discard attributes area of those were in such link and expiration of fluids only is a problem because would be well worthwhile . allowing easy recovery and that he needs the material could be adapted with a backing to protect it from being compromised during shipment and storage for sale the apparatus , as described herein , is capable of several modifications , some of which have been already discussed . for instance , the items could be manufactured according to set sizes and a sufficient variety to ensure appropriate fit for each person . on the other hand , the items could be manufactured so as to permit minor modification by the user , for instance having or slight reshaping , to permit mass manufacture of a standard size which could be modified or adjusted for each use by the concerned person or to achieve not only some measure of cost savings but also to improve the comfort and efficiency . the basic apparatus has been described with particular variations with respect to the configuration , size , shape , materials , and thicknesses of materials to be used . each of these variations should be seen as keeping in the spirit and scope of the present invention . it should also be seen that each of variations may be used with other variations or alone . they are not to be seen as exclusive but as inclusive . further modification and variation can be made to the disclosed embodiments without departing from the subject and spirit of the invention as defined in the following claims . all such modifications and variations , as included within the scope of these claims , are meant to be considered part of the invention as described .

the apparatus comprises an absorbent material adjacent to an adhesive material which is further adapted to protect and prevent saliva or other oral fluids from being released to soil bedding material or to cause discomfort during sleep .

before beginning a detailed description of the subject invention , mention of the following is in order . when appropriate , like reference materials and characters are used to designate identical , corresponding , or similar components in differing figure drawings . the figure drawings associated with this disclosure typically are not drawn with dimensional accuracy to scale , i . e ., such drawings have been drafted with a focus on clarity of viewing and understanding rather than dimensional accuracy . a surgical tunnel retractor is provided . referring to fig1 a surgical tunnel retractor 10 according to the present invention is shown comprising an elongated handle 12 having opposing first and second ends , 30 and 32 respectively , and an arched plate member 14 connected to said first end 30 of said handle . as shown in fig1 the surgical tunnel retractor can be further provided with a second arched plate member 16 connected to said second end 32 of said handle . as shown in fig3 and 4 , the first and second arched plate members are preferably of different size to provide more options to the user , but the sizes need not be different . as shown in fig1 said surgical tunnel retractor can be further provided with shank elements , 34 and 36 , disposed between said handle ends and said arched plate members . the handle portion is preferably straight and tapered on both ends . those skilled in the art will know that said handle be configured in numerous equivalent ways . the arched plate member is semi - circular in cross - sectional shape with proximal 14 a and distal 14 b ends in relation to handle , as shown in fig1 , 3 , and 4 . as shown in fig2 towards the distal end 14 b of said arched plate , the lateral edges of said plate taper into the curvature to the height of the arch , rounding off in plow - like tip for inserting in and under the gum tissue of patient . the tip , as seen in fig5 provides for broaching incisions in soft tissue 22 while the arched plate member lifts and retracts the tissue in a convenient tunnel - like shape for passing materials 18 into , along , and under the tissue . the arch plate member can have a varying arc radius preferably in the range of 1 . 5 mm to 4 mm . the arch plate member preferably has a longitudinal length in the range of 4 mm to 20 mm . those skilled in the art will know that said arched plate members be configured in numerous equivalent ways . the dimensions provided are adapted for use of the instrument on human patients . those skilled in the art will know that the disclosed tunnel retractor can equally be used on non - human patients with a simplistic adaption of the foregoing dimensions to scale . the invention is thus not limited to human patients and by the foregoing dimensions . when the surgical retractor is provided without shank elements , the arched plate members extend away from the handle at an obtuse angle to the longitudinal axis of the handle , with the distal ends of said plate members furthest away from the ends of said handle . as shown in fig1 , 3 , 4 and 5 , when a shank element 34 is provided , the shank element connects to arched plate member at the proximal end 14 a on the convex side of the arched plate at the general apex of said arched plate . the shank element connects to the arched plate member preferably to form right angle , 90 degrees , between the longitudinal axes of the arched plate member and the shank element , oppositely extending from the angle to which the shank element connects to the handle . the angle between the longitudinal axes of the shank element and the arched plate member can be any angle in the range of 10 degrees to 150 degrees . the shank element connects to the handle preferably to form an obtuse angle , preferably 135 degrees , between the longitudinal axes of the handle and the longitudinal axes of the shank . the obtuse angle between the longitudinal axes of the shank element and the handle can be any angle in the range of 60 degrees to 170 degrees . the present invention is made of medical grade metal . methods and procedures for making surgical implements of medical grade metal are well known in the art . in operation , after a surgical incision is made into the gum tissue of a patient , cutting into the gingival membrane overlying the jawbone , the distal end of either the first or second arched plate members is inserted into the incision and along and under the gum tissue , with the arched plate member lifting and spreading the gum tissue , and the arched plate member creating a tunnel under the gum tissue and along the alveolar ridge of the jaw bone . this is displayed in fig5 . a portion of the arched plate member may remain outside of the gum tissue leaving an opening into the tunnel created by the insertion of the tunnel retractor portion . material 18 , which can be graft material , is pushed into the created tunnel , the arched plate member acting to guide the flexible graft material along under the gums and along the bone until the tunnel is filled . the graft material is tamped down . the arched plate member is then removed from incision and the tissue is closed over the cavity , and in some cases the tissue is sutured depending upon the size of the incision . the present invention , while particularly well suited for use in the field of dentistry to aid in the provision of support for artificial teeth , is of general medical application for humans and other vertebrates . those skilled in the art will recognize that numerous modifications and changes may be made to the preferred embodiment without departing from the scope of the claimed invention . it will , of course , be understood that modifications of the invention , in its various aspects , will be apparent to those skilled in the art , some being apparent only after study , others being matters of routine mechanical , chemical and electronic design . no single feature , function or property of the preferred embodiment is essential . other embodiments are possible , their specific designs depending upon the particular application . as such , the scope of the invention should not be limited by the particular embodiments herein described but should be defined only by the appended claims and equivalents thereof .

an instrument for broaching and dilating an incision of soft tissue in a tunnel - like shape , the instrument stretches and supports tissue to allow the insertion and passage materials , and comprises a handle , and one or more arched plate members .

not wishing to be bound by theory , it is believed that the amount of formaldehyde formed during a puff is dependent upon the heating rate , the amount of tobacco and char consumed , the temperature of the tobacco prior to the puff , and the amount of condensate on the rod behind the coal . the first puff is distinctly different when considering each of these conditions . the concentration of formaldehyde increases with increasing heating rate . the increase in heating rate of the lighting puff compared to subsequent puffs in which the coal is established results in an increase in concentration . more formaldehyde is produced in the first puff because the tobacco is being heated from room temperature whereas in subsequent puffs the tobacco located directly behind the coal is already at elevated temperatures as a result of the static burn . char that is burnt in these puffs following the lighting puff produces very little formaldehyde compared to uncharred tobacco . because the level of condensate on the cigarette rod in the first puff is significantly less than in subsequent puffs , the effect of rod filtration is diminished resulting in increased levels of formaldehyde . ammonium salts and burley tobacco release ammonia which then reduces the level of formaldehyde by reaction . formaldehyde is reduced through the selective treatment of the front of the cigarette such that the remainder of the cigarette is essentially left unchanged . salts can be applied to this portion of the cigarette rod which if used throughout the cigarette rod would cause the coal to extinguish or have an impact on taste of the cigarette . during a cigarette smoking process , the first puff yields a large amount of formaldehyde , while the later puffs only show small amounts of formaldehyde formation . this phenomenon is explained by selective filtration of formaldehyde gas by tobacco rod and the condensation of tarry products on the tobacco rod , and also by the interaction of formaldehyde with the materials generated behind the coal . during the lighting puff , the formaldehyde formed passes through a fresh tobacco rod where the filtration is only conducted by the tobacco shreds , little char has formed and no condensate exists during the first puff . in consecutive puffs after lighting , where a static burning coal is established , there is a condensation of tarry products built up on the tobacco rod , and the condensation increases as the puff count increases . those tarry condensations selectively absorb formaldehyde gas ( and other gases ), and the formaldehyde interacts with the materials behind the coal , so the gas phase formaldehyde detected drops tremendously after the first puff ( the lighting puff ). differences between the first puff and rest of the puffs during a cigarette smoke process explains the gas phase formaldehyde detected on a per puff base . the heating rate , tobacco thermal treatment , and tobacco / char consumed during a puff were found to play important roles on the mainstream gas phase formaldehyde detected . for example , the heating rates experienced by the tobacco shreds during the lighting puff , where temperature increases from room temperature to around 950 ° c . in a fraction of second , is very different from that of the rest of the puffs , where a coal and a temperature gradient had been established . also , the amounts of fresh tobacco consumed during the first puff and the rest of the puffs are quite different . during the lighting puff , only fresh tobacco is burned , but in consecutive puffs , a mixture of tobacco and charred material is consumed as well . another factor is that during the static burn after the coal is established or after the first puff , the tobacco behind the coal is exposed to elevated temperature . in other words , the tobacco is thermally treated and no longer fresh before the next puff . those factors , combined with the previously proposed selective filtration and interaction theory , provide a more complete picture and explanation on the observed difference in amounts of formaldehyde from the first puff and consecutive puffs . with more understanding of the differences between the first puff and the remainder of the puffs , it is now possible to modify only that portion of cigarette corresponding to the first puff to selectively reduce the compounds that have significantly higher deliveries from the first puff without changing the overall delivery and taste of the cigarette . the taste of the mainstream smoke is dependent on the total particulate matter ( tpm ). while modifications to a cigarette discussed in this invention reduce selected compounds as well as the particulate matter in the first puff , there will be little affect on the tpm of the modified cigarette . one such compound is formaldehyde , of which a large portion occurs in the first puff . another compound is benzo ( a ) pyrene ( bap ), which is present in large amounts in the first puff relative to all subsequent puffs when the cigarette is lit using a yellow flame . gas phase analysis was performed by ftir on per puff base . a bruker ifs 66 / s ftir spectrometer ( bruker optics , billerica , mass .) with a linear gas flow cell ( axiom analytical inc ., irvine , calif .) was used . the linear gas flow cell ( 50 ml volume and 1 . 0 m path length ) was kept at 100 ° c . to minimize the condensation of gases on kbr windows and on the cell surface . the infrared spectra were collected with 64 scans at a resolution of 0 . 5 wavenumber and a mirror velocity of 100 khz . a narrow range liquid nitrogen cooled mercury cadmium telluride ( mct ) detector was used for the spectral range of 3800 - 750 cm − 1 . a fresh small cambridge pad ( 9 mm in diameter ) was used for each puff and placed at the entrance of the gas flow cell to filter out the particulates and to ensure the reproducibility of each experiment . a single - port smoke machine ( kc automation , richmond , va .) was used with a square wave profile , 35 ml volume and 2 seconds duration , and 60 seconds interval between puffs . the gas cell was flushed with nitrogen gas between puffs . 1r4f cigarettes and specially made testing cigarettes with different rod density and porosity were used as the samples . the lighting of the cigarette was performed by using a borgwaldt electric lighter in a consistent manner . the limit of detection and linearity of detector response were evaluated with formaldehyde standard gas . several inorganic salts , including potassium bicarbonate ( khco 3 , em science , ( gibbstown , n . j . ), potassium phosphate ( k 2 hpo 4 , j . t . baker inc ., phillipsburg , n . j . ), sodium chloride and ammonium bicarbonate ( nacl and nh 4 hco 3 , fisher scientific , pittsburgh , pa . ), were used without further purification . several treatments of the tip portion of cigarette were applied to examine their effectiveness in reducing formaldehyde deliveries in the gas phase of mainstream smoke . these include treating the cigarette tip with different salts , using pure burley tobacco in the tip , changing the rod density , ventilation , and applying thermal treatment on the tip of tobacco rod . the formaldehyde deliveries were compared with that of a untreated cigarette , or a standard cigarette . it should be pointed out that these ftir experiments are not designed or intended to precisely measure the deliveries of formaldehyde in the mainstream smoke , rather the ftir system is used as a quick screening method to evaluate the effects of reducing formaldehyde formation by different treatments on the cigarette tip portion . indeed , other techniques such as tdl ( tunable diode laser infrared spectroscopy ) and hplc ( high performance liquid chromatography ) are available for the purpose of accurately measuring the total deliveries of formaldehyde . a description of the tdl method for formaldehyde measurement is given below to support the investigation using the ftir technique . pahs are measured using two gc / ms analytical methods . the first is a single puff , semi - quantitative screening technique that was developed to measure the pah content with good sample throughput . each puff constitutes one sample replicate . the second is a quantitative method for bap requiring the smoking of 20 cigarettes per sample replicate and extensive and time - consuming sample cleanup prior to separation and detection by gc / ms . for the semi - quantitative method the particulate matter from a single puff was collected on a small aluminum foil disc , about 8 mm in diameter , in an impaction trap . the disc was weighed before and after the puff to determine the quantity of particulate matter deposited . the sample deposited and dcollected on the disc then was dissolved in 50 μl of a 5 : 5 : 1 mixture of toluene , hexane , and isopropyl alcohol . the sample / solvent mixture was sonicated at room temperature for 10 minutes and 1 μl of the solution was injected into a gc - ms in a splitless mode . the gc / ms was a hewlett - packard 6890 series gas chromatograph with a db - 17 ms ( 30 meter × 0 . 25 mm id × 0 . 25 μm film thickness ) column and a hp 5973 mass spectrometer detector . the ms detector is operated in the selected ion monitoring ( sim ) mode and electron impact ( ei ) ionization is used to generate the ions . standards are tested to determine the retention time of benzo ( a ) pyrene under identical chromatographic conditions . the capability of verifying mass spectral patterns as well as chromatographic retention times makes the gc / ms technique a very reliable method for pah analysis . for the quantitative method the mainstream smoke from 20 cigarettes was collected onto a pre - weighed 92 mm cambridge filter pad using a 20 - port borgwaldt smoking machine . upon completion of the smoking , the pad is weighed to determine the tpm deposited . the filter is extracted with 40 ml of a 7 : 3 solution of methanol and deionized water for 10 minutes . the solution is twice extracted with 30 ml aliquots of 2 : 1 hexanes : toluene . a 10 ml aliquot of the combined organic extracts is evaporated down to 1 ml at 50 - 60 ° c . the 1 ml concentrate is transferred to a preconditioned nh 2 sorbent and eluted with approximately 15 ml of hexanes . the pah - containing fraction is concentrated down to approximately 1 ml and 1 μl aliquots of this concentrate are injected for analysis into the same gc / ms as described above . benzo ( a ) pyrene is determined by this method . fig1 shows the average amount of formaldehyde in mainstream smoke for different puffs from kentucky reference ir4f cigarettes using the tdl technique . formaldehyde in cigarette smoke is measured on a per puff basis using second derivative tunable diode laser ( tdl ) infrared spectroscopy . an ls - 3 spectrometer ( laser photonics , wilmington , mass .) was modified to include a computer - controlled , heated sampling system for handling whole cigarette smoke using a 3 - way air - actuated valve and impaction trap ( no filter pads ) for continuous flow using a laminar flow element with differential pressure transducer and control valve ( mks , burlington , mass .). the spectrometer was modified further to accept a 50 - cm path length , 0 . 3 l volume reference gas cell and liquid nitrogen - cooled mercury cadmium telluride ( hgcdte ) reference detector containing formaldehyde vapors , and a 13 l volume multipass gas sample cell with the path length set at 16 m and a second liquid nitrogen - cooled hgcdte detector . the formaldehyde measurement is not different from the results obtained when whole smoke ( gas phase and particulate phase ) is sampled directly without using the impaction trap . equivalent results ( within ± 5 %) are obtained for 1r4f cigarette smoke using several different formaldehyde absorption lines in the 2800 cm − 1 region . these data confirm that it is unlikely that there are any significant interferences present from other components found in the smoke sample . the detection limit of the tdl system is 0 . 1 ug / puff ( obtained at 3σ ) using an actual smoke sample , which is a more demanding determination than using a diluted formaldehyde standard . when performing the ms smoke analysis , a formaldehyde standard , having a concentration similar to that of the lighting puff delivery of a 1r4f reference cigarette , is measured just prior to each cigarette analysis . the standard is generated continuously at a maximum flow of 180 ml / min . from nist - traceable paraformaldehyde permeation tubes using the dyna - calibrator model 314 ( vici metronics inc ., santa clara , calif .). the accuracy of the tubes is certified by metronics to be within ± 2 %. the precision of the tdl ms smoke system using these standards is ≦ 1 %. cigarette samples are conditioned at 60 % relative humidity ( rh ) and 75 ° f . for 48 hours and sealed in glass ball ® jars until needed for smoking . the cigarettes are inserted 11 mm into the 3 - way valve . cigarettes are smoked using a square - wave puff profile , with a puff volume of 35 . 0 ± 0 . 1 second duration , once every 60 ± 1 seconds . a 35 - ml bubble flow meter ( r24 . 00 , heinr . borgwaldt gmbh , hamburg , germany ) is used for setting the puff volume . the kentucky reference 1r4f is a filtered cigarette that has been provided by the tobacco and health research institute , university of kentucky over the years for research purposes . the 1r4f specifications are : 83 . 5 mm length , 25 mm circumference , 35 mm butt length , 10 . 6 mg / cigt total particulate mater ( tpm ), 28 % filter ventilation , 27 . 2 mm filter length , filter rtd ( resistance to draw ) of 117 mm of water , and total cigarette rtd of 134 mm of water . the 1r4f is smoked to a 35 mm butt length . the puff - by - puff formaldehyde deliveries for ten determinations of 1r4f , using the heated sampling system with an impaction trap , are given in table 1 . the average formaldehyde cigarette delivery based on ten determinations of one cigarette each is 27 ± 5 μg / cigt ., having a relative standard deviation ( rsd ) of 17 %. the first puff ( 12 ± 2 μg ) accounts for 44 % of the total delivery . the averages with standard deviations for each puff are shown in fig1 . the formaldehyde formation from cellulose pyrolysis and the effects of inorganic salts on cellulose pyrolysis have been studied . tar was found to be the major precursor of formaldehyde formation in cellulose pyrolysis , and additions of some inorganic salts were found to affect the relative yields of char and tar , and therefore the formation of formaldehyde . cellulose is a major component in a cigarette , accounting for about 20 % of the dry weight of the tobacco and for over 70 % of the weight of the wrapping paper . factors affecting formaldehyde formation in cellulose pyrolysis also may have similar effects on formaldehyde deliveries in cigarette smoke . fig2 shows a comparison of the formaldehyde detected in the first puff of ir4f cigarettes , with and without salt treatments . three to five cigarettes were tested for each group , and both the infrared absorbance ( which is directly related to the concentration of formaldehyde ) and the standard deviation were shown in the figure . four different inorganic salts were tested here . instead of using the traditional aqueous solution method , such as spraying a salt solution onto the tobacco shreds and then removing the solvent and leaving the salt on the tobacco , a small amount of solid salt powder was simply added to the tip of the cigarettes . this approach of directly adding a small amount of solid salt on the tip of a tobacco rod simplifies the procedure and introduces minimum perturbation on the cigarette . the cigarette then was lighted and the gas phase ftir spectrum recorded in a consistent manner . among the four salts applied , including ammonium bicarbonate ( nh 4 hco 3 ), sodium chloride ( nacl ), potassium bicarbonate ( khco 3 ), and potassium phosphate ( k 2 hpo 4 ), the nh 4 hco 3 salt was the most effective in reducing formaldehyde formation in the first puff , yielding more than 90 % reduction compared with that of an untreated ir4f cigarette . addition of nacl , khco 3 , and k 2 hpo 4 on the cigarette tips also helped to reduce formaldehyde formation , but to a lesser extent . even though the statistical uncertainties due to the variations among the treated cigarette samples and the difficulties in lighting the cigarettes consistently are observed , the effectiveness of these three salts on reduction of formaldehyde formation is consistent with their known catalysis properties as flame retardants in cellulose pyrolysis and combustion studies . the much higher reduction of formaldehyde by nh 4 hco 3 salt is due to the additive effect of this salt as a condensed phase flame retardant , like the other three salts , as well as the gas phase reaction of nh 3 , which is produced by nh 4 hco 3 on heating , with formaldehyde at elevated temperatures . preferably , the treated zone or bands as described above are approximately 3 to 7 mm , if the treatment is to be limited to the first puff . the band would be wider if treatment were to include the second puff location along the rod , or more . a typical american - type blended cigarette contains four types of tobacco , referred to are virginia ( bright ), burley , maryland , and oriental . detailed comparisons of the major chemical characteristics of the four tobacco types have been published . burley tobacco is characterized as having low sugars and has relatively high nitrogen content producing more nh 3 in smoke . to further investigate the role of nh 3 in reduction of formaldehyde in mainstream smoke , pure burley tobacco shreds were used to replace the tip portion of ir4f cigarettes ( about the first 5 mm from the tip of cigarette rod ), and compared the formaldehyde deliveries with that of a control 1r4f cigarette . similar treatments with pure bright tobacco and expanded tobacco were performed and the data , together with that of burley and control 1r4f , are displayed in fig3 . the tobacco was cut into sizes similar to that of a regular ir4f cigarette shreds . to minimize the variance resulting from repacking the cigarette tips , the tobacco shreds of ir4f were removed and repacked into the tip portion of the cigarettes . the data for 1r4f cigarette shown in fig3 was from such repacked cigarettes . as shown in fig3 , applying burley tobacco in the tip reduced the formaldehyde delivery , a reduction of more than 80 % in the first puff compared with the control ir4f cigarette . this reduction of formaldehyde is attributed to two possible factors : 1 ) gas phase reaction of nh 3 with formaldehyde or its precursor ( s ), and 2 ) low sugar content in burley tobacco , since sugar is known to produce formaldehyde in smoke . it is possible that some type of maillard reaction products are formed , which also would account for the aroma flavor detected in cellulose pyrolysis with nh 3 doped carrier gas . it is interesting to note that replacement of bright tobacco in the tip portion of a ir4f cigarette caused a large increase of first puff formaldehyde delivery . again , this may be caused by the high sugar and low nitrogen content in bright tobacco . tobacco expanded with co 2 did not yield significant change on the first puff formaldehyde delivery . the unique differences between the first puff and all other puffs of a cigarette explains the gas phase formaldehyde detected on a per puff base . the first puff ( lighting puff ) is significantly different from the rest of the puffs . one such difference is that only fresh tobacco is burned at the lighting puff , while during the static burn after the coal is established or after the first puff , the tobacco behind the coal is exposed to elevated temperature . in other words , the tobacco is thermally treated and no longer fresh before the next puff . the existence of the coal provides a high temperature source that pre - treats the tobacco shreds . when the next puff is started , the tobacco consumed is not fresh . fig4 shows the first puff mainstream gas phase formaldehyde detected when the tobacco rod was fresh , tip portions treated at 200 ° c . for 30 minutes , 200 ° c . for 18 hours , and 250 ° c . for 30 minutes . the infrared absorption of each sample was normalized with that of the fresh tobacco in this figure for easier comparison . the same lighting method was used for all samples . it is clear from the fig4 that with some simple thermal treatment of the tobacco rod tip , the final amount of formaldehyde detected in the gas phase of the mainstream smoke of the first puff can be greatly affected greater than a 90 % reduction . apparently , the thermal exposure of the cigarette rods somehow changed the tobacco composition ( probably to have some char formed , as indicated by the darker color after thermal treatment ) and consequently the smoke chemistry when the cigarettes were smoked . a similar thermal treatment effect on formaldehyde formation was observed in the study of cellulose pyrolysis , where thermally treated cellulose was found to produce up to 90 % less formaldehyde . cigarettes treated at 150 ° c . for 20 hours do not show any significant reduction of formaldehyde . fig5 shows the first puff formaldehyde deliveries from specially made cigarettes with different rod densities . the ventilation levels of the filter and the wrapping paper were kept constant . it is clearly seen that as the tobacco rod density increased by 0 . 244 g / ml to 0 . 325 g / ml , the formaldehyde delivery decreased by approximately 50 % on the first puff . fig6 shows the effect of changing the wrapping paper porosity on the formaldehyde delivery . at a constant tobacco rod density , the formaldehyde delivery decreased by approximately 50 % on the first puff as the wrapping paper porosity increased by 33 to 200 coresta units ( cu ). rod density and paper porosity are important factors affecting the flow dynamics , resistance to draw ( rtd ), and the coal temperature . as the rod density and paper porosity increase , the air drawn into the coal ( or the tip portion of tobacco rod in the case of first putt ) decreases . the reduction of air flow reduces both the coal temperature , which could greatly affect the smoke chemistry and the product of tobacco detected in the gas phase . formaldehyde is a relatively high temperature combustion product of tobacco , and its delivery would be reduced at lower coal temperature as in the case of high rod density and paper porosity . to further demonstrate the effect of ventilation on the formaldehyde delivery , an increase of the ventilation level of the tobacco rod was made by applying a string of holes ( about 0 . 5 mm m diameter , 20 holes ) at different distances from the tip of the tobacco rod . fig7 shows the first puff formaldehyde deliveries with addition of the holes at different positions from the tip of tobacco rod of ir4f cigarettes . clearly , additional ventilation holes reduced the formaldehyde formation , and as the holes are moved further away from the tip , greater reductions of formaldehyde from the first puff were observed . this is straight forward because since as the holes move away from the tip , more dilution through the holes and consequently , more reduction of air flow through the tip portion would be expected . again , the reduction of air flow through the tip portion of tobacco rod could reduce the coal temperature and the amount of tobacco materials burnt , both of which reduce formaldehyde delivery in mainstream smoke . when an im16 ( an industrial monitor , blended , non - ventilated cigarette ) is lit with a match or butane lighter , the pahs of naphthalene , phenanthrene , pyrene , and benzo ( a ) pyrene increase compared to an electric lighter as shown in fig8 for the first puff . these data are obtained using the single puff , semi - quantitative gc / ms method described previously . bap is increased two - fold on a cigarette or tpm ( total particulate matter ) basis by lighting with a match or butane lighter as shown in table ii . the data presented in table ii are obtained using the multiple cigarette , quantitative gc / ms method previously described . it is believed that this increase in pahs is a result of the effect of the lighter on the first puff , as shown in fig9 for bap , and is reduced by eliminating direct contact of the tip of the cigarette with the yellow flame by modification of cigarette . the results in table iii using the single puff , semi - quantitative gc / ms method show that pahs , including bap , are reduced in the lighting puff of im16 cigarettes modified 1 ) with ventilation holes placed 3 mm from the cigarette tip , and 2 ) with a carbon - based disc placed at the tip . the experiments are performed using a butane lighter and the percent reductions are calculated based on results obtained using unmodified im16 cigarettes as the control . such modifications of the cigarette reduce the levels of pahs in the first puff using a yellow flame lighting source . the carbon - based materials may have absorption properties that contribute to the reduction of pahs , as well as acting to alter the natural flow patterns during the lighting process . modifications to the cigarette to reduce pahs include replacing the tobacco in the tip with an alternate fuel source that produces no or very little pahs , blocking the end with a thin (˜ 1 mm ) circularly shaped carbon - based and / or metallic disc placed on the tip , placing ventilation holes at the tip , or placing a catalyst in the filler at the tip end . the approaches taken to modify a cigarette are shown in fig1 a through 10f where in fig1 a , the tobacco at the tip 10 of the cigarette is either replaced or modified as described previously , in fig1 b , the outer wrap 12 has been modified chemically , in fig1 c , a section of reconstituted tobacco 14 treated with added ammonium salts is attached to the tip of the cigarette , in fig1 d , ventilation holes 16 are placed near the tip , in fig1 e , resistance to draw ( rtd ) is increased by blocking the end with either reconstituted tobacco or metal foil 18 , and in fig1 f , the cigarette is modified by placing an attenuator 20 at a predetermined location along its length where the target ( predetermined ) smoke constituent is maximum . referring to fig1 a benzo ( a ) pyrene ( bap ) and formaldehyde may be partially abated by placing a small carbon - based and / or metallic patch 22 at the tip of cigarette 24 . the patch 22 is smaller than the cross - sectional area of the cigarette . upon lighting the cigarette , it is believed the patch 22 conducts heat away from the coal and restricts airflow thereby partially abating production of bap and formaldehyde . other constructions having similar abatement results are shown in fig1 b through 11f . fig1 b shows a carbon - based and / or metallic disc 26 with flavorants and / or ammonium salts 28 associated with the disk fitted within a recess 30 at the tip of cigarette 24 . fig1 c shows a patch of reconstituted tobacco mat 32 , preferably of a type having an elevated level of ammonium salts . also , the paper at the tip end of the cigarette 10 in fig1 c may include or be coated with magnesium ammonium phosphate and a row of circumferential perforations 36 may be provided in the paper at the tip end . in another embodiment shown in fig1 d a tape of tacky reconstituted tobacco or an aluminum clip 38 may be attached to the cigarette tip for the abatement of bap and formaldehyde . fig1 e shows the tip end of cigarette 24 with a coating of magnesium ammonium phosphate 34 and a carbon - based and / or metallic patch 27 at the end . lastly , fig1 f shows the tip end of cigarette 24 with a row of perforations 36 and a tobacco patch 32 at the end . percent reduction of pahs for im16 cigarettes modified with ventilation holes at the

smoke constituent reduction is achieved by resolving from puff - to - puff analysis at which location along a tobacco rod production of a particular smoke constituent is maximized , and locally applying an attenuator at said resolved location to reduce production of the constituent . a remainder of the rod is left untreated so as to minimize impact on taste and burn characteristics of the cigarette . reduction of the first puff formaldehyde formation is achieved by treating the cigarette tip with salts , using burley tobacco in the tip , increasing the rod density , ventilation at the tip , and thermal treatment of the tip . other classes of smoke constituents such as tsnas , pahs , etc ., in particular the pahs of naphthalene , phenanthrene , pyrene , flouranthene and benzopyrene may be reduced with placement of a carbon - based and / or metallic disc at the tip and with practices of the invention herein .

a fast cook pasta machine in accordance with this invention that includes the following : a raw food ingress staging aperture 62 that is positioned above the inlet of a cook chamber 14 separated by a proprietary design upper slide plate valve assembly 33 a . the raw food ingress staging aperture 62 is used to temporarily contain a portion of an uncooked food - stuff such as dry pasta prior to cooking and aligns and directs the food stuff for entry through the upper slide plate valve assembly 33 a and into the cook chamber 14 . when the upper slide plate valve assembly 33 a opens , the food stuff contained within the raw food ingress staging aperture 62 is dispensed and directed into the cook chamber 14 . the upper slide plate valve assembly 33 a is rigidly mounted to the top - side surface of the cooking assembly top plate 13 a , and the lower slide plate valve assembly 33 b is rigidly mounted to the bottom - side surface of the cooking assembly bottom plate 13 b . both valve assemblies are aligned directly with the center bore of the cook chamber 14 . the upper slide plate valve assembly 33 a is actuated by the upper slide plate valve assembly drive mechanism 35 a , and the lower slide plate valve assembly 33 b is actuated by the lower slide plate valve assembly drive mechanism 35 b . both are electrically driven and independently processor controlled by a common process control circuit . an electrically powered pressure pump 5 delivers supply water 1 to the boiler 12 until the boiler 12 is filled and the design pressure is reached . boiler 12 is pressurized between five and ten atmospheres ( 75 to 150 psi ) in order to superheat water . final pressure is factory - adjustable and the set is dependent upon the design boiler 12 output temperature . boiler 12 pressures are monitored and controlled by a low temperature pressure switch 31 . a safety feature to prevent excessive boiler 12 pressure includes the incorporation of a pressure relief valve 32 into the design , which opens in any extreme over - pressure situation . any flow from the pressure relief valve 32 is diverted to a drain line by the pressure relief conduit 116 , which is then tied into external drainage . the pressure pump 5 is connected to supply water 1 by the water supply conduit 100 and connects to the inlet of the boiler 12 by the boiler feed conduit 102 . the pressure pump 5 is powered by a power relay that energizes the pump and is controlled by the process control circuit . the low temperature pressure switch 31 is mounted on the boiler feed conduit 102 and electrically connected to the pressure pump 5 control circuit to energize the pressure pump 5 when pressure within the boiler 12 has dropped below a factory preset pressure . when boiler 12 pressure drops below the minimum predetermined set - point , the regulating low temperature pressure switch 31 closes the electrical control circuit , energizing the pump relay and in turn the pressure pump 5 to increase the pressure within the boiler 12 to a predetermined maximum set - point . electric heating elements provide heat inside and outside of the boiler 12 raising the water temperature within the boiler 12 to the design temperature . a temperature sensor within the heating element 16 inside the boiler 12 detects the temperature within the boiler 12 and can open and close the electrical power to the heating element 16 maintaining the pre - selected temperature of the water within the boiler 12 . a rigidly encapsulated , variable volume expansion tank 27 is mounted and securely installed to enable the boiler 12 water access to a volume of space that can expand to accommodate liquid volume changes as the boiler 12 water thermally expands and contracts . the expansion tank 27 also acts as a water reservoir and guarantees a consistent supply of pressurized water to the boiler 12 and in turn to the high pressure temperature water pump , when the cook chamber 14 is being charged and pressurized with superheated water . the water expansion tank 27 is connected to the cold water side of the boiler 12 by an expansion tank conduit 26 that is unencumbered by valves or restrictions . the cooking chamber is mounted in close proximity to , but independent of the boiler 12 , and connected thereto by the boiler to high pressure temperature pump conduit 108 through which pressurized superheated water flows from the boiler 12 to the cook chamber 14 . the boiler 12 and cook chamber 14 are not sized identically , with the boiler 12 being larger than the cook chamber 14 . water flow to the cook chamber 14 is enabled or disabled by an electrically powered cook chamber inlet solenoid valve 47 and the cook chamber 14 operating pressure is increased to predetermined operating pressures and regulated by energizing the high pressure temperature pump 38 . the cook chamber inlet solenoid valve 47 is mounted onto the cook chamber inlet conduit 110 that connects the cook chamber 14 to the high pressure temperature pump 38 discharge . the cook chamber 14 is mounted to , sealed to , and penetrates the cooking assembly top plate 13 a and the cooking assembly bottom plate 13 b . uncooked food enters the cook chamber 14 from the raw food ingress staging aperture 62 through the upper slide plate valve assembly 33 a mounted onto the exterior surface of the cooking assembly top plate 13 a . after a predetermined , user - programmable time period , cooked food exits the cook chamber 14 when the lower slide plate valve assembly 33 b , mounted to the exterior surface of the cooking assembly bottom plate 13 b opens . in order to insure that design temperatures are maintained within the cook chamber 14 at the predetermined operating range throughout the entire cooking cycle and to increase boiler 12 heating efficiency , the cook chamber 14 and the boiler 12 are sealed within the cooking assembly 10 . the cooking assembly 10 includes the cooking assembly enclosure 13 c , which is mechanically attached to and sealed to the cooking assembly top plate 13 a and the cooking assembly bottom plate 13 b . the enclosure assembly is rendered liquid tight . the top and bottom plates also act as the end plates to the boiler 12 and cook chamber 14 to which the boiler 12 and cook chamber 14 are mechanically fastened to and sealed to . the cooking assembly 10 contains the heat transfer fluid 18 . the heat transfer fluid 18 is heated by one or multiple heating element 16 to a predetermined temperature and surrounds the outer vertical walls of the boiler 12 and cook chamber 14 . the use of heat transfer fluid 18 reduces the time necessary to heat water contained within the boiler 12 , and provides the heat necessary to maintain the cook chamber 14 and the superheated water within the cook chamber 14 at design temperature . this eliminates the need for a powered heat source within the cook chamber 14 . each heating element 16 contains a temperature sensor that detects the surface temperature of the element and regulates the heating element 16 output are interconnected for maintaining the pre - selected temperature of the water within the boiler 12 . some heating elements are electrically interconnected and one sensor may regulate multiple heating elements . the heat transfer fluid 18 provides all supplemental heat to the cook chamber 14 and improves energy efficiency by providing an increased heat transfer surface contact area . the fluid also functions as a heat reservoir , thereby reducing process temperature swings . an air space maintained in the cooking assembly 10 allows for heat transfer fluid 18 thermal expansion . the cooking assembly top plate 13 a and cooking assembly bottom plate 13 b are ported for fluid transfers from within to without and machined for the attachment of process components such as heating elements , temperature probes , fluid conduits , and fasteners . fluids that will traverse the porting in the plates include water , hot water , superheated water , air , water vapor , and steam . the entire cooking assembly 10 is isolated and wrapped in insulation 20 to reduce radiant , conductive and convective heat losses . insulators are installed where practical to separate the enclosure from applicable mounting apparatus and further reduce conductive heat losses . upon start - up , the heating elements located within the heat transfer fluid 18 are energized and supply water 1 enters the boiler 12 . when the heat transfer fluid 18 temperature has reached its predetermined set - point , the supply water 1 pressure pump 5 is energized to boost boiler 12 pressures to a minimum preset pressure . once the boiler 12 is pressurized , the boiler 12 heating element 16 is energized . only when boiler 12 minimum pressure and temperature set - points are reached will the machine control circuit be energized , enabling the automatic sequential operation of the process controlled machine . once the machine control circuit is activated , the lower slide plate valve assembly 33 b is actuated by the lower slide plate valve assembly drive mechanism 35 b . the lower slide plate valve assembly 33 b is rigidly attached to the underside of the cooking assembly bottom plate 13 b through which cooked food can exit from the cook chamber 14 . during start - up the lower slide plate valve assembly 33 b is returned to its closed position , sealing the bottom to the cook chamber 14 prior to the upper slide plate valve assembly 33 a being opened and enabling entry of the uncooked food into the cook chamber 14 from the raw food ingress staging aperture 62 and its retention within the cook chamber 14 . after the pre - measured portion of uncooked food enters the cook chamber 14 , the upper slide plate valve assembly 33 a is mechanically engaged and closed , sealing the cook chamber 14 . with both valves in their closed position , the cook chamber inlet solenoid valve 47 is opened and the cook chamber 14 is charged with superheated water under pressure from the boiler 12 . to boost cook chamber 14 pressure to the designated cooking pressure , a high pressure , high temperature rated electrically powered positive displacement pump is actuated . the high pressure temperature pump 38 boosts the superheated water pressure in the cook chamber 14 to a process pressure ranging from 23 to 34 atmospheres ( 340 to 500 psi ), depending on the wall thickness , density , and fragility of the food - stuff to be cooked . cook time for dry - goods such as pasta can range from less than a minute to about 4 - minutes based on temperature and pressure set - points . temperature and pressure are monitored and controlled . a temperature probe 19 to detect fluid temperature is immersed into both the heat transfer fluid 18 and the boiler 12 . a first pressure transducer 70 and a second pressure transducer 72 are fluidly interconnected to the cook chamber 14 to sense and control cooking pressure . the pressure transducers are mounted to rinse conduit 1 104 and rinse conduit 2 106 . rinse conduit 1 104 and rinse conduit 2 106 connects the pressure pump 5 discharge to the cook chamber 14 bottom plate . heating elements inserted in the heat transfer fluid 18 contain surface temperature regulating controls and maintain the heating element 16 at a near - constant temperature . the heat transfer element provides precise heating of the heat transfer fluid 18 , the cook chamber 14 , the boiler 12 , and supplements any make up heat necessary to replace heat lost through the peripheral enclosure of the cooking assembly 10 and mounting apparatus . the immersed temperature probes are connected electronically to a process control circuit , which in turns using solid state relays , modulates the power from a power source to the heating element 16 . heating elements within the boiler 12 and within the cooking assembly 10 heat transfer fluid 18 are energized to raise and maintain fluid temperatures to predetermined set - points . the heating element 16 contains built - in temperature regulation that limits the high temperature of each element so as not to allow a heating element 16 to overheat the surface of each element beyond a pre - set temperature . this prevents charring of the heat transfer fluid 18 , extending the fluids and heating element &# 39 ; s useful life . pressure transducers are electronically connected to the high pressure temperature pump 38 process control circuit . the process control circuit energizes the pump relay and the high pressure temperature pump 38 operates and builds pressure to a predetermined set - point . when pressure within the cook chamber 14 drops , the second pressure transducer 72 senses that pressure within the cook chamber 14 has fallen below the minimum pressure set - point . the process control circuit interprets the analogue signal from the pressure transducer energizes the high pressure temperature pump 38 electrical circuit which activates the high pressure temperature pump 38 to build pressure . when the high pressure temperature pump 38 is activated to boost cook chamber 14 pressure , the boiler 12 heating element 16 is de - energized and the pressure control circuit of the boiler 12 pressure pump 5 is energized . the pressure pump 5 operates until the boiler 12 pressure reaches the pre - set maximum pressure and the low temperature pressure switch 31 is triggered . this is to maintain a minimum operating pressure within the boiler 12 . once boiler 12 pressures have reached a pre - set value , the boiler 12 heating element 16 is re - energized and the pressure pump 5 is disabled . when pressure within the cook chamber 14 has reached a pre - set pressure , the first pressure transducer 70 signals the process control circuit to de - energize the high pressure temperature pump 38 control circuit , de - activating the pump control power relay that supplies power to the high pressure temperature pump 38 . once food product within the cook chamber 14 has been sufficiently subjected to the superheated water for the operator selected time period , the process control circuit de - energizes the cook chamber inlet solenoid valve 47 , enabling it to close . the cook chamber inlet solenoid valve 47 is located on the cook chamber inlet conduit 110 on the discharge side of the high pressure temperature pump 38 . to depressurize the cook chamber 14 , both the first venting solenoid valve 56 , and the second venting solenoid valve 58 , which are mechanically and fluidly connected to the inlet side of the cook chamber 14 open . the superheated water within the cook chamber 14 depressurizes and flashes to steam as it exits the cook chamber 14 . the escaping steam is vented into the drain pan 64 , where the steam mixes with cooler air , residual rinse water and condenses . vented steam is ported from the cook chamber 14 , through the two venting solenoid valves and to the drain pan 64 through 2 venting conduits . venting conduit 1 112 and venting conduit 2 114 fluidly connect the cook chamber 14 to the drain pan 64 . the vented steam condensate subsequently exits the drain pan 64 through the drain conduit 86 . after a predetermined period of time , the cook chamber 14 venting solenoid valves are closed and the cook chamber 14 , rinse solenoid valve 8 is actuated . the cook chamber 14 is then charged with unheated water to cool the cooked food and halt secondary cooking , to rinse the cooked food - stuff to remove starch , and aid product discharge from the cook chamber 14 . rinse water pressure in the cooking chamber is limited to 3 atmospheres during rinsing and then reduced to about 0 . 5 atmospheres prior to product discharge . the slightly pressurized water in the cooking chamber together with the cooked food - stuff exits the cook chamber 14 into the drain pan 64 area through the opened lower slide plate valve and is collected into a strainer 63 , separating the remaining water from the cooked product . design criteria are based on nema and gmp standards as warranted , and constructed of materials that resist corrosion , thermal degradation and are capable of performing reliably at design conditions and the working environment . food contact surfaces are made from materials considered food safe and designed for easy clean up and for maintaining sanitary operation . heating elements are selected and sized to heat and maintain the process temperatures to design criteria , without impeding pre - set time parameters programmable into the process controller . the heating elements located within the cooking assembly 10 and the boiler 12 are in intimate contact with the fluids and are selected for material compatibility and reliability . heating elements also contain internal temperature limiters that prevent the surface temperature of the heating elements from exceeding pre - programmed set - points . the entire cooking assembly 10 is insulated with a high efficiency , non - thermally conductive material to reduce heat loss and operating cost . process safety devices include fail - safe redundancy such as a high temperature pressure switch 30 , pressure relief valves on the pumps and the expansion tank 27 , a second venting solenoid valve 58 on the cook chamber 14 , and failure mode process temperature sensors that interrupt control power , shutting down the machine should a heating element 16 solid state relay fail . upon emergency shutdown all valves fail closed . start - up programming provides for a safe sequence with immediate sequence interruption should operator safety interlocks be disengaged . operator safety interlocks include a strainer interlock 80 and a strainer sensor 82 which verify the proper installation of the strainer 63 in order seal off the drain pan 64 and prevent exposing the operator to hot fluids and surfaces , as well as the lower slide plate valve assembly 33 b moving parts . a second operator safety interlock is the raw food ingress staging aperture sensor 84 which isolates the operator from the upper slide plate valve assembly 33 a . all pumps , venting solenoid valves , mechanically actuated slide plate valves , motors , and control elements are electrically driven . all elements of the operation including sequence of operation , time - delays , counting functions , and other programmable operations that are engaged and controlled by the process control circuit . limited end - user / operator interaction is available through a keypad / touch screen interface . program operation and control are internal to the machine using the process control circuit . using control elements and sensors , the factory programmed process control circuit provides automatic timed , temperature , pressure and sequence control of the various operations and components of the fast - cook machine . the machine is energized by external standard line voltage . the machine is electrically energized by manually activating a switch or can be activated remotely with optional hardware . once the process control circuit is energized , a virtual on / off switch is displayed on the touch screen , from which the machine can be started and begin the heating of the heat transfer fluid 18 within the cooking assembly 10 . the process control circuit can be electronically slaved to another device such as vending equipment or a cash register . this screen also enables the user to selectively clean , sterilize and shutdown the equipment . since other modifications and changes varied to fit particular operating requirements and environments will be apparent to those skilled in the art , the invention is not considered limited to the example chosen for purposes of disclosure , and covers all changes and modifications which do not constitute departures from the true spirit and scope of this invention . having thus described the invention , what is desired to be protected by letters patent is presented in the subsequently appended claims .

a machine to fast cook raw food - stuff including dry - goods such as pasta on demand . cook time is user selectable and varies from less than one minute to 4 minutes . higher cook times are user programmable and food type dependent . the separate boiler and cook chamber are sealed within an enclosure containing a heat transfer fluid . porting enables the ingress , egress and transfer of raw and cooked food - stuff , liquid and vapor . proprietary slide plate valves control food - stuff ingress and egress to the cook chamber . the upper slide plate valve assembly separates the cook chamber from the raw food ingress staging aperture . rinse water and cooked food - stuff discharges into the drain pan containing and enclosing the food collection strainer through the lower slide plate valve assembly . discharge of the cooked food product completes the cook cycle . the cooked food can then be deposited from the strainer onto a serving vessel .

the composite includes two regions that exhibit different rates of dissolution with respect to each other . the regions of the composite are macroscopic and can exist in a variety of forms in the composite such as , e . g ., layers and geometrical shapes , e . g ., spheres . the regions can be continuous or discontinuous , and one or more regions can exist within another region or regions . the regions consist of compositions that include calcium sulfate and , optionally , an additive . examples of sources of calcium sulfate suitable for use in preparing the compositions include alpha - calcium sulfate hemihydrate powder , beta - calcium sulfate hemihydrate powder , calcium sulfate dihydrate powder made from calcium sulfate hemihydrate powders including alpha - calcium sulfate hemihydrate and beta - calcium sulfate hemihydrate , and combinations thereof . a preferred alpha - calcium sulfate hemihydrate powder has a purity greater than 98 wt . % calcium sulfate hemihydrate , a bet surface area of from about 0 . 2 m 2 / g to about 1 . 0 m 2 / g ( preferably from about 0 . 35 m 2 / g to about 0 . 9 m 2 / g , more preferably from about 0 . 35 m 2 / g to about 0 . 7 m 2 / g ), a density of about 2 . 6 g / cm 3 to about 2 . 9 g / cm 3 ( more preferably from about 2 . 73 g / cm 3 to about 2 . 80 g / cm 3 ), and a mean particle size of from about 12 μm to about 23 . 5 μm . preferably from about 0 . 1 % to about 2 . 0 % of the alpha - calcium sulfate hemihydrate has a particle size of less than about 2 . 0 μm . preferably at least 80 % of the alpha - calcium sulfate hemihydrate has a particle size of from about 12 μm to about 22 μm , more preferably from about 16 μm to about 22 μm . a preferred beta - calcium sulfate hemihydrate powder has a purity greater than 98 wt . % calcium sulfate hemihydrate , a bet surface area of from about 4 . 5 m 2 / g to about 7 . 5 m 2 / g ( more preferably from about 5 m 2 / g to about 6 m 2 / g ), a density of from about 2 . 5 g / cm 3 to about 2 . 6 g / cm 3 , and a mean particle size of from about 10 μm to about 15 μm ( more preferably from about 13 μm to about 14 μm ). the calcium sulfate composition of each region , the combination of regions , and the composite can be selected to achieve a desired rate of elution of one or more additives present in the composite , a desired rate of dissolution of the pellet including its regions , and combinations thereof . the composite can include regions of calcium sulfate prepared from a single form of calcium sulfate ( e . g ., alpha - calcium sulfate hemihydrate or beta - calcium sulfate hemihydrate powder ), or multiple forms of calcium sulfate ( e . g ., a combination of one or more of alpha - calcium sulfate hemihydrate , beta - calcium sulfate hemihydrate , and the dihydrate prepared from alpha - calcium sulfate hemihydrate and beta - calcium sulfate hemihydrate ). one example of a useful composite includes an interior region of calcium sulfate dihydrate prepared from beta - calcium sulfate hemihydrate , and an exterior region surrounding the interior region where the exterior region includes calcium sulfate dihydrate prepared from alpha - calcium sulfate hemihydrate . another example of a useful composite includes an interior region that includes calcium sulfate dihydrate prepared from alpha - calcium sulfate hemihydrate , and an exterior region surrounding the interior region where the exterior region includes calcium sulfate dihydrate made from beta - calcium sulfate hemihydrate . other examples of composites include one or more calcium sulfate dihydrate regions prepared from a combination of alpha and beta - calcium sulfate hemihydrate . one example of a useful calcium sulfate composition that includes a mixture of beta - calcium sulfate hemihydrate powder and alpha - calcium sulfate hemihydrate powder , includes a weight ratio of beta - calcium sulfate hemihydrate powder to alpha - calcium sulfate hemihydrate powder of between 0 and about 3 . narrower ranges of this ratio , e . g ., 0 to about 0 . 11 , 0 to about 0 . 05 , and 0 to about 0 . 02 , are also contemplated . when used to carry growth factors , the weight ratio of the beta - calcium sulfate hemihydrate powder to the alpha - calcium sulfate hemihydrate powder may range up to about 3 : 1 . the composition , a region of the composite , or the composite , itself , can also include additives that are controllably released as the region dissolves . examples of suitable additives include medicaments and pesticides . examples of useful medicaments include antibiotics , chemotherapeutic agents , growth factors , and analgesics . examples of useful antibiotics include tetracycline hydrochloride , vancomycin , cephalosporins , and aminoglycocides such as tobramycin and gentamicin . examples of chemotherapeutic agents include cis - platinum , ifosfamide , methotrexate , and doxorubicin hydrochloride ( adriamycin ®). examples of growth factors include transforming growth factor beta ( tgf - beta ), bone morphogenic protein (“ bmp ”), demineralized bone matrix (“ dbm ”), basic fibroblast growth factor , platelet - derived growth factor , and other polypeptide growth factors . examples of analgesics include anesthetics such as lidocaine hydrochloride ( xylocalne ®), bipivacaine hydrochloride ( marcaine ®), and non - steroidal anti - inflammatory drugs such as ketorolac tromethamine ( toradol ®). the composite can include distinct regions each containing 0 to about 25 wt . % additive , preferably about 2 wt . % to about 10 wt . % additive , most preferably about 2 wt . % to about 5 wt . % additive . one method of preparing a composite includes preparing two or more regions , and then combining , e . g ., through pressure , adhesion or molding , two or more regions to form the composite , e . g ., a pellet , a tablet or other geometric shape . the regions can be prepared by combining a source of calcium sulfate with an aqueous liquid to form a calcium sulfate composition , and then molding or applying pressure to the calcium sulfate composition to form the region . the aqueous liquid can include salt , e . g ., sodium chloride , i . e ., it may be a saline solution . an alpha - or beta - calcium sulfate hemihydrate powder will convert to the dihydrate form upon contact with water or saline . the water to calcium sulfate weight ratio is preferably in the range of from about 0 . 22 to about 1 , more preferably in the range of from about 0 . 27 to about 0 . 35 for alpha - calcium sulfate hemihydrate , and from about 0 . 65 to about 0 . 85 for beta - calcium sulfate hemihydrate powder . the consistency of a calcium sulfate powder ( i . e ., ml solution / grams calcium sulfate ) is proportional to its surface area and is dependent upon the morphology of the crystal . additives can be incorporated into the composite using a variety of methods including , e . g ., incorporating the additive into the calcium sulfate powder mixture ( e . g ., by mixing the additive with the calcium sulfate in powdered form prior to forming the calcium sulfate and aqueous liquid composition ), addition of the additive to the calcium sulfate and aqueous liquid composition , and impregnating the formed region with an additive , e . g ., by contacting the region with an additive in the form of a liquid or aerosol . another useful method for incorporating an additive into the composite includes dissolving or suspending the additive into a solution and subsequently impregnating the additive into the calcium sulfate powder . the composite can be formulated to provide a predetermined rate of dissolution or rate of release . factors that influence the rate of dissolution or rate of release of the composite include , e . g ., the composition of the composite , the composition of the regions , and the structure of the composite , e . g ., the location of the regions within the composite . in addition , the form of calcium sulfate , the number of different forms of calcium sulfate , and the amount of each form of calcium sulfate present in the composition can be selected to provide a region having a desired rate of dissolution . the composite , or a region of the composite , can be pre - formed for ease of use or custom formulated to meet a specific rate of dissolution , or rate of release or profile , e . g ., a release rate or profile specified by a surgeon during the performance of an operation . the invention will now be further described by way of the following example . the dissolution rate of a pellet was determined by immersing the pellet in distilled water and periodically taking it out of the solution so that the pellet could be weighed . 100 ml of distilled water was placed in a polyethylene bottle . a pellet was immersed in the distilled water and the bottle was then placed in a water bath maintained at 37 ° c . at 24 hour intervals (+/− 1 hour ) the pellet was removed from the bottle , weighed (“ wet weight ”), dried in an oven at 40 ° c . for 40 minutes , and weighed again (“ dry weight ”). the weight was recorded to the nearest milligram . the polyethylene bottle was then refilled with 100 ml of fresh distilled water and the dried pellet was immersed in the distilled water . the bottles were again placed in the water bath maintained at a temperature of 37 ° c . the above process was repeated for 8 days or until the pellet had completely dissolved . the average weight % (“ wt . %”) pellet remaining at each interval for each of the pellets tested was determined . the elution rate of the medicament from a pellet was determined by weighing a pellet and then placing the pellet in a water - tight plastic container containing 20 ml of phosphate buffered saline ( dulbeccos phosphate buffered saline , sigma chemical co .). the container was then immersed in a water bath maintained at 37 ° c . for 24 hours . after 24 hours , a 2 - 4 ml sample of the eluant was removed and pipeted into a labeled cryogenic vial , which was then used to determine the concentration of tobramycin present in the sample as described below . a metal mesh captured the pellet as the remaining solution was discarded . the container was then filled with 20 ml of fresh phosphate buffered saline solution , and the pellet was again immersed in the saline solution for another 24 hour period . after 24 hours a 2 - 4 ml sample was removed from the container and tested to determine the concentration of tobramycin present in the sample , as described below . this process was repeated for a total of seven days . the concentration of tobramycin present in the 24 ml samples was measured using a tdx flx automated fluorescence polarization analyzer ( abbott laboratories ). to obtain a reading , the sample was diluted to a concentration in the range of between 1 - 10 ug / ml and analyzed by tdx to determine the concentration , in ug / ml , of tobramycin in the sample . dilutions varied from 1000 to 1 ×, from day 1 to day 7 , respectively . the average tobramycin concentration , in ug / ml , of the pellets tested was determined for each interval . pellets containing an outer layer prepared from beta - calcium sulfate hemihydrate and tobramycin and an inner core prepared from alpha - calcium sulfate hemihydrate and tobramycin (“ dual βt / αt pellets ”) were prepared as follows . 5 g beta - calcium sulfate hemihydrate ( u . s . gypsum ) and 0 . 09 g stearic acid ( j . t . baker ) were combined and mixed on a roll mixer for approximately 10 minutes . 0 . 29 g tobramycin sulfate ( eli lilly ) dissolved in 3 . 75 g water was combined with 5 . 09 g of the beta - calcium sulfate / stearic acid mixture . the composition was allowed to hydrate for 1 minute and then mixed for one minute to form a paste . the resulting paste was cast into a bottomless mold . a 3 mm osteoset t pellet prepared from alpha - calcium sulfate hemihydrate and 4 % tobramycin sulfate ( eli lilly ) was inserted into the paste in the mold cavity . the paste was smoothed around the pellet to completely cover the pellet to form a dual βt / αt pellet . the dual βt / αt pellet was covered and allowed to dry for 15 minutes at ambient temperature , and then turned over and allowed to dry for 2 minutes at ambient temperature . the dual βt / αt pellet was covered and dried for approximately 2 hours . the dual βt / αt pellet was then removed from the mold , placed in an oven and dried for approximately 5 hours at 40 ° c . dual βt / αt pellets made by this process yielded , on average , 4 % by weight tobramycin sulfate ( approximately 3 . 2 mg / composite ). pellets containing an outer layer prepared from alpha - calcium sulfate hemihydrate and tobramycin and an inner core prepared from beta - calcium sulfate hemihydrate and tobramycin (“ dual αt / βt pellets ”) were prepared as follows . 20 g alpha - calcium sulfate hemihydrate ( usg ) was combined with 0 . 38 g stearic acid and mixed on a roll mixer for approximately 10 minutes . 1 . 14 g tobramycin sulfate dissolved in 5 g water was combined with 20 . 38 g of the alpha - calcium sulfate / stearic acid mixture . the composition was allowed to hydrate for 1 minute and then mixed for one minute to form a paste (“ the alpha paste ”). the resulting alpha paste was then cast into a bottomless 4 . 8 mm diameter mold . a 3 mm calcium sulfate and tobramycin pellet prepared from beta - calcium sulfate hemihydrate (“ the 3 mm beta pellet ”) was prepared as follows . 10 g beta - calcium sulfate hemihydrate and 0 . 18 g stearic acid were combined and mixed on a roll mixer for approximately 10 minutes . 0 . 58 g tobramycin sulfate dissolved in 7 . 5 g water was combined with 10 . 18 g of the calcium sulfate / stearic acid mixture . the composition was allowed to hydrate for 1 minute and then mixed for one minute to form a paste . the resulting paste was cast into a 3 mm diameter bottomless mold and dried to form a 3 mm beta pellet . the dried 3 mm beta pellet was then inserted into the 4 . 8 mm mold cavity that had been filled with the above - described alpha paste . the alpha paste was smoothed over the surface of the beta pellet so as to encase the beta pellet and form a dual αt / βt pellet . the dual αt / βt pellet was cast at ambient temperature , turned over after 7 minutes , and allowed to dry for 5 minutes at ambient temperature . the dual αt / βt pellet was then covered and dried for approximately 2 hours . the dual αt / βt pellet was then removed from the mold , placed in an oven and dried for approximately 5 hours at 40 ° c . dual αt / βt pellets made by this process yielded 4 % by weight tobramycin sulfate ( approximately 4 mg / composite ). pellets containing an outer layer prepared from alpha - calcium sulfate hemihydrate and tobramycin and an inner core prepared from alpha - calcium sulfate hemihydrate and tobramycin (“ dual αt / αt pellets ”) were prepared and follows . 25 g alpha - calcium sulfate hemihydrate was combined with 0 . 475 g stearic acid and mixed on a roll mixer for approximately 10 minutes . 1 . 43 g tobramycin sulfate dissolved in 6 . 25 g water was combined with 24 . 475 g of the alpha - calcium sulfate / stearic acid mixture . the composition was allowed to hydrate for 1 minute and then mixed for one minute to form a paste . the resulting paste was cast into a bottomless mold . a 3 mm osteoset t pellet prepared from alpha - calcium sulfate hemihydrate and containing 4 % tobramycin sulfate ( eli lilly ) was inserted into an empty mold and covered over with the above - described paste to form a dual αt / αt pellet . the dual αt / αt pellet was cast at ambient temperature , turned over after 10 minutes , and allowed to dry for 4 minutes at ambient temperature . the dual αt / αt pellet was covered and dried for approximately 48 hours . the dual αt / αt was then removed from the mold , placed in an oven and dried for approximately 8 . 5 hours at 40 ° c . dual αt / αt pellets made by this process yielded 4 % by weight tobramycin sulfate ( approximately 4 . 6 mg / composite ). five pellets prepared according to each of examples 1 - 3 were tested according to the dissolution test procedure set forth above . the average wt . % of pellet remaining at each interval for examples 1 - 3 is recorded in table 1 . three pellets prepared according to each of examples 1 - 3 were tested according to the elution test procedure set forth above . the average tobramycin concentration in ug / ml of three pellets of each of examples 1 - 3 is recorded in table 2 . [ 0050 ] table 2 ave . ave . day 1 day 2 day 3 day 5 day 7 day 10 day 15 day 22 initial initial ave . ave . ave ave ave ave ave ave wt of wt of concen - concen - concen - concen - concen - concen - concen - concen - composite tobramycin tration tration tration tration tration tration tration tration example ( mg ) ( mg ) ( ug / ml ) ( ug / ml ) ( ug / ml ) ( ug / ml ) ( ug / ml ) ( ug / ml ) ( ug / ml ) ( ug / ml ) 1 . dual 639 . 0 17 . 12 750 60 . 9 16 . 2 6 . 4 3 . 5 3 . 3 3 . 5 5 . 0 βt / αt 2 . dual 813 . 7 21 . 81 820 78 . 8 9 . 7 5 . 5 3 . 1 αt / βt 3 . dual 956 . 3 25 . 41 1277 130 . 5 41 . 1 17 . 3 6 . 6 5 . 0 0 . 0 αt / αt other embodiments are within the following claims . for example , although the composite has been described as having two regions , the composite can include multiple regions of different calcium sulfate compositions such that within one composite there exists multiple regions having differing dissolution rates . in addition , each region can include one or more additives .

a composite is disclosed having a controlled rate of dissolution . the composite includes a first region that includes a first composition that includes calcium sulfate , the first region exhibiting a first rate of dissolution ; and a second region that includes a second composition that includes calcium sulfate , the second region exhibiting a second rate of dissolution , the first rate of dissolution being different from the second rate of dissolution .

the following description of the preferred embodiments of the present invention is merely illustrative in nature , and as such it does not limit in any way the present invention , its application , or uses . numerous modifications may be made by those skilled in the art without departing from the true spirit and scope of the invention . referring to the drawings , a balloon catheter is depicted , with one of the preferred embodiments of the present invention being shown at reference number 10 in fig1 . the balloon catheter of fig1 has an inflatable balloon 12 , a relatively long and flexible tubular shaft 14 , and a hub 16 . the balloon 12 is affixed to the shaft 14 near a distal end of the shaft 14 , and the hub 16 is affixed to the proximal end of the shaft 14 . the shaft defines at least two passages or lumens , one of which is an inflation lumen 18 connected to the balloon 12 for selectively inflating and deflating the balloon 12 . the inflation lumen 18 thus provides fluid communication between the interior of the balloon 12 at the distal end of the inflation lumen 18 , and a hub inflation port 20 having a coupling or luer - lock fitting at the proximal end for connecting the inflation lumen to a source of pressurized inflation fluid ( not shown ) in the conventional manner . a second lumen defined by the catheter 10 is a guidewire lumen 26 is adapted to receive an elongated flexible guidewire 28 in a sliding fashion . the guidewire 28 and catheter 10 may thus be advanced or withdrawn independently , or the catheter 10 may be guided along a path selected with the guidewire 28 . in the illustrated embodiment , shaft 14 is constructed of an inner and outer tubular body 22 and 24 . the inner body 22 defines the guidewire lumen 26 , while inflation lumen 18 is defined by an annular space between the inner and outer tubular bodies 22 and 24 . the guidewire lumen 26 extends through the inner tubular body 22 from a distal guidewire port 30 near the catheter distal end to a proximal guidewire port 32 defined by hub 16 . a flexible tubular strain relief 34 surrounds shaft 14 at a transition between the shaft 14 and hub 16 . strain relief 34 is affixed to shaft 14 and / or hub 16 in any desired manner . the balloon 12 shown in fig1 , 2 , 3 , and 9 has a central portion 36 defining an inflated size and a working length , flanked by a pair of tapering conical segments 38 and 40 , flanked by a pair of “ legs ” or collars 42 and 44 . proximal collar 42 is affixed to outer body 24 near its distal end , and distal collar 44 is affixed to inner body 22 near its distal end . fig3 shows inner body 22 , outer body 24 , and balloon 12 . a pair of radiopaque markers 46 indicate the position of the central working length portion of the balloon to a physician using x - ray video . a proximal portion of inner body 22 is reinforced with a hypotube 48 component . the hypotube 48 is affixed to and surrounds a portion of inner body 22 , extending from proximal hub 16 along a proximal segment of the shaft 14 . hypotube 48 has a cylindrical segment 50 and a spiral - cut segment 52 . spiral - cut segment 52 provides a graduated transition in bending flexibility . the spiral pattern cut into hypotube may have a pitch that changes , to increase flexibility in specific areas . for example , the longitudinal distance between adjacent coils of the spiral cut path may become shorter as the spiral cut progresses from its proximal beginning to the distal end of the hypotube , as shown in fig5 . in other words , the spiral cuts are closer together at the distal end of the hypotube , and farther apart at the proximal end of the spiral cut . as a result , the distal end of the hypotube is more flexible than the proximal portion of the hypotube . this transition in flexibility may be accomplished in various ways . for example , the pitch of the spiral cut may have a proximal pitch , proceeding in a linear fashion down to a smaller distal pitch . in another example , the pitch of the spiral cut may decrease from a proximal pitch a to a distal pitch b in a non - linear manner , as depicted in fig6 . in the example of fig6 , an exponential progression has been selected . other non - linear pitch curves may be selected . one particular example of an inner tubular body 22 is shown in fig7 . in this example , the inner body tube 22 has a multi - layer construction . the inner layer 54 is a lubricious polymer material , such as for example high density polyethylene ( hdpe ) or polytetrafluoroethylene ( ptfe ). the outer layer 56 is a strong polymer material , which is selected to bond well with the material ( s ) selected for the hub 16 and the balloon 12 . examples of acceptable materials are nylons or polyether block amide ( peba ). in the specific example shown in fig7 , the outer layer 56 has multiple segments of differing flexibility . for example , fig7 shows a proximal , middle , and distal segment of outer layer material 58 , 60 and 62 , arranged in order of increasing flexibility from the proximal to the distal direction . in addition , the example shown in fig7 has an internal reinforcement in the form of braid 64 . the braided reinforcement is depicted in a diagrammatic manner for clarity , and may be at least a pair of wires coiled around inner body 22 , between the inner and outer layers 54 and 56 , in a criss - crossing fashion . the braid wires 64 may be a metal such as stainless steel , or another strong material such as kevlar fibers . in the example of fig7 , the braid wires 64 are arranged with a pitch that decreases in the distal direction . in other words , the wraps of the braid wires are closer together near the distal end of inner body than at the proximal end . this decreasing pitch , measured in increasing wires per inch , may be arranged progressively along the length of the inner body , in linear or non - linear fashion , or in specific segments , illustrated in fig8 . the braid segments in fig7 may be arranged to align with the segments of different flexibility of the outer layer material , but need not be so aligned , as shown in fig7 . fig8 shows the number of braid wires per inch , along the length of inner body 22 . of course , other curves and arrangements may be selected . if desired , inner body may be provided with radiopaque markers , to indicate specific locations on the catheter to a physician using an x - ray video . in the example of fig7 , a pair of marker bands 66 made of a radiopaque material such as for example tungsten , platinum , etc . are provided near the distal end of the inner body . the markers may be placed on the outside of inner body , or between the inner and outer layers , as shown in fig7 the distal end of inner body may be arranged to form part of the distal tip of the catheter . if so , it should be optimally shaped at some point during construction of the catheter , as shown in fig7 . the inner surface of tubular inner body defines at least a portion of the guidewire lumen . to enhance ease of operation , this inner surface may be of a material selected for high lubricity , which will present low frictional resistance to movement of a guidewire inserted within guidewire lumen . some prior catheters have used an inner layer defining a guidewire lumen that is made of teflon ®, or ptfe , and it is possible to likewise use ptfe in a catheter according to the present invention . another possibility is to use a different material for the guidewire lumen . because many guidewires have a ptfe coating , in some operating conditions , it is possible that the resulting interface between similar materials , ptfe tube on ptfe - coated guidewire , to exhibit a slight “ slip stiction ” effect . accordingly , another lubricant material may be used , for example hdpe , as the inner layer of inner body . the markers may be placed around the outside of the inner body , or inside the wall of the inner body . in fig7 , marker bands 66 are placed between inner and outer layers 54 and 56 of inner body 22 . the outer body 24 may be a conventional polymer tube or a more sophisticated construction . an example outer body 24 is depicted in fig4 , in which the outer body tube 24 tapers from a proximal size to a smaller distal size . in particular , outer body 24 of fig4 is a bump extrusion , in which the outer size and inner size ( and therefore the wall thickness ) draws down and narrows simultaneously along the length of the outer body 24 . the hypotube may be made of metal which is selected to be biocompatible , such as for example stainless steel . other acceptable metals may include nitinol , titanium , etc . the inflation lumen 18 extends from the inflation port 20 , through a proximal portion of the inflation lumen 18 defined by the hypotube , through a distal portion of the inflation lumen 18 defined by the annular space between the inner and outer bodies 22 and 24 , and into the balloon . the balloon catheter and stent delivery system of the present invention may be made using various methods , including extruding polymer tubes , injection - molding the proximal hub , and extruding a balloon parison and then blowing the parison into a balloon having the desired properties . it is also possible to affix polymer components to each other by heat - sealing , or by using an adhesive such as a uv - cured adhesive . it should be understood that an unlimited number of configurations for the present invention could be realized . the foregoing discussion describes merely exemplary embodiments illustrating the principles of the present invention , the scope of which is recited in the following claims . those skilled in the art will readily recognize from the description , claims , and drawings that numerous changes and modifications can be made without departing from the spirit and scope of the invention .

a balloon catheter for medical treatment of a patient , including therapeutic dilatation or deployment of medical devices such as stents or grafts . the balloon catheter has an “ over - the - wire configuration , including a proximal hub defining an inflation port and a guidewire port , a flexible shaft defining an inflation lumen and a guidewire lumen , a balloon near a distal end of the catheter , and a distal guidewire port . at least a portion of the shaft has an inner tubular body defining at least a portion of the guidewire lumen , surrounded by an outer tubular body defining at least a portion of the inflation lumen . a proximal portion of the inner body is reinforced by a hypotube , which provides much greater column strength and torsional stiffness . a distal end of the hypotube provides a graduated flexibility transition with a distal spiral - cut segment , in which the pitch of the spiral cut pattern decreases to provide increasing flexibility .

in the drawings and in the description which follows , in which like reference numerals identify similar or identical elements , the term “ proximal ” will refer to the end of the apparatus closest to a clinician during the use thereof , while the term “ distal ” will refer to the end which is furthest from the clinician , as is traditional and known in the art . with reference to fig1 a - 1b , a seal member 100 is disclosed that defines respective proximal and distal surfaces 102 , 104 , a periphery 106 and an aperture 108 that is configured to removably receive a surgical object “ i ” ( fig2 b ) such that a substantially fluid - tight seal is formed therewith . seal member 100 includes at least one cable member 110 which is discussed in detail below . seal member 100 may exhibit any configuration suitable for the intended purpose of receiving surgical object “ i ” so as to form a substantially fluid - tight seal therewith , including but not being limited to a substantially planar configuration , as seen in fig1 a , or a generally conical configuration , as seen in fig1 b . seal member 100 may be formed of any suitable biocompatible material that is at least semi - resilient in nature , including but not limited to elastomeric materials . forming seal member 100 of such a material facilitates the resilient deformation of seal member 100 , and aperture 108 in particular , upon the insertion and removal of surgical object “ i ”. the resilient nature of seal member 100 allows seal member 100 to exhibit various degrees of deformation during use , thereby facilitating the accommodation of surgical objects of various sizes , as well as the maintenance of a substantially fluid - tight seal therewith during the axial or lateral manipulation thereof within seal member 100 , as discussed in further detail below . as seen in fig2 a - 2b , prior to receiving surgical object “ i ”, seal member 100 is in a first condition in which aperture 108 of seal member 100 defines a first diameter “ d 1 ” that is substantially less than the diameter “ d ” of surgical object “ i ”. aperture 108 may be closed in the first position , i . e ., such that “ d 1 ” equals zero , to thereby prevent the escape of any insufflation gas through seal member 100 in the absence of surgical object “ i ”. upon the insertion of surgical object “ i ”, aperture 108 deforms , or stretches , to accommodate the larger diameter “ d ” of surgical object “ i ”, thereby transitioning into a second condition . in the second condition , aperture 108 of seal member 100 defines a second diameter “ d 2 ” that substantially approximates the diameter “ d ” of surgical object “ i ”, thereby forming a substantially fluid - tight seal with surgical object “ i ” and substantially preventing the escape of insufflation gas . the diameter “ d ” of the surgical object “ i ”, and thus the diameter “ d 2 ” of the aperture 108 of seal member 100 in the second condition , will generally lie within the range of about 5 mm to about 15 mm , as is conventional in the art , although substantially greater and lesser values for diameter “ d 2 ” are also within the scope of the present disclosure . referring still to fig2 a - 2b , cable member 110 of seal member 100 will be discussed . the cable member , or members , 110 may be formed of any suitable biocompatible material that is substantially non - rigid and substantially non - extensible in character , e . g . stainless steel , polymeric material , etc ., such that the length of cable member 110 remains substantially constant during the use of seal member 100 . cable member 110 has respective first and second ends 112 , 114 that are attached to seal member 100 at respective first and second sections 116 , 118 thereof . the first and second ends 112 , 114 of cable member 110 are attached to the first and second sections 116 , 118 at first and second locations 120 , 122 , respectively , that are disposed substantially adjacent to aperture 108 and spaced apart from one another . various arrangements for securing the first and second ends 112 , 114 of the cable member 110 are envisioned . for example , seal member 100 may have posts embedded within the material of the seal member 100 . the first and second ends 112 , 114 may be attached or secured to the posts . in the alternative , the first and second ends 112 , 114 may be embedded within the seal member 100 during manufacture of the seal member 100 , such as , for example , during a molding process . other means for attaching the first and second ends 112 , 114 are also envisioned . the respective first and second sections 116 , 118 , and consequently the respective first and second locations 120 , 122 , are in substantially diametric opposition to each other . with reference now to fig2 c , in one embodiment , a seal member 100 a is disclosed that includes a first cable member 110 a having respective first and second ends 112 a , 114 a attached to first and second sections 116 a , 118 a of seal member 100 a at first and second locations 120 a , 122 a , respectively . in this embodiment , seal member 100 a further includes a second cable member 110 b having respective first and second ends 112 b , 114 b attached to first and second sections 116 b , 118 b of seal member 100 a at first and second locations 120 b , 122 b , respectively . as with seal member 100 of fig2 a - 2b , each of the first and second locations 120 a , 122 a , 120 b , 122 b are disposed substantially adjacent aperture 108 a and spaced apart from one another . the incorporation of additional cable members , e . g ., a second cable member 110 b , or three or more cable members , facilitates more uniform deformation of aperture 108 a upon laterally manipulating a surgical object “ i ” ( fig2 b ) inserted therethrough , as discussed below . as seen in fig3 a - 3d , in one embodiment , seal member 100 defines at least one channel 124 configured to at least partially receive cable member 110 . channels 124 may be formed either in an outer surface of seal member 100 , e . g . proximal surface 102 ( fig3 a ), distal surface 104 ( not shown ) or periphery 106 ( fig3 b ), or within seal member 100 ( fig3 c - 3d ) such that cable member 110 is at least partially concealed by seal member 100 . referring now to fig4 a , a surgical access member , in the form of , e . g ., a cannula assembly 10 , is illustrated that may be used in conjunction with seal member 100 . at a proximal end 12 , cannula assembly 10 includes a housing 14 that is configured to accommodate the seal 100 that is the subject of the present disclosure . extending distally from housing 14 is a cannula or elongate member 16 . as illustrated , cannula assembly 10 may optionally further include a zero - closure valve 18 . housing 14 may be any structure suitable for the intended purpose of accommodating seal member 100 . as seen in fig4 b , in one embodiment , housing 14 defines at least one conduit 20 on an internal surface 22 thereof . conduit 20 is configured to receive cable member 110 and to permit the displacement thereof during lateral manipulation of surgical object “ i ” within seal member 100 , as discussed in further detail below . further information regarding seal housing 14 may be obtained through reference to commonly owned u . s . pat . no . 7 , 169 , 130 to exline et al ., the entire contents of which are hereby incorporated by reference . cannula 16 extends distally from housing 14 and defines a longitudinal passage 24 that is configured to permit a surgical object “ i ” ( fig2 b ), to pass therethrough , e . g ., an obturator , trocar or endoscope . at its distal end 26 , cannula 16 defines an opening 28 that is configured to allow the surgical object “ i ” to pass therethrough . conventionally , surgical objects generally define a diameter substantially within the range of about 3 mm to about 15 mm . accordingly , longitudinal passage 24 will be dimensioned similarly , although substantially larger and smaller surgical objects and a cannula 16 defining a substantially larger or smaller longitudinal passage 24 and opening 28 are also within the scope of the present disclosure . referring now to fig2 a , 4 a and 5 - 7 , the use and function of seal member 100 will be described in conjunction with a surgical access apparatus , e . g ., cannula assembly 10 . initially , the target surgical site is insufflated with a suitable biocompatible gas , e . g ., co 2 gas , such that a larger internal workspace may be created within a patient , thereby providing greater access to the patient &# 39 ; s internal organs and / or cavities . the insufflation may be performed with an insufflation needle or similar device , as is conventional in the art . thereafter , a variety of surgical objects , depicted generally as surgical object “ i ”, are inserted into cannula assembly 10 and advanced distally through seal member 100 and elongate member 16 to percutaneously access the insufflated workspace and carryout the minimally invasive procedure . subsequent to insufflation , seal member 100 substantially prevents the escape of insufflation gas , thereby maintaining the integrity of the insufflated workspace in both the absence and presence of surgical object “ i ”. as seen in fig2 a , prior to the insertion of surgical object “ i ”, seal member 100 is in the first condition , in which aperture 108 defines a first diameter “ d 1 ”. upon the insertion of surgical object “ i ” ( fig5 ), seal member 100 , and in particular the aperture 108 thereof , is subjected to a force “ f r ” applied by surgical object “ i ” that is directed radially outward . force “ f r ” forces open aperture 108 , thereby transitioning seal member 100 into the second condition thereof in which aperture 108 defines a second , larger diameter “ d 2 ” that substantially approximates the diameter “ d ” of surgical object “ i ”. in the second condition , aperture 108 exerts a biasing force “ f b ” directed radially inward that attempts to return seal member 100 to the first condition . biasing force “ f b ” is exerted upon surgical object “ i ”, thereby creating a substantially fluid - tight seal therewith . as previously discussed , it is often necessary to axially or laterally manipulate surgical object during the course of a minimally invasive procedure to access different areas of a surgical workspace . fig6 describes the impact of such lateral manipulation upon a known seal “ s ”. as would be appreciated by one of ordinary skill , laterally manipulating surgical object “ i ” in the direction of arrow “ a ” can laterally distort the enlarged aperture 108 s of the seal “ s ”, thereby creating a leak path 128 and potentially resulting in the escape insufflation gas therethrough . seal member 100 of the present disclosure mitigates this potentiality through the incorporation cable member , or members , 110 . as seen in fig7 , upon the lateral movement of surgical object “ i ” in the direction of arrow “ a ”, a force “ f l ” is applied to seal member 100 at the first section 120 thereof . force “ f l ” attempts to distort aperture 108 in the direction of arrow “ a ” and thereby create a leak path 128 ( fig6 ). upon the application of force “ f l ” to the first section 116 , the first end 112 of cable member 110 is subjected to force “ f l ” through the connection between the first end 112 of cable member 110 and seal member 100 at first location 120 . force “ f l ” displaces the first section 116 , thereby displacing the first end 112 of cable member 110 , and ultimately the second end 114 thereof . through the connection between the second end 114 of cable member 110 and seal member 100 at the second location 122 , the second section 118 of seal member 100 is subjected to the influence of force “ f l ” and is also displaced in the direction indicated by arrow “ a ”. consequently , aperture 108 deforms in a substantially uniform manner , maintaining its diameter d 2 in the second condition and minimizing the dimensions of leak path 128 , if any , such that the substantially fluid - tight seal formed with surgical object “ i ” is preserved and the escape of insufflation gas through seal member 100 is curtailed . the incorporation of additional cable members ( fig2 c ) further ensures uniform deformation of aperture 108 upon the lateral movement of surgical object “ i ” and the preservation of a substantially fluid - tight seal therewith . the present disclosure contemplates that that material comprising cable member 110 , and the configuration and dimensions thereof , may be such that the degree of distortion realized by the second section 118 of the seal member 100 will approximate that of the first section 116 , thereby substantially maintaining the diameter “ d 2 ” of aperture 108 in the second condition during the lateral manipulation of surgical object “ i ”. although the illustrative embodiments of the present disclosure have been described herein with reference to the accompanying drawings , the above description , disclosure , and figures should not be construed as limiting , but merely as exemplifications of particular embodiments . it is to be understood , therefore , that the disclosure is not limited to those precise embodiments , and that various other changes and modifications may be effected therein by one skilled in the art without departing from the scope or spirit of the disclosure .

a surgical access apparatus includes an access member defining a longitudinal axis and having a longitudinal passageway for reception and passage of a surgical object , a seal member mounted to the access member and having inner seal portions defining an aperture to removably receive the surgical object in substantial fluid - tight sealing relation therewith and at least one cable member . the at least one cable member has a first cable end connected to a first radial section of the seal member and a second cable end connected to a second radial section of the seal member displaced from the first radial section . the first and second cable ends are adapted to be laterally displaced relative to the longitudinal axis during offset lateral movement of the surgical object , to thereby cause corresponding lateral displacement of the inner seal portions of the seal member whereby the inner seal portions maintain the substantial fluid tight sealing relation with the surgical object .

the present invention provides improved methods of making catheter structures . in one embodiment , a catheter 10 having a polymeric body with small - diameter tubular section 12 forming the distal end 13 of the catheter and a larger connecting section or &# 34 ; hub &# 34 ; 14 at the proximal end is provided with a layer of an etchable metal such as copper or a copper - based alloy covering the exterior surface of the catheter . for example , the exterior surface may be electrolessly plated or sputtered with a conductive metal and then electroplated to the desired thickness . following formation of the metal layer , a layer of a photoresist is applied . the photoresist may be a conventional type as commonly used in formation of electrical circuits ( commonly referred to as &# 34 ; printed &# 34 ; circuits or &# 34 ; flex &# 34 ; circuits ) in the electronics industry . following application of the photoresist , the catheter is exposed to light as shown in fig1 . with the catheter body supported on a mandrel 16 , and the mandrel held by a movement device 18 , the catheter is advanced past a bank of variable - focus illuminators 20 arranged to project beams of light radially inwardly towards a central axis . the movement device 18 simultaneously rotates and translates the mandrel which moving the catheter along the central axis . as each point on the catheter passes axially past each beam , the beam traces a helical pattern along the catheter , and exposes the photoresist in that helical pattern . after exposure to the light , the photoresist is developed , and becomes solid in the exposed regions . the unexposed photoresist is removed , leaving the metal layer covered only in the areas exposed to light . the catheter is then exposed to an etchant to remove the metal in the unexposed areas , thereby forming helical metal stripes 22 ( fig2 ) extending along the length of the catheter . the illuminators can be actuated to vary the widths of the light beams at their point of impingement on the catheter . for example , each illuminator may include a variable - focus lens linked to a stepper motor or other electronically controllable actuator . this action is coordinated with the rotation and translation of the catheter , so as to form variable - width stripes , with wide regions 19 and narrow regions 21 at different points along the length of the catheter . one example of such a pattern is illustrated in fig2 wherein each stripe 22 bears a different cross - hatching for ease of identification . gaps 24 are provided between the stripes , as also shown on fig2 . additionally , the ratio of rotational movement to translational movement can be varied during the advance of the catheter so as to vary the pitch of the helical stripes along the length of the catheter . for example , the movement device may include a stepper motor or other electronically controllable rotary actuator for turning the mandrel , and may also include an electronically controllable actuator for the translational movement . the movement device and the variable - focus illuminators may all be controlled and coordinated by a common computer ( not shown ) using conventional control interfaces . the rotational movement can be entirely stopped during some part or all of the translational movement , to form straight stripes or stripes having straight portions integral with helical portions . the rotational movement can also be reversed along the length of the catheter , to form stripes with opposite pitch over different parts of the catheter length . further one or more of the illuminators can be selectively turned off during the movement , to interrupt one or more of the stripes . following formation of a first set of stripes 22 , the catheter body or first polymeric layer 10 can be covered with a second polymeric layer 26 ( fig3 ) and the foregoing steps can be repeated , so as to form second metallic stripes 28 on the outside of the second polymeric layer . a further coating can then be applied over the outside of the catheter to provide a smooth surface . the coating steps can be performed by applying a curable material ( e . g ., an epoxy composition or , preferably , a curable polyamic acid composition which can be cured to form a polyimide ), by applying a plastisol ( dispersion of polymer ); by applying a polymer in solution ; by applying a polymer in molten form ; or by any other process capable of applying a polymer layer . more than two sets of stripes can be provided , using additional polymer layers between successive sets . each layer of stripes can include any number of stripes , in any desired size and configuration . the ability to vary the width and helical pitch of the stripes along the length of the catheter can be used to provide different properties along the length of the catheter . for example , where a relatively flexible zone is desired , the stripes may be relatively thin ; where a stiff region is desired , the stripes may be relatively wide . in a particularly preferred arrangement , the different sets of stripes in different layers ( such as the first stripes 22 and second stripes 28 in fig3 ) have opposite pitches . for example , the first stripes may be right - hand helices whereas the second stripes may be left - hand helices . this arrangement provides uniform bending properties in all directions . although continuous stripes extending from adjacent the proximal end to adjacent the distal end normally are preferred , other patterns can be applied using the same process . an electronic device may mounted inside the interior bore of the catheter , or disposed on or in the catheter wall . the electronic device may be connected to the ends of the stripes by techniques such as wire bonding ( connection of the stripe to the device by a fine gold wire ) or direct thermosonic bonding of the stripe end to the device . the portions of the stripes extending onto the hub at the proximal end of the catheter may be enlarged to form large , readily connectable pads on the hub . the photoresist technique can be varied . for example the resist may harden only in unexposed areas , so that the exposed areas are removed , and the copper layer is removed in exposed areas but left in unexposed areas . in this case , the exposed areas will define gaps between the stripes . also , the resist may be applied and patterned by exposure to light before the electroplating step , so that only those areas which do not bear resist will be electroplated . as shown in fig4 the same processes may be performed using continuous or semicontinuous tubes 110 , by advancing the tube between rollers 102 while moving the light sources 120 ( only one of which is shown ) around the advancing tube . here again , the width and pitch of each stripe can be varied along the length of the tube by changing the beam width and rate of rotation per unit advance as desired . alternatively , the tube can be twisted as it advances , as by rotating one or both sets of rollers around the axis of the tube , as well as around the roller axes . the other steps , such as plating , etching and resist development , may be performed on a the tube as it is fed continuously through process chambers ( not shown ). in a further embodiment , the catheter may be maintained stationary and the beam or beams of light may be moved lengthwise along the catheter while also rotating the beam or beams around the catheter , to achieve the same relative motion as discussed above . for example , the light source can include a movable light emitting element or a movable light - directing element such as a movable mirror or a fiber optic . this is advantageous where the catheter is of small diameter and substantial length , so that the catheter and supporting mandrel ( if used ) tend to flex laterally , i . e ., transverse to the longitudinal axis . by holding the catheter in fixed position , flexing is minimized . the longitudinal axis of the catheter and mandrel extend vertically to further minimize flexing . in a further refinement , the actual position of the catheter may be sensed at numerous points along the length , so as to record a map of lateral flex versus length , and the motion of the light source may be compensated for lateral flex of the catheter . thus , where the catheter is displaced in a particular lateral direction from its theoretical location , the light source can be similarly displaced . the actual position of the catheter can be detected by a conventional machine - vision system , provided that the light required by such system does not substantially expose photoresist . for example , if the photoresist is substantially sensitive only to ultraviolet light , the machine vision system may operate at infrared wavelengths . in another variant , the position of the catheter can be sensed by detecting capacitance or inductance between one or more probes of known position and the conductive layer on the catheter or a conductive mandrel within the catheter . for example , a pair of capacitive probes in the form of plates 202 , and 203 as shown in fig5 may be mounted to a carriage 204 which in turn is mounted for reciprocating motion on a track parallel to the theoretical longitudinal axis of the catheter . one plate 202 is offset from the theoretical axis in a first lateral direction , whereas the other plate 203 is offset from the axis in a second lateral direction orthogonal to the first lateral direction . variation in capacitance between the conductive layer of the catheter and the first plate corresponds to variation in position in the first direction , whereas variation in capacitance between the catheter conductive layer and the second plate corresponds to variation in position in the second direction . in a further variation , a plurality of fixed capacitive or inductive probes may be disposed in an array around the catheter , and the position of the catheter can be deduced mathematically from the interaction between the catheter conductive layer ( or mandrel ) and all of these probes . the terms &# 34 ; light &# 34 ; and &# 34 ; illuminating &# 34 ; as used herein should be understood as encompassing radiant energy outside of the visible spectrum as well as visible light . the radiant energy may be in the form of a beam or beams of charged particles , such as electron beams . where charged particle beams are employed , the metallic layer on the tube desirably has a charge opposite to the charge of the particles . in this case , the beams will be attracted to the tube . if the tube is displaced from its theoretical position , the beams will tend to follow the tube . accordingly , centering of the tube with respect to the beams may be less significant than with other forms of radiant energy . for example , the tube may be positively charged and the radiant energy may be in the form of electron beams . also , the spiraling motion of the beams on the tube surface can include deflection of the electron beams imparted by controlled , varying magnetic or electrical fields to sweep the beams circumferentially around the tube . the focus of an electron beam can be varied to vary the strip width . the word &# 34 ; catheter &# 34 ; as used in this disclosure should be understood as encompassing both the tubular devices commonly referred to as catheters and other tubular devices , such as those commonly referred to as endoscopes , endotracheal tubes , gastric tubes and others .

a polymeric tube for a medical catheter is provided with elongated metal stripes extending lengthwise along the tube by illuminating the exterior surface of the tube patternwise and treating metal responsive to the illumination . the tube may be covered with a photoresist and moved axially past a plurality of light beams while rotating the tube about its axis so as to form a helical pattern . after development of the photoresist , the metal is deposited or removed in a pattern corresponding to the pattern formed in the photoresist , so as to leave helical metallic stripes . the metallic stripes may have varying helical pitch , varying width or both along the length of the tube , and may serve as electrical connectors and physical reinforcements for the tube wall .

as illustrated in fig1 , an aerosol inhalator 10 according to one embodiment includes a cylindrical outer tube 12 opening at both ends , and a mouthpiece 14 detachably connected to a proximal end of the outer tube 12 . the outer tube 12 and the mouthpiece 14 are each made of heat - resistant synthetic resin . the outer tube 12 has a lid 16 located at its distal end , and the lid 16 is detachable from the outer tube 12 . the outer tube 12 contains a power supply unit 18 as a source of electricity , a liquid tank 20 as a solution supply source , and an inner tube 22 . the power supply unit 18 , the liquid tank 20 and the inner tube 22 are arranged sequentially in the mentioned order from the lid side coaxially with the outer tube 12 . the inner tube 22 communicates with the mouthpiece 14 . the power supply unit 18 and the liquid tank 20 are each replaceable , and with the lid 16 detached from the outer tube 12 , the power supply unit 18 and the liquid tank 20 are replaced with new ones . the power supply unit 18 includes a cell holder 24 and a commercially available battery cell , for example , an aa size cell 26 , held by the cell holder 24 . the cell 26 has a nominal voltage of 1 . 5 v and is arranged coaxially with the outer tube 12 . the liquid tank 20 is illustrated in detail in fig2 . the liquid tank 20 includes a cylindrical tank casing 28 . the tank casing 28 has a plurality of ribs formed on an outer peripheral surface thereof . the ribs are spaced from each other in a circumferential direction of the tank casing 28 and extend in an axial direction of the tank casing 28 except an end portion of the casing 28 close to the power supply unit 18 . the ribs serve to form a plurality of axial passages 27 ( see fig1 ) between the outer surface of the tank casing 28 and an inner surface of the outer tube 12 , and also serve to secure an annular chamber 29 ( see fig1 ) between the aforementioned end portion of the tank casing 28 and the inner surface of the outer tube 12 . the annular chamber 29 is connected to the axial passages 27 . a tube coil 30 is contained in the tank casing 28 . the tube coil 30 extends in the axial direction of the outer tube 12 and has opposite open ends . an inlet conduit 32 extends from one end of the tube coil 30 to the outer surface of the tank casing 28 and opens on the outer surface of the tank casing 28 to be connected to the annular chamber 29 . a check valve 34 is arranged in the inlet conduit 32 and opens only in one direction toward the one end of the tube coil 30 . an outlet conduit 36 extends from the other end of the tube coil 30 and is connected to a capillary tube 40 through a joint 38 . the capillary tube 40 projects from the tank casing 28 into the aforementioned inner tube 22 and is located coaxially with the inner tube 22 . the projecting end of the capillary tube 40 forms a discharge end 42 , which opens in a direction toward the mouthpiece 14 . another check valve 44 is arranged in the outlet conduit 36 and opens only in one direction toward the capillary tube 40 . an internal flow channel ( inlet conduit 32 , tube coil 30 and outlet conduit 36 ) of the liquid tank 22 and the capillary tube 40 are filled with a solution to be aerosolized , and the solution reaches the discharge end 42 of the capillary tube 40 . the solution may contain , for example , propylene glycol , glycerin or the like . as is clear from fig1 , the inner tube 22 extends from the liquid tank 20 toward the mouthpiece 14 and is connected to an absorbent sleeve 48 . the absorbent sleeve 48 is located in alignment with the inner tube 22 and has an inner diameter identical with that of the inner tube 22 . a portion of the outer tube 12 surrounding the inner tube 22 and the absorbent sleeve 48 has a larger thickness than a portion of the outer tube 12 surrounding the power supply unit 18 and the liquid tank 20 . specifically , the inner tube 22 is made of stainless steel or ceramic , for example . on the other hand , the absorbent sleeve 48 is , for example , a paper tube or hollow tubular paper filter capable of absorbing the solution . the absorbent sleeve 48 has a volume sufficient to retain a required absorption amount of the solution . as illustrated in fig1 , the outer tube 12 has a plurality of atmospheric ports 50 formed therein . the atmospheric ports 50 adjoin the liquid tank 20 , for example , and are spaced from each other in the circumferential direction of the outer tube 12 . each of the atmospheric ports 50 extends from the outer peripheral surface of the outer tube 12 and penetrates through the inner tube 22 . thus , the atmospheric ports 50 provide atmosphere - exposed openings 52 that open on the outer peripheral surface of the outer tube 12 , and are connected to the annular chamber 29 through the axial passages 27 . accordingly , the atmospheric ports 50 and the inner tube 22 form a suction path connecting the atmosphere - exposed openings 52 to the mouthpiece 14 . also , the atmospheric ports 50 serve to keep the interior of the annular chamber 29 at atmospheric pressure , and as a consequence , the solution in the liquid tank 20 remains in a state such that the solution is always acted upon by the atmospheric pressure through the open end of the inlet conduit 32 . when the user inhales the air in the inner tube 22 through the mouthpiece 14 , a negative pressure is created in the inner tube 22 , so that ambient air is introduced into the inner tube 22 through the atmospheric ports 50 . such introduction of the ambient air produces , within the suction path , a flow of air toward the mouthpiece 14 . the negative pressure created in the inner tube 22 causes the solution to be discharged from the discharge end 42 of the capillary tube 40 into the suction path , namely , into the inner tube 22 , and the amount of the solution discharged is determined by the intensity of the negative pressure . on the other hand , the capillary tube 40 is replenished with the solution from the liquid tank 20 in an amount corresponding to the discharge amount . since the solution in the liquid tank 20 is always applied with the atmospheric pressure as stated above , the solution in the internal flow channel of the liquid tank 20 moves toward the capillary tube 40 accompanying the replenishment of the solution . a cylindrical heater 56 is arranged in the inner tube 22 . the heater 56 is located immediately downstream of the discharge end 42 of the capillary tube 40 , as viewed in the direction of the flow of air produced in the suction path . provided that as shown in fig3 , the inner diameters of the inner tube 22 and capillary tube 40 are d it and d ct , respectively , the outer diameter d o of the heater 56 is smaller than the inner diameter d it of the inner tube 22 and at the same time is larger than the inner diameter d ct or outer diameter of the capillary tube 40 . that is , the outer diameter d o satisfies the following relationship : the heater 56 penetrates through the inner tube 22 in a diametrical direction of the tube 22 and has an axis intersecting perpendicularly with the axis of the inner tube 22 . the heater 56 is supported at both ends by the outer tube 12 . considering that the capillary tube 40 is located coaxially with the inner tube 22 as stated above , the discharge end 42 of the capillary tube 40 is hidden by the heater 56 when the heater 56 is viewed from the downstream end of the inner tube 22 . in other words , the cross section of the discharge end 42 can be totally projected onto the outer surface of the heater 56 . further , when the solution is discharged from the discharge end 42 in the aforementioned manner , the discharged solution forms a liquid droplet at the discharge end 42 , and a maximum diameter of the liquid droplet is determined by the inner diameter d ct of the capillary tube 40 . provided the maximum diameter of the liquid droplet is d max , a gap z between the discharge end 42 and the heater 56 fulfills the following relationship : thus , when the solution is discharged from the discharge end 42 , the discharged solution is received on the outer surface of the heater 56 without fail . table 1 below shows the relationship observed where the solution is propylene glycol ( pg ; density : 1 . 036 g / mm 2 ), among the discharge amount and volume of the solution discharged in the form of a liquid droplet and the diameter of the liquid droplet with respect to the inner diameter d ct of the capillary tube 40 and the flow rate of intake air flowing through the inner tube 22 . the liquid tank 20 illustrated in fig3 has a structure different from that of the liquid tank already explained above . specifically , the liquid tank 20 in fig3 has an internal flow channel 30 a extending in a zigzag , in place of the coil tube 30 . this means that the coil tube 30 is not indispensable to the liquid tank 20 . the structure of the heater 56 will now be described in detail . the heater 56 includes , for example , a nichrome wire 58 as a resistance heating element , and a cylindrical sheath element 60 enclosing the nichrome wire 58 . in this embodiment , as is clear from fig3 , the nichrome wire 58 axially penetrates through the sheath element 60 three times and has two ends projecting from the respective opposite ends of the sheath element 60 . as illustrated in fig4 , the nichrome wire 58 is connected in series with the aforementioned cell 26 via a power feed circuit 63 , and the power feed circuit 63 has a switch 64 . although not illustrated in fig1 , the power feed circuit 63 and the switch 64 are arranged on the inner surface of the outer tube 12 , and the outer tube 12 is provided , on its outer surface , with a push button ( not shown ) for operating the switch 64 . the sheath element 60 is made of a ceramic such as alumina or silicon nitride , and constitutes the outer surface of the heater 56 . further , as is clear from fig4 , an annular groove 62 , for example , is formed in part of the outer surface of the sheath element 60 , and a ring - shaped heat - resistant net 64 , which serves as a wetting enhancement element , is preferably fitted around the annular groove 62 . the net 64 directly faces the discharge end 42 of the capillary tube 40 , and the aforementioned gap z is secured between the discharge end 42 and the net 64 . the sheath element 60 not only protects the nichrome wire 58 but thermally connects the nichrome wire 58 and the net 64 . specifically , where the cell 26 is in a usable state and the nichrome wire 58 is applied with a voltage of 1 to 1 . 5 v , the sheath element 60 performs the function of quickly transferring heat generated by the nichrome wire 58 to the outer surface of the heater 56 and keeping the heating temperature of the outer surface of the heater 56 within a temperature range required to atomize the solution . that is , the nichrome wire 58 and the sheath element 60 constitute an internal structure whereby the heating temperature of the outer surface of the heater 56 is kept within the required temperature range , and to this end , the sheath element 60 has a predetermined thickness and volume . referring now to fig5 to 9 , the principle of operation of the aerosol inhalator according to the embodiment will be explained . in fig5 to 9 , the net 64 of the heater 56 is not illustrated . fig5 illustrates a state in which the aerosol inhalator is ready for use with the switch 64 of the power feed circuit 63 turned on . the heating temperature of the outer surface of the heater 56 is quickly raised and kept within the required temperature range , and since the relationship indicated by the aforementioned expression ( 2 ) is fulfilled , the solution in the capillary tube 40 is not atomized by the radiant heat from the heater 56 . that is , no aerosol is generated . on the other hand , when the user inhales through the mouthpiece 14 of the aerosol inhalator in the state illustrated in fig5 , the solution is discharged from the discharge end 42 of the capillary tube 40 as mentioned above . since the relationships indicated by the expressions ( 1 ) and ( 2 ) hold between the capillary tube 40 and the heater 56 , the discharged solution l is reliably received on the outer surface of the heater 56 , as shown in fig6 and 7 . where the net 64 is fitted around the outer surface of the heater 56 , the discharged solution is received by the net 64 and then spreads over the net 64 . at this time , since the heating temperature of the outer surface of the heater 56 is already kept within the required temperature range , the discharged solution l is immediately atomized by being heated by the heater 56 , generating an aerosol x inside the inner tube 22 . the user can therefore inhale the aerosol x through the mouthpiece 14 . also , where the heater 56 is provided with the net 64 , the net 64 serves to enhance the wettability of the heater 56 with respect to the discharged solution l , so that the discharged solution l can be atomized over a wider area , enabling prompt generation of the aerosol . as soon as the user ceases breathing in , the discharge of the solution from the discharge end 42 of the capillary tube 40 stops immediately . as is clear from the above explanation , since the gap z between the discharge end 42 and the outer surface of the heater 56 is greater than at least the inner diameter d ct of the capillary tube 40 , the solution in the discharge end 42 is not atomized by the radiant heat from the heater 56 insofar as the heating temperature of the outer surface of the heater 56 is kept within the aforementioned temperature range . accordingly , the generation of the aerosol stops at the same time as the cessation of the user &# 39 ; s inhalation , so that the solution in the capillary tube 40 is not wasted . as a result , the user can inhale the aerosol without fail each time he / she breathes in , and the amount of the aerosol inhaled by the user is determined by the intensity and duration of the user &# 39 ; s inhalation . on the other hand , even though the heating temperature of the outer surface of the heater 56 is kept within the required temperature range , the discharged solution l fails to be received on the outer surface of the heater 56 and drops to the inner surface of the inner tube 22 , as shown in fig8 , if the relationship indicated by the aforementioned expression ( 2 ) is not fulfilled and the gap z is greater than the maximum diameter d max of the liquid droplet of the solution . in such a case , the discharged solution l is not atomized , so that the user cannot inhale the aerosol . conversely , if the gap z is smaller than the inner diameter d ct of the capillary tube 40 , the solution in the capillary tube 40 is possibly atomized by the radiant heat from the heater 56 , as shown in fig9 . in this case , the aerosol x is generated independently of the user &# 39 ; s inhalation , with the result that the solution in the liquid tank 20 is wasted . thus , in the case of the aerosol inhalator of this embodiment , the discharged solution l fails to be atomized , that is , the aerosol fails to be generated , or waste of the solution is unavoidable unless the relationships indicated by the expressions ( 1 ) and ( 2 ) are fulfilled and also the heating temperature of the outer surface of the heater 56 is kept within an appropriate temperature range . specifically , it is necessary that the relationships indicated by the expressions ( 1 ) and ( 2 ) be fulfilled and also that , where the solution is propylene glycol , the heating temperature of the outer surface of the heater 56 be kept within a temperature range of 180 to 280 ° c . the aerosol inhalator of the embodiment does not include a control circuit for controlling the heat generated by the nichrome wire 58 . thus , in order to keep the heating temperature of the outer surface of the heater 56 within the above temperature range , the thickness ( volume ) of the sheath element 60 needs to be properly set . if the sheath element 60 has a larger thickness , it takes a longer time for heat to transfer from the nichrome wire 58 to the outer surface of the heater 56 via the sheath element 60 , and since the area of the outside surface of the sheath element 60 increases , the amount of heat radiated from the sheath element 60 also increases . thus , it is thought that the larger the thickness of the sheath element 60 , the lower the heating temperature of the outer surface of the heater 56 becomes . in order to confirm such lowering of the heating temperature of the outer surface of the heater 56 , the inventors hereof prepared heaters 56 a to 56 g which differed from one another only in the thickness of the sheath element 60 . the sheath elements 60 of the heaters 56 a to 56 g had thicknesses progressively increasing in order of 56 a to 56 g each by a fixed increment . fig1 illustrates a heating test apparatus for a heater 56 x ( x represents any one of a to g ). the heating test apparatus includes a power feed circuit 66 for applying a voltage to the heater 56 x , and the power feed circuit 66 includes a direct - current power supply 68 capable of varying the applied voltage , a shunt resistor 70 ( 1 mω ), and a voltmeter 72 . the heater 56 x is connected in series with the shunt resistor 70 . further , the heating test apparatus includes a temperature sensor 74 , which is capable of measuring the temperature of the heater 56 x , that is , the temperature of the outer surface of the sheath element 60 . specifically , the temperature sensor 74 includes a type k thermocouple . when the heater 56 x is connected to the power feed circuit 66 as illustrated in fig1 , a voltage is applied from the direct - current power supply 68 to the nichrome wire 58 of the heater 56 x , so that the nichrome wire 58 generates heat . the heat generated by the nichrome wire 58 is transferred through the sheath element 60 , thus increasing the temperature of the sheath element 60 , and on the other hand is released to the outside from the outer surface of the sheath element 60 . consequently , the heating temperature of the outer surface of the sheath element 60 is determined by a difference between the amount of heat generated by the nichrome wire 58 and the amount of heat released from the sheath element 60 , and the rate of temperature increase of the outer surface of the sheath element 60 is determined by the rate of heat transfer through the sheath element 60 . a heating test was conducted on the heater 56 x in such a manner that with the applied voltage , applied to the nichrome wire 58 from the direct - current power supply 68 , sequentially varied within a range of 0 . 8 v to 1 . 6 v , the heating temperature of the outer surface of the sheath element 60 was measured by the temperature sensor 74 with respect to each of the applied voltages of the nichrome wire 58 . the measurement results are shown in fig1 . as is clear from fig1 , the outer surface of the sheath element 60 of the heater 56 x is heated to a higher temperature as the voltage applied to the nichrome wire 58 increases . considering , however , ordinary use of the aa size cell 26 which is expected to apply a voltage of 1 . 0 v to 1 . 5 v , the heater 56 f alone is capable of keeping the heating temperature of the outer surface of the sheath element 60 within the aforementioned temperature range ( 180 to 280 ° c .) this means that where the heater 56 f is used as the heater 56 of the aerosol inhalator 10 of the embodiment , the heating temperature of the outer surface of the heater 56 can be kept within the required temperature range without the need to use a control circuit for controlling the voltage applied to the nichrome wire 58 . since the aerosol inhalator 10 need not be provided with such a control circuit , the load on the cell 26 is reduced , whereby the aerosol inhalator 10 can be used for a long period of time . further , the use of the cell 26 serves to make the aerosol inhalator 10 smaller in size and slenderer , improving handiness of the aerosol inhalator 10 . if , on the other hand , the user inhales in a situation where the heating temperature of the outer surface of the heater 56 is lower than the aforementioned temperature range due to voltage reduction of the cell 26 , the solution discharged from the capillary tube 40 may be insufficiently atomized and part of the discharged solution may possibly adhere to the inner surface of the inner tube 22 . further , it is also conceivable that even though the heating temperature of the outer surface of the heater 56 is kept within the aforementioned temperature range , the generated aerosol condenses on the inner surface of the inner tube 22 , with the result that the solution adheres to the inner surface of the inner tube 22 . in such cases , as the user inhales , the adherent solution may move toward the mouthpiece 14 and possibly flow into the user &# 39 ; s mouth . however , since the absorbent sleeve 48 , which is a paper tube or paper filter , is arranged between the inner tube 22 and the mouthpiece 14 , the adherent solution , if moved toward the mouthpiece 14 , is reliably absorbed into the absorbent sleeve 48 and does not flow into the user &# 39 ; s mouth . the present invention is not limited to the aerosol inhalator 10 of the foregoing embodiment and may be modified in various ways . as regards the heater 56 , for example , the resistance heating element is not limited to nichrome wire , and the cross - sectional shape of the heater 56 is not limited to circle and may instead be ellipse , polygon or the like . the sheath element 60 may be made of metal and , as shown in fig1 by way of example , may have a rough outer surface 66 formed on at least a portion thereof where to receive the discharged solution , in place of the aforementioned net 64 . the rough outer surface 66 is constituted , for example , by a large number of narrow annular grooves spaced from each other in the axial direction of the sheath element 60 , and when the discharged solution is received on the outer surface 66 of the sheath element 60 , the annular grooves serve to spread the discharged solution , like the net 64 . further , where the sheath element 60 of the heater 56 and the inner tube 22 are to be made of the same ceramic , the sheath element 60 and the inner tube 22 are preferably formed as a one - piece molded article , and in this case , the number of parts of the aerosol inhalator can be reduced .

an aerosol inhalator of the invention has an inner tube forming part of a suction path , a capillary tube extending within the inner tube and configured to discharge a solution therefrom in conjunction with a user &# 39 ; s inhalation , and a heater extending in a direction perpendicular to the axis of the inner tube so as to traverse the inner tube and configured to receive the solution discharged from the capillary tube , wherein the heater atomizes the received solution by heating to generate , inside the inner tube , an aerosol to be inhaled by the user .

in the present invention , it is shown that integrase mj1 of φfc1 from enterococcus faecalis also functions in human cells as well as e . coli . on extrachromosomal vector system , each plasmid which has attp , attb and integrase mj1 coding sequence was constructed and cotransfected into human cell line hek 293t ( fig1 ). the site - specific integration and excision reaction in trans , in the presence or absence of mj1 , was monitored by green fluorescent protein ( gfp ) as a reporter . plasmids that carry attb ( pcb ) gene and integrase mj1 coding gene ( pcmj1 ) have cytomegalovirus ( cmv ) promoter . however , plasmid ( pgp (−)) harboring both attp and gfp couldn &# 39 ; t express gfp because it does not have cmv promoter , so recombinant plasmid ( prec - i ) could not be created . in this way , site - specific excision reaction could be observed when attp and attb is replaced with attl and attr . in addition , it was confirmed that mj1 integrase functions in human cell without any accessory factors on an extrachromosomal vector based system , and efficiency of integrase mj1 was the better for no excision . also , several hundred base pair of att site could be reduced to about 50 bp . in the present invention , attp means the attachment site of the bacteriophage ( 739 bp ) and attb means the attachment site of the bacterium ( 290 bp ). and , attl and attr mean the left region ( 404 bp ) and the right region ( 624 bp ) which are created by site - specific recombination between attp and attb . to clone the attb , a genomic dna of the indicator strain of bacteriophage φfc , enterococcus faccalis kbl707 strain ( accession no . kfcc 12177 ) deposited with korean culture center of microorganisms ( kccm ), was used as a template of pcr . as for attl and attr , a genomic dna of kbl703 strain ( kim et al . mol . cells 4 ; 155 - 158 ) of which chromosome was integrated with bacteriophage φfc was used as a template of pcr . as for attp , pfe1 which is inserted with 7 . 7kb of φfc1 dna ( kim and y . w . 1999 . genetic studies of bacteriophage fc1 from enterococcus faecalis . ph . d . thesis . korea university . korea ) was used as a template of pcr . in the present invention , the base sequence of mj1 gene was shown in seq id no . 1 and the amino acid sequence of mj1 integrase was shown in seq id no . 2 . further , the base sequence of the attp gene was shown in seq id no . 3 and the base sequence of the attb was shown in seq id no . 4 . detection of minimal size at attp and attb site is valuable for taking advantage of efficiency strategy for gene therapy . full length of 739 bp attp and 290 bp attb , already reported , are so long to utilize of useful gene therapy . therefore nested deletion of attp and attb was performed based on mj1 binding site at att to find the minimal size of aft site . these results demonstrate that efficient minimal size of attp and attb is 54 ( 160 - 233 of seq id no . 3 ) and 48 bp ( 66 - 113 of seq id no . 4 ), and that the size is enough functional to integration by mj1 . in the concrete examples of the present invention , the bacterium and bacteriophage were cultured , the plasmids containing mj1 gene , attp or attb site were constructed , human fetus kidney cell line 293 was cotransfected with the plasmids , fluorescence activity of gfp reporter was measured , rt - pcr of mj1 gene was performed in animal cell , facs analysis was carried out , and integration of attp and attb and excision of attl and attr was confirmed . the present invention now will be described in greater detail by means of the following examples . the following examples are for illustrative purpose and are not intended to limit the scope of the invention . enterococcus faecalis kbl703 strain and kbl707 strain ( accession no . kfcc 12177 ) were cultured in todd hewitt broth ( thb : difco co . u . s . a ) at 37 ° c . without shaking . e . coli ( dh5α ) was cultured in lb at 37 ° c . with shaking . temperate bacteriophage φfc1 was inducted from enterococcus faecalis kbl703 with uv - radiation and purified . the bacteria strains and plasmids used in this invention was listed in the below table 1 . to synthesize the mj1 intergrase gene of about 1500 bp , attb gene of 290 bp and attl gene of 347 bp , pcr reactions were performed using dna of bacteriophage cpfc1 and genomic dna of kbl707 and kbl703 as templates and primers shown in the below table 2 . the pcr products were subcloned between bamhi and ecori sites or hindiii and bamhi sites of pcdna3 ( invitrogen carsbad , calif .) to construct pcmj1 ( fig1 c ), pcb ( fig1 a ) and pcl ( fig1 d ). plasmid pg (−) was created by deleting its small ndei - bgiii fragment from pegfp - n1 ( clontech , palo alto , calif .) and blunt - end self ligation using klenow treatment . plasmids pgp (−) ( fig1 b ) and pgr (−) ( fig1 e ) were made by subcloning the attp and attr pcr products amplified with primers shown in the below table 2 . synthetic oligonucleotides used as primers in this invention are listed in table 2 . human embryonic kidney 293t cells ( american type culture collection , manassas , va .) were grown in dulbecco &# 39 ; s modified eagle &# 39 ; s medium ( dmem ) supplemented with 10 % heat - inactivated fetal bovine serum ( fbs ) and 100 u / ml penicillin in 100 - mm plates . cells were split into eight six - well culture plates or 60 - mm plates and grown , until they were about 50 % confluent . plasmids prepared in example 2 that carry attp , attb and mj1 coding sequence were transfected in equimolar amounts ( 6 μg or 3 μg of total dna ) by using the calcium phosphate method . the transfected cells were grown on cover slip placed in a six - well culture plates . after 72 h incubation the cells were examined under the confocal fluorescence microscope ( zeiss ) for the expression of gfp . the efficiency of transformation was determined by the percentage of fluorescing cells in the transfected cells . total rna was extracted from pcmj1 transfected 293t cell using trizol reagent ( invitrogen ). reverse transcription and pcr amplification were performed using superscript ii rnaseh - reverse transcriptase ( invitrogen ) and pfu dna polymerase ( promega ). the level of expression of gapdh gene served as internal control and the sequences of the primers were described in table 2 . pcr was performed for 25 cycles at 94 ° c . for 5 min , 94 ° c . for 20 s , 52 ° c . for 30 s , and 68 ° c . for 40 s . the pcr products were analyzed on a 1 . 5 % agarose gel and stained with ethidium bromide for visualization . as shown in fig2 , expression level of mj1 mrna was elevated considerably as compared to that of the internal control gene gapdh . the pcr generated a 320 bp product with specific primer pair for the mj1 coding region ( fig2 ). rt - pcr showed that integrase mj1 is ectopically expressed in human cell . facs was performed for the expression of gfp . 72 hr post - transfection , cells were harvested , resuspended with 3 ml of 5 mm edta / pbs and washed twice , and then fixed in 300 μl of 0 . 1 % bsa and 0 . 05 % nan3 / pbs . facs was performed on a facscan analysis ( becton dickinson immunocytometry systems ) using the cellquest program ( becton dickinson ). below , the experimental result which verifies the result of the above - mentioned examples of this invention is disclosed . different constructs could monitor either the integration reaction ( attp × attb ) or the excision ( attl × attr ). to determine effect of mj1 on the reaction of integration , 293t cells were cotransfected with plasmids pcb and pgp (−), together with pcmj1 or without pcmj1 . after 72 hr , cells were observed by confocal microscope . in the case of plasmid prec - 1 ( fig1 f ) created by mj1 - mediated integration , expression of gfp only occurred ( fig3 a ). in contrast , gfp expression was not observed in the cell cotransfected without mj1 expectably ( fig3 b ). to show that each cases was not owing to promoter , cells that were transfected with plasmid pgp (+) or pgp (−) with or without cmv promoter , respectively , were also observed by confocal microscope ( fig5 c and 5d ). as expected , gfp expression was not investigated in cell transfected with only pgp (−). to search integration efficiency , the 293t cells were transfected with plasmids pcb and pgp (−) together with or without mj1 expressing plasmid pcmj1 and 72 hr after transfection the cells underwent a facs analysis . histogram plots that depict the fluorescence of transfected cells in the absence or presence of mj1 are shown in fig4 a and 4b . cells transfected with plasmids that carry att sites along , in the absence of mj1 , showed a fluorescence of 396 cells ( fig4 a ). in contrast , in the presence of mj1 the cell number of fluorescence was 1237 in the integration reaction , so their gap came up to about 4 times as shown fig4 c . in the case of excision , plasmids that carry attr ( pgr (−)) and attl ( pgl ) instead of pgp (−) and pcb were cotransfected into 293t cell . as a result , gfp expression was not observed in contrast to integration ( fig5 a ). to prove that the result was not caused by promoter , cells transfected with plasmid pgr (+) or pgr (−), with or without cmv promoter , respectively , were observed by confocal microscope . pgr (+), but not pgr (−) showed gfp activity ( fig5 b and 5c ). this result means that putative recombinant plasmid prec - e ( fig1 g ) was not created by mj1 . it is shown that mj1 - catalyzed excision does not occur between attl and attr . it is demonstrated that mj1 mediates site - specific integration between attp and attb efficiently in human cell on an extrachromosomal vector base , but mj1 - catalyzed excision does not occur between attr and attl . before this invention , no information about minimal size of attb and attp sites on which the mj1 functions had been reported . to minimal functional sizes for these att sites , site - specific integration assay system described above was performed using nested set of deletion clones of attb and attp ( fig6 ). each plasmid that carries deleted site bearing 3 bp conserved core sequences was made by nested deletion centering around the site known for mj1 binding . short double - stranded adaptor molecules containing att sites of various lengths were created by annealing single - stranded oligonucleotides . these deleted sites were used to replace the full - length att sites in the pgp (−) and pcb plasmids , the plasmids were cotransfected with or without pcmj1 and integration efficiencies were determined by facs analysis . as a result , integration efficiency owing to size of attp and attb site was indicated as fig7 . the discrepancy of cell that transfected with or without plasmid pcmj1 was graphed to % numerical value . the integration efficiency was not been decreased in proportion to reduction attp and attb site . however , the efficiency of integration was gradually decreased from integration efficiency between 54 bp attp and 48 bp attb . in the final analysis , almost integration functions were lacked between 50 bp attp and 44 bp attb . these results demonstrate that efficient minimal size of attp and attb is 54 ( 160 - 233 of seq id no . 3 ) and 48 bp ( 66 - 113 of seq id no . 4 ), and that the size is enough functional to integration by mj1 . integrase mj1 has lots of advantage to construct gene transfer system than any other viral vector or existing gene transfer system . first , mj1 does not need any requirements for e . faecalis - specific cofactor for site - specific integration . in contrast , λ integrase requires ihf for both type of recombination and ihf is required in many types of recombination , including that of phage hk022 and hp1 ( dorgai et al ., ( 1998 ) j . mol . biol ., 277 , 1059 - 1070 ). this invention demonstrates that site - specific integration in human cell occurred between attp and attb with only integrase mj1 without any cofactor as observing gfp expression . second , unlike other integrases ( recombinases ) from phage which mediate both integration and excision , integrase mj1 was shown to only have integration function . it was reported that integrase ( recombinase ) from phage hk022 could perform both integrative ( attp / attb ) and excisive ( attl / attr ) recombination in mouse nih3t3 cells ( kolot et al ., ( 1999 ) mol . biol . rep ., 26 , 207 - 213 ). in this invention , mj1 only mediates the integration function , and that integrated gene was not excised from host genome , so desired gene could be expressed continuously . third , it was shown that 48 - bp and 54 - bp minimal sizes for the attb and attp sites enabled mj1 to mediate the integration . it appears that this integration may be done at naturally occurring pseudo - att sites in eukaryotic genomes having significant similarity to native att sequences ( thyagarajan et al ., ( 2000 ) gene , 244 ). the expected rarity of good matches with att sites may limit recombination to a small number of chromosomal pseudo - att sites , which may produce usable integration frequencies at endogenous locations in the chromosomes . besides these advantages , mj1 - mediated site - specific integration system is profitable for development of gene transfer system . the probability that has an effect on expression of essential genes or / and on interference of host cell mechanism was decreased certainly because this system get inserted gene to integrate into pseudo - site on host genomic dna . also integrase from phage could transfer more than ten kilo - base pair of insertion gene into target site , allowing for the several tens of kb - sized of phage congestion , because phages can transfer integrated their whole phage genome into bacterial genome using its integrase by nature .

the present invention relates to a recombinant vector comprising mj1 gene coding an integrase derived from enterococcus temperate bacteriophage φ fc1 and an integration method using the vector . more particularly , the present invention relates to a recombinant vector comprising mj1 gene which can make a site - specific integration in the human cell independently without other factors but not cause an excision and an integration method using the vector . therefore , the present invention can be very useful in gene therapy in mammalian animal .

a surgical manipulation instrument according to the present disclosure , which is especially suited for use in minimally invasive surgery , comprises an extra - corporeal drive device 10 . the same may , in particular , comprise one or a plurality of electric motors and transmissions whereby actuation elements 12 ( fig2 ) are displaced in the axial direction ( arrows 14 ). in the embodiment illustrated , the first actuation elements 12 are in the form of rods . however , they may also be cables via which only pulling forces are transmitted . further , the surgical manipulation instrument comprises a manipulator part 16 ( fig1 ). within a tubular shaft 18 , rod - shaped second actuation elements are arranged . these are adapted to be displaced in the longitudinal direction 20 . the second actuation elements are connected with an end effector 22 . displacing the second actuation elements thus causes a manipulation of the end effector . again , the second actuation elements may be rod - shaped actuation elements , but also actuation cables . a coupling device 24 is provided for the connection of the first actuation elements 12 and the second actuation elements arranged in the tubular shaft . in a first preferred embodiment ( fig3 and 4 ) the first actuation elements 12 indicated in fig2 are formed as three rods extending in parallel with each other . first coupling elements 26 are provided at the ends of the rods . the coupling elements 26 each have a pin - shaped projection 28 . in the embodiment illustrated , the pin - shaped projection 28 is cylindrical and projects outward under an angle of 90 degrees with respect to the longitudinal axis of the first actuation element 12 . as obvious in top plan view ( fig3 , right hand side ), the three cylindrical projections 28 are distributed uniformly and thus take on an angle of 120 degrees to each other . in the embodiment illustrated , second coupling elements 30 have a pivot arm 32 . the pivot arm 32 comprises two arm parts 34 extending in parallel with each other so that a bifurcated recess 36 is formed . as described hereinafter , the bifurcated recess 36 receives the pin - shaped projection 28 of the first coupling elements 26 . the pivot arm 32 is rigidly connected with a disc - shaped element 38 of the intermediate element 32 . in the embodiment illustrated , the disc element 38 has a groove 40 in which a cable 42 is arranged . for reasons of clarity , the latter is illustrated only at one of the discs . when the disc element 38 is rotated in a corresponding sense , the cable 42 is pulled . the cable 42 corresponds to the second actuation device or is at least connected with the same . in order to close the coupling device , all the three first actuation elements 12 are rotated together clockwise , seen in top plan view ( fig3 , right hand side ), so that the projections 28 of the individual coupling elements 26 engage the corresponding bifurcated recesses . after the coupling of the coupling elements 26 , 30 , the first actuation elements 12 are adapted to transmit forces onto the second actuation devices 42 by displacement of the former in the direction of an arrow 44 ( fig4 ). since , in the embodiment illustrated , the second actuation device 42 is a cable , only pulling forces can be transmitted . if , for example , the first actuation element 12 is shifted to the right in fig4 , the disc element 48 is rotated clockwise and thereby the only second actuation device 42 illustrated in fig4 is pulled . the three pivotable intermediate elements 32 of the embodiment illustrated are held in a manner pivotable about pivot axes 48 in a housing 46 illustrated only in part . in another preferred embodiment of the disclosure ( fig5 and 6 ) identical and similar components are identified by the same reference numerals . the first actuation elements 12 are again rod - shaped and have projections 28 that have a different spatial arrangement due to the arrangement of the second coupling elements 30 . the bifurcated recesses 36 of the coupling elements 30 , numbering three in this embodiment , are arranged one behind the other in the embodiment illustrated in fig5 . accordingly , the lower first actuation element 12 in fig5 has a projection 28 that protrudes from the plane of the drawing . behind this actuation element 12 , a further first actuation element 12 is arranged , whose projection 28 is directed in the opposite direction . the third actuation element 12 , which is the top element in fig5 , has a projection 28 extending in both directions , which , however , as a shorter length . this projection 28 engages into the central bifurcated opening 36 in fig6 . in the coupled stat , a displacement of the first actuation elements 12 in the longitudinal direction 14 causes the pivot arm 32 to pivot about a pivot axis 50 . in the embodiment illustrated , the pivot axes 50 of all intermediate elements 32 are coaxial . in the embodiment illustrated in fig5 and 6 , the intermediate element 32 is rigidly connected with a respective connecting arm 52 . in the embodiment illustrated , the connecting arm 52 of the intermediate elements 32 is at a right angle with respect to the pivot arm 32 . the connecting arm 52 is connected with two cables . this is particularly visible for the upper connecting arm 52 in fig6 that is connected with the two cables 54 , 56 . the two cables 54 , 56 are connected to the connecting arm 52 on different sides . thereby , depending on the sense of rotation of the intermediate element 32 , the one or the other cable 54 or 56 is pulled . when the intermediate element 32 in fig6 is pivoted clockwise , the cable 54 is pulled . the latter is passed over a guide roller 58 and is connected with a second actuation element or passes into the second actuation element . when the intermediate element 32 is pivoted counterclockwise ( fig6 ), the cable 56 is pulled . the latter is guided over two guide rollers 60 , 62 and then extends in parallel with the cable 54 . depending on the direction of displacement of the first actuation element 12 in the axial direction , the cable 54 or 56 is pulled . in this embodiment , both directions of movement of the first actuation elements can be used even if cables are provided . in the embodiment illustrated the two other intermediate elements are each also connected with two cables that are also guided over guide rollers . as such , six cables are provided via which pulling forces can be transmitted directly or indirectly to elements of the end effector 22 ( fig1 ) with interposition of second actuation elements . in another embodiment of a coupling device for a surgical manipulation instrument , actuation element pairs are again provided , wherein the first actuation elements 12 are also rod - shaped . in the embodiment illustrated , the second actuation elements 64 are rod - shaped as well . corresponding to the above described embodiment , the first actuation elements 12 are connected with the drive device 10 illustrated in fig1 and 2 and the second actuation elements 64 are connected with the end effector 22 . the embodiment illustrated in fig7 and 8 is an independent disclosure . in this embodiment , the connection of the actuation element pairs 12 - 64 is effected by screwing . to this end , the second actuation elements 64 comprises a pin - shaped projection 66 fixedly connected with the second actuation element . the pin - shaped projection 66 is connected with a connecting sleeve 68 having an female thread and adapted to be rotated . the first actuation elements 12 comprise a pin 70 with a male thread at their end directed towards the second actuation element 64 . by rotating the connecting sleeves 68 about their longitudinal axis , it is possible to screw , i . e . couple the actuation element pairs 12 - 64 together without rotating the same . in order to connect the element pairs 12 - 64 , numbering three in the embodiment illustrated , simultaneously , an inner ring 72 similar to a sun wheel is provided which , in the embodiment illustrated , surrounds the connecting sleeves 68 , which have an external toothing , and , in the coupled position , meshes with the teeth of the connecting sleeves . the sun wheel 72 has a female thread cooperating with a thread provided on the outside of the sleeves 68 . thus , by rotating the inner ring 72 , the actuation elements 12 , 64 are screwed together . in order to allow as fast an opening and closing of the screw connection as possible , an outer ring 74 is provided in the manner of a hand wheel surrounding the sun wheel 72 . at least one , preferably three transmission gears 76 are provided as planet wheels between the two rings 72 , 74 , which mesh with a toothing provided on the inner side of the hand wheel 74 and with a toothing provided on the outer side of the sun wheel 72 . in order to compensate for manufacturing tolerances , an elastic compensation element is provided between the actuation element 12 and the connecting sleeve 68 , against which compensation element the connecting sleeves 68 are tightened by rotating the sun wheel 72 .

a surgical manipulation instrument which is particularly suitable for minimal invasive surgery , comprising an extra - corporeal drive device to which several axially displaceable first actuation elements are connected . the disclosure also relates to a partial intra - corporeal manipulator part which comprises several axially displaceable second actuation devices for actuating an end effector . pairs of actuation elements are detachably connected together by means of a coupling device . a pivotable intermediate element is provided between the second coupling element and the second actuation element .

referring to fig1 and 2 , the harness 100 of the present invention is described . this harness 100 comprises a rigid and non - flexible frame 101 which is formed as a rigid arch . at each end of the frame there is provided a medial rigid support 103 and a lateral rigid support 102 . the distance between the ends is fixed or adjustable . the harness 100 further comprises two resilient clamping means , 116 and 117 as shown in fig2 a and 2 b , each of them comprising a rigid housing 104 and 105 in which there is retained two rigid abutment elements 106 and 107 each having an outer end configured to fit the shape of a condyle . springs 118 and 119 , or any other resilient means , apply an outward force on the abutment elements . at least one of the clamping means 116 or 117 could be secured to rigid supports 102 or 103 by adjustable means , e . g . in sliding fit adjustment in a cavity 120 formed in rigid support 102 . this adjustable means is hereinshown as being an adjustment screw 121 having a finger gripping head 122 . the springs 118 and 119 are also interchangeable to vary the force of the abutment elements 106 and 107 . the harness 100 further comprises a non - resilient adjustable stabilising element 123 comprising a threaded rod 113 having an abutment pad 111 at an outer end thereof . this stabilising element 123 is being secured to a support frame 112 , which support frame 112 is connected to the rigid frame 103 by adjustable means herein a screw attachment 115 . the position of the pad 111 is adjusted by an adjustment wheel 114 . the harness 100 further comprises an attachment means in the form of a bar 108 . this attachment bar 108 is in the form of a long narrow flat plate and could be formed of two sections interconnected by a hinge 109 or by a pivot . the attachment bar 108 could be secured by a velcro ™ strap 110 or by other attachment means above the knee of the wearer . referring now to fig3 , the tibial attachment means is described . this attachment means comprises a tibia attachment bar 124 secured below the knee by means of two adjustable velcro straps 125 and 126 , or by other attachment means . this attachment bar 124 is also in the form of a long narrow flat plate . referring to fig1 , 4 a and 4 b , the installation of the harness 100 on knee 127 is described . the harness 100 is installed on the knee 127 by urging the abutment elements 105 and 107 of the clamping means 116 and 117 against the skin at predetermined sites 128 and 129 on the knee . these predetermined sites are located medially between the vastus medialis 130 and the sartorius tendon 131 of the knee and laterally between the ilio - tibial band 132 and the biceps femoris tendon 133 of the knee . the harness 100 is thereafter secured proximally , rigidly attaching the attachment bar 108 against the medial side of the thigh and securing this attachment bar by means of the velcro ™ strap 110 . without affecting subject &# 39 ; s comfort , the harness stability is adjusted by means of the adjustable screw wheel 114 as well as the adjustment of the abutment element 106 by rotating the head 122 . the abutment pad 111 of the stabilising element 123 is urged against skin in alignment with the centre of the medial condyle 128 . referring to fig3 , 4 a and 4 b , the installation of the tibial attachment on the knee 127 is described . the tibia attachment bar 124 is installed by adjusting its position so that the bar 124 urges on the anterior side of the tibia , below the tuberosity 134 of the tibia 135 , securing the tibia attachment bar 124 below this tuberosity by means of the adjustable straps 125 and 126 . referring to fig5 , 6 , 7 a and 7 b , the method for analysing the three - dimensional kinematic of a knee will be described . a harness 100 and the tibial attachment bar 124 are provided with localising sensors 136 , 137 or 141 on the femur of the knee and on the tibia . the localising sensors are designated by reference numeral 136 , 137 and 141 and can be of different types , herein illustrated are electromagnetic sensors 137 , opto - electronic sensors 136 , and ultrasonic sensors 141 . these sensors are incorporated in a system to provide data on their three - dimensional positions or their three - dimensional positions and orientations , with respect to an external reference , or with respect to one another . fig6 illustrates an example of the position of opto - electronic sensors 136 on the harness 100 . their positions are tracked using a camera ( not shown ). when using the ultrasonic sensors 141 , their positions are tracked by ultrasound tx / rx methods . their three - dimensional position and orientation can also be determined by their relationship to one another . when using electromagnetic tracking sensors 137 their three - dimensional position and orientation is tracked with electromagnetic field emitter / receiver methods . the harness 100 and the tibial attachment bar 124 are installed on the knee to be analysed . a knee posture is adopted or movement of the knee is performed . this movement could consist of walking , or walking on a treadmill , or bending and / or stretching the knee . . . the movement could be guided by a person or by an apparatus . data is generated by the localising sensors 136 , 137 , and 141 and the data is treated and analysed by computerised program means 138 or equivalent electronic means . the treatment of the data could reside in the calculation of mathematical relationships relating the femur with the tibia in space during time . these relationships could be calculated with the definition on the femur and on the tibia of a coordinate system representing the location of the femur and the tibia , respectively . this latter definition could be accomplished on computerised models which are thereafter calibrated on real bones . the mathematical relationships , rotations , translations , helicoïdal axis , . . . etc are used to calculate knee movement indexes data 139 used in the description of the posture , or the movement of the knee . briefly summarising the method of determining the kinematic of a knee in a non - invasive manner comprising the harness of the present invention , the method comprises attaching the harness about a knee femur in the manner as above described and securing the tibial attachment bar to the knee tibia in a fixed relationship . data is generated by the localising sensors secured to the harness and the tibial attachment bar . this data localises the sensors in space and in time . the location of the sensors is detected at specific time intervals to provide location data at the time intervals . this data is treated , analysed and resulting data is generated which describes the knee to which the harness and tibial attachment means is secured . in installing the harness about the knee care is taken to place one of the clamping means between the vastus medialis and the sartorius tendon of the knee . the other clamping means is positioned between the ilio - tibial band and the biceps femoris tendon of the knee . the attachment rod which is connected to the harness is placed against the medial side of thigh and attached by means of straps above the knee . the stability of the harness is verified even after the knee has been flexed a few times . the position of the stabilising element on the medial side is adjusted so that one extremity urges against the skin in alignment with the centre of the condyle when the knee is in extension . the position of the attachment means is adjusted so that it urges on the interior side of the tibia below the two tuberosity of the tibia and it is attached below the two tuberosity of the tibia . the measurements are taken when the knee is in movement and this is achieved by walking on a floor surface or walking on a treadmill or jumping at least one or a few times , or bending the knee at least once or stretching the knee at least one time . the movement is guided by a person or an apparatus . the analysis of data consists of defining a coordinate system relative to the group of sensors fixed to the harness , and defining a coordinate system relative to the group of sensors fixed on the tibial attachment rod . the mathematical relationship between the coordinate systems one to another is then calculated . the measurement is effected by a computerised three - dimensional representations of the femur and tibia and these representations are calibrated in order to be accurately positioned and oriented relative to real femur and tibia bones . the mathematical relationship is defined by rotations and translations to the femur and tibia with respect to one another as well as a finite helicoïdal axis of the knee . the resulting data represents euler angles and distances described at predetermined time intervals . the resulting data not only represents three - dimensional orientations and positions of finite helicoïdal axis of the knee but also angle of rotation around the helicoïdal axis and translation along the helicoïdal axis described at predetermined time intervals . the tibial attachment bar 124 is composed of a rigid rod approximately 3 cm wide , 25 cm long and 3 mm thick . it is within the ambit of the present invention to cover any obvious modifications of the preferred embodiment described herein , provided such modifications fall within the scope of the appended claims .

a harness for attachment about a knee femur and comprised of a rigid and non - flexible frame support two resiliently mounted clamping means and sensors is described for the non - invasive measurement of knee motion and its analysis in 3 - d is described . the clamping means elements are urged under pressure outwardly for application against a skin outer surface at predetermined medial and lateral sites relative to a femur . a non - resilient adjustable stabilizing element is connected to the rigid frame and disposed at a predetermined location with respect to the medial clamping element in spaced relationship therewith and adjustable for clamping contact on a skin outer surface and in alignment with the center of a medial condyle of the femur whereby to stabilize the rigid frame about a knee . an attachment rod is secured to the harness and has straps for securing the rod above the knee .

referring now to the drawings , the details of exemplary embodiments of the present invention are schematically illustrated . like elements in the drawings will be represented by like numbers . referring to fig2 a , a front elevation view of an intraocular lens with optic 210 and haptic 218 is illustrated . a plan view of the lens and haptics is shown in fig2 b . the lens may have side plates 212 , orientation tab 213 and foot plates 214 . fig3 a shows optic 210 with its haptics fitted onto lens holder 230 . lens holder 230 has base 232 and legs 234 and 236 . the legs have channels 235 and 237 , respectively , within which lens haptics 218 are placed to secure the lens for shipping , as illustrated in fig3 b . fig3 c shows a front elevation view of optic 210 as it sits within the legs of lens holder 230 . lens holder 230 may be adapted for any lens or other device that is to be folded and inserted through an opening or incision into a patient . fig4 a illustrates lens folding guides 220 and 222 . right folding guide 220 has shoulder 221 and semi - cylindrical concave inner face 228 . left folding guide 222 may be a mirror image of right folding guide 220 , with the former having shoulder 223 and semi - cylindrical concave face 226 . lens folding guides 220 and 222 may have keys 224 , which are used to keep the folding guides oriented correctly during transition from the shipping mode to the injection mode , as described below . fig4 b shows the folding guides 220 and 220 in the injection mode , with the folding guides moved together . by forcing folding guides 220 and 222 together , respective concave faces 228 and 226 may force a lens to deform into a round cylinder , much like rolling one &# 39 ; s tongue . in any case , a lens is deformed into a cylinder that is small enough to be inserted through an incision in an eye . if needed , friction - reducing additives may be used on surfaces to reduce friction as a lens or other device is deformed for insertion or is displaced from the folding guides . fig5 shows driving cam 240 . driving cam 240 has internal shoulders 241 and 243 that may be constructed and arranged to fit slideably against shoulders 221 and 223 of folding guides 220 and 222 ( fig4 a ). driving cam 240 may have sides 244 and 246 that fit within a body , and two or more detent tabs 248 . fig6 a is a front elevation view of “ u ” shaped body 250 . body 250 has a bottom 252 and sides 254 and 256 that mate with the sides 244 and 246 , respectively , of driving cam 240 ( fig5 ). each side 254 and 256 is fitted with openings 258 and 259 into which the detents 248 of driving cam 240 fit . body 250 has openings 255 within bottom 252 ( fig6 b ). openings 255 are constructed and arranged to accommodate legs 234 and 236 of lens holder 230 . lens holder 230 may have any shape adapted to hold a foldable medical device . front and back members 260 of body 250 may have attached thereto track guides 225 , which may be disposed to allow key 224 ( fig4 ) to slide between track guide 225 and bottom 252 of body 250 as lens guides ( fig4 ) move to deform an implantable device before it is displaced from body 250 . although folding guides 220 and 222 are illustrated to form a cylindrical - shaped medical device after folding , it should be understood that other cross - sectional shapes may be formed , such as elliptical or rectangular . fig7 a , 7 b , 7 c , 7 d , 7 e and 7 f illustrate by isometric views the assembly and use of lens shipping , storage and injection system 1000 . referring to fig7 a , within injection system assembly 1000 , body 250 is equipped with two rectangular upper shipping mode openings 258 and two rectangular lower injection mode openings 259 . each of openings 258 and 259 can be made of any convenient shape , but are intended to be constructed and arranged to accommodate tab 248 of driving cam 240 ( fig5 ), with one tab 248 within one hole 258 when assembly 1000 is in the shipping mode , and one tab 248 each within one hole 259 when assembly 1000 is in the injection mode . the shape of tab 248 is constructed and arranged to fit within either of the holes 258 and 259 so that the driving cam 240 can be moved from the shipping mode to the injection mode by deformation of either or both of driving cam 240 or sides 254 and 256 of body 250 . while assembly 1000 may be disposable , alternate embodiments may be designed for reloading and reuse . referring again to fig7 a , lens holder 230 may be inserted into body 250 through separate holes in bottom 230 . other shapes of lens holder 230 may be used . as illustrated in fig7 b , optic 210 and haptics 218 may then be placed on lens holder 230 . folding guides 220 and 222 may be placed within body 250 , as illustrated in fig7 c . then , driving cam 240 may be inserted into body 250 , as illustrated in fig7 d until tabs 248 engage in the retaining slots 258 , at which point system 1000 is in the shipping mode . the system may then be placed in a sealed container , which may contain a liquid suitable for storing and shipping the lens . upon receipt of system 1000 by the user , the system 1000 must be transitioned from the shipping mode to the injection mode . to make the transition , the user simply removes lens holder 230 by detaching it from the bottom of the body 250 , as illustrated in fig7 e . once lens holder 230 is detached , the lens is suspended within body 250 between folding guides 220 and 222 . the user then may depress driving cam 240 downward until tabs 248 are engaged with lower slots 259 , as illustrated in fig7 f . in the process of depressing driving 240 , folding guides 222 and 222 are pushed together as illustrated in the lower half of fig7 f . the inner concave shape of folding guides 220 and 222 , within which sits optic 210 , forces lens 210 to fold into a round shape that is suitable for injecting . fig8 a , 8 b and 8 c show cross - sections halfway between front and back of the assembled device of system 1000 . when assembly 1000 is received by the user , the first step in the preparation process is to remove lens holder 230 from body 250 . to do so , the user grasps base 232 of lens holder 230 and pulls lens holder 230 away from the bottom of body 250 so that the legs 234 and 236 of the lens nest 230 are withdrawn through 250 . during the removal step , lens 210 , unable to slip out between the folding guides 220 and 222 , is detached from lens holder 230 and comes to rest within the concave faces 226 and 228 of folding guides 222 and 220 , respectively . referring to fig8 a , base 232 of lens holder 230 is shown at the bottom adjacent to the underside of the body 250 . locking nub 239 may be used to hold lens holder 230 in position within body 250 . detents 248 of driving cam 240 are locked within upper openings 258 of body 250 to secure driving cam 240 in the shipping mode . in fig8 b , lens holder 230 has been removed , as shown in fig7 e . shoulder 223 of folding guide 222 is mated to the shoulder 243 of the driving cam 240 . once lens holder 230 has been removed , the user may press down on the top of driving cam 240 until detents 248 move from upper holes 258 to lower holes 259 . fig8 c shows the apparatus in the injection mode , after the user has moved the detents to the lower holes and the folding guides together . as lens 210 and haptics 212 are now contained within the concave faces 226 and 228 , lens 210 and haptics 212 are rolled into the injection position as folding guides 220 and 222 are brought together . once in the injection mode , an injection device , such as a syringe , can be attached to assembly 200 at one end , and an injection nozzle can be attached to the opposite end so that when the plunger of the syringe is operated , the lens is forced into the nozzle and then into a patient &# 39 ; s eye , as shown in fig9 . referring to fig9 , nozzle 924 may be attached to one end of body 250 and a syringe , such as the stylus type syringe 940 , may be attached to the opposite side of body 250 . syringe 940 may be collinear with folding guides 220 and 222 such that when the plunger of syringe 940 is pressed , a gelled fluid or , alternatively , a silicone - tipped push rod 941 in syringe 940 forces optic 210 into nozzle 924 for injection into a patient &# 39 ; s eye . in another embodiment , only one folding guide may be used . for instance , the concave inner face that was opposing one folding guide , such as guide 222 of fig1 c , can be part of body 250 . consequently , only one movable folding guide ( 220 ) would be needed . driving cam 240 can be modified appropriately to move only one folding guide . the material or materials for the components of system 1000 are preferably capable of withstanding high temperatures , such as those encountered in an autoclave . moreover , the material for the shipping container should be such that it does not leach into the solution surrounding the lens , lest the lens be contaminated by the container material . possible materials include polyolefins , nylon , teflon and other plastics . in another embodiment , a slipping agent ( a material to reduce friction between surfaces ) may be applied to one or more of the components of system 1000 to aid in the transition and / or injection processes . such slipping agent may be any of or a combination of known slipping agents . the body 250 of the system 1000 may contain a solution , such as saline , that provides a suitable environment for a medical implant ( e . g ., a lens ). body 250 may be sealable for shipping , or , instead , body 250 in the shipping mode may be placed within a sealable container for transport to the user . during shipment , system 1000 may or may not have the injection mechanism 924 or the injection actuation mechanism 940 attached to body 250 . an alternative embodiment of the insertion assembly is shown in fig1 . the assembly 2000 for insertion of the lens 210 includes body 350 which is adapted to receive the lens storing and folding assembly , as well as lens holder 230 . as shown in fig1 and 16 , body 350 is similar to body 250 of the first embodiment and includes upper and lower openings 358 and 360 respectively to receive detents 248 of driving cam 240 . body 350 also has openings 355 within its bottom to accommodate legs 234 and 236 of lens holder 230 . body 350 may also have attached thereto track guides 325 , which may be disposed to allow key 224 to slide between track guide 325 and the bottom of body 350 as lens guides 220 and 222 move to fold an implantable device before it is displaced form body 350 . a nozzle 312 extends outwardly from one side of the body and hollow cylindrical casing 315 extends from an opposite side of body 250 . formed integrally with the cylindrical casing 315 is flange member 311 that extends from opposite sides of the casing , which may be slightly arcuate . a resilient ring member 310 also formed integrally with the body portion extends outwardly from arcuate flange member 311 as shown in fig1 . the nozzle 312 , body 250 , casing 315 , flange 311 and ring 310 are preferably of a unitary , one piece construction , made of a suitable nylon material such as vrydyne 21 spf / 21 spg , sold by solutia , inc . however , other suitable materials include polyolefins , other nylons , teflon and other plastics . as shown in fig1 , plunger 314 extends from thumb engaging portion 336 to a cylindrical tip 337 that pushes the ocular device through nozzle 312 . a solid cylindrical portion 332 connects a lower tapered portion 331 with intermediate portion 333 . intermediate portion 333 has a x - shaped cross section . the top portion of the intermediate plunger portion 333 has a flat planar section 339 and a plurality of resilient fingers 334 extending outwardly from the planar member 339 . when the injector assembly is initially assembled , the plunger is inserted through a hole 342 extending through the upper portion of ring member 310 and then into the body portion 315 . in their unflexed state , fingers 334 extend a distance outwardly from portion 333 greater than the diameter of hole 342 . thus as they engage hole 342 , the fingers are compressed inwardly . once they clear the hole , they return to their normal state and prohibit the plunger from being withdrawn from the body portion of the assembly . fingers 334 are compressed inwardly as they enter the upper portion of casing 315 as shown in fig1 . the upper portion of the plunger 335 has a x - shaped cross section and terminates in a circular disk portion 336 which is adapted to be engaged by the thumb of the surgeon . when the top portion 336 of the plunger initially engages ring 310 , the tip 337 is positioned at the entrance of nozzle 312 as shown in fig1 . as the tip portion 337 passes through the outlet of nozzle 312 , a shoulder portion 319 of the plunger abuts a shoulder 318 within casing 315 as shown in fig1 . this prevents further movement of the plunger within the eye . the arrangement of fig1 - 15 allows the surgeon to inject the lens into the lens capsule , preferably using a pulsating technique . this technique involves the surgeon intermittently depressing the plunger and then releasing it . the iol lens is moved along the interior of nozzle 312 in a series of discrete movements prior to being placed in the lens capsule . this overcomes the tendency of the haptics to bind between the nozzle and the cylindrical tip 337 of the plunger as the lens is being inserted . fig1 - 21 illustrate a further embodiment of the invention . as shown in fig1 , the injector 400 includes body 404 which is adapted to receive the lens storing and folding assembly 1000 , hollow cylinder casing 403 , finger engaging ring 402 and spring ring 401 . the body section 404 includes upper and lower slots 406 , 408 that receive flanges 248 on the storing and folding assembly 1000 in the shipping and dispensing modes respectively as explained above . guide rails similar to guide rails 325 and openings similar to openings 355 are also provided in the body 404 . the end face 409 of body 404 includes two l - shaped track members 410 that form a slot 411 for receiving attachable nozzle 500 show in fig1 . l - shaped track members 410 are inclined slightly toward each other at the bottom looking at fig1 and as shown in fig2 in order to provide a snap fit as will be discussed below . leg portions 412 of the track members are also slightly angled back toward end portion 409 . as shown in fig1 , the attachable nozzle assembly 500 includes a flat planar member 503 having a forwardly projecting flange 505 at the top thereof and laterally extending tabs 504 on the lower portion of the planar member 503 . nozzle assembly 500 is formed of a suitable resilient material such as polypropylene so that as the planar member 503 is inserted into slot 411 from above , it will deform slightly to allow tabs 504 to slide through the slot and then expand laterally outwardly beyond the end portions of the lower slot and thus be locked into engagement with the injector 400 . flange 505 prevents further downward movement as the nozzle body snaps into place . nozzle assembly includes a passageway 508 for the medical device which terminates at an outlet 509 . an opening 507 for the passageway is formed in planar member 503 . a further aspect of the invention resides in the provision of slots 502 in the terminal portion of the nozzle as shown in fig1 . this allows the end portion of the nozzle to flex inwardly as it is inserted into the surgical opening in the eye . as mentioned above , this is important due to the fact that smaller incisions are being made in surgical procedures that involve replacing the natural eye lens . the present invention has been described in terms of specific exemplary embodiments . in accordance with the present invention , the parameters for a system may be varied , typically with a design engineer specifying and selecting them for the desired application . further , it is contemplated that other embodiments , which may be devised readily by persons of ordinary skill in the art based on the teachings set forth herein , may be within the scope of the invention , which is defined by the appended claims . the present invention may be modified and practiced in different but equivalent manners that will be apparent to those skilled in the art and having the benefit of the teachings set forth herein .

a shipping system for a medical device , such as implantable lens for an eye , is provided that may be reconfigured from a shipping mode into an injection mode without manually handling the contained lens or other device . upon manufacture , a lens may be placed within the system assembly in the shipping configuration . upon arrival at the destination , the user may attach a nozzle assembly for injecting the device into a body . a new assembly for a medical device utilizing the shipping systems is also disclosed . the insertion assembly includes a body for containing the medical device , a plunger casing , a finger - engaging flange , and a resilient ring member all of which are formed as a single piece assembly . additionally a nozzle assembly may be integrally formed with the insertion assembly or formed as a separate body that is attachable to the insertion assembly .

the preferred embodiment and other embodiments , including the best mode of carrying out the invention , are hereby described in detail with reference to the drawings . further embodiments , features and advantages will become apparent from the ensuing description or may be learned without undue experimentation . the figures are not drawn to scale , except where otherwise indicated . the following description of embodiments , even if phrased in terms of “ the invention ,” is not to be taken in a limiting sense , but describes the manner and process of making and using the invention . the coverage of this patent will be described in the claims . the order in which steps are listed in the claims does not indicate that the steps must be performed in that order . broadly , an embodiment of the present invention generally is an amusement ride system designed to provide interactive play shooting from a moving ride vehicle to interactive targets or other player / ride vehicles . in an embodiment of the present invention , which could be called the “ blammo ” system , the device uses guest operated shooting devices that propel or launch impact safe dry media allowing the guests to see know if their shots are hitting the targets , and creating a kinetic and dynamic ride environment . embodiments of the present invention provide shooting , launching , propelling , or projectile capabilities within the ride vehicle to interactive , fixed , or moving targeting systems using impact - safe projectiles . the system also includes automated conveyers to collect , re - circulating , and transport impact - free projectiles , and to reload each ride vehicle . interactive targeting systems also re - set , shoot back , or activate other devises within the show , setting elements , or ride vehicle track . an embodiment of this device may include the following components or aspects : a ride system ; guest operated projectile shooting / launching / propelling devices ; soft , impact - safe projectiles ; projectile collection , gathering ; conveyors / transporters to deliver the projectiles from the target areas to where they can be loaded onto the ride vehicles ; loading of projectiles onto vehicles , as part of the show ; targets , themed or un - themed ; targets that respond to impact , and reset ; targets in groups that reset after all the targets in the group have been hit ; and target areas that are sloped to allow for the projectiles to drain to a collection area . in an embodiment , the aiming facility might be handles for the user &# 39 ; s hands to rotate the shooting device . the triggering device might be a trigger or button , possibly on or near the handle for the user &# 39 ; s hands , or any other activator . another embodiment includes the vehicles , tracks , targets and / or return system in a package . an embodiment may be an add - on , by adding a media launching device , consisting of a shooting device with an aiming facility and a triggering device , to an existing ride vehicle . embodiments are methods for rides , or for adding - on to rides . an embodiment of the system may have dry media launchers or gun mechanisms incorporated into amusement ride vehicles . these guns may be operated by guests who will activate a triggering device to propel the dry media , which may be called projectiles . the media may be propelled by using a compressed air system , an electrically operated launcher or by other means . the ride environment may include targets that react when impacted by the dry media . the dry media may be impact safe , and possible targets may include other ride vehicles and other guests . embodiments of rides may consist of numerous scenes or target areas . in an alternate embodiment of the invention , each of the target areas may be configured to have the media drain to a collection area , where a conveyor or collection device re - circulates the media to an area where the media can be loaded onto vehicles . an embodiment of the invention can be incorporated into existing or new ride systems by others . the targets and target areas are designed to channel the dry media to a local collection point . a conveyor or transporter system may return dry media to a central collection point , where it is loaded onto the ride vehicles . an embodiment of the invention can be incorporated into several different types of existing or new amusement ride systems , and adapted to any intellectual property or theme . a ride layout may be created based on the ride system , theme , desired capacity and other requirements of a specific client . a building may be designed to incorporate the rides system , the scenes and all the specified components , including the target areas and the media collection system . the ride vehicles may be designed and modified to accept the “ blammo ” shooting devices , and scenes may be designed with the interactive targets . as depicted in fig1 , an embodiment of the present invention may include media launching devices 10 , ride vehicles 12 , a media repository 14 , feeder tubes 16 , ride tracks 18 , targets 20 , and a return system 22 . as to media launching devices 10 , guests can aim launching devices and propel the media by activating a triggering device . the aiming facility for the users to fire the triggering device can be handles or another mechanism to indicate or control where to shoot the projectile . as to ride vehicle 12 , embodiments can be adapted to work with any existing or new type of ride system by others , including hanging rides , trackless dies , omni - mover type rides , boat rides , or any other ride system . embodiments can work with any number of guests per vehicle and any seating configuration . as to media repository 14 , impact safe media are carried on board ride vehicles in bins . the media can be loaded onto vehicles any time during the ride sequence , including prior to guest loading , while guests are loading or after guests have been loaded . media can also be recharged one or more times during a ride sequence . as to feeder tubes 16 , media are fed from repository to launching devices via tubes , channels , tracks or other means . as to ride tracks 18 , embodiments may work with any new or existing ride system that uses any type of track system , including surface mounted tracks , overhead tracks , wire guided or any other trackless based system . as depicted in fig2 , an embodiment of the present invention may include the media launching devices 10 , vehicles 12 , tracks 18 , targets 20 and / or return system 22 in a package . as to targets 20 , targets are to respond to the impact of the impact safe media . targets can be of any shape or size and can be alone or in groups , and each scene can have any variety of groups and types of targets . the targets could be un - themed and generic in nature or be designed to be part of a specific or non - specific intellectual property . as to return system 22 , the impact safe media is collected from the scene areas and returned to a central location where it can be loaded onto vehicles . the embodiment of fig2 shows a sloped set area that allows the media to drain to a machine that conveys it to an overhead trough that uses gravity to transport the media to the central collection area . embodiments can utilize any number of methods of collection and recirculation of the media , including conveyors , vacuums , sloped surfaces or other means . the collection of media could be hidden from guests or be exposed to the guests and be part of the show experience . an embodiment of the invention could be used by theme parks , location based entertainment venues or any place people gather for amusement or entertainment . it should be understood , of course , that the foregoing relates to exemplary embodiments of the invention and that modifications may be made without departing from the spirit and scope of the invention as set forth in the following claims .

an amusement ride system includes : a shooting device adapted to shoot a projectile ; an aiming facility operable by a user to aim the shooting device ; and a triggering device operable by the user to fire the shooting device . the user rides the vehicle , aims the shooting device , and fires the device to shoot the projectile . a method for a ride includes : providing a shooting device ; providing a plurality of projectiles ; and aiming and shooting the projectiles utilizing the shooting device .

one or more objects of the present invention are accomplished by the provision of a fluid , preferably liquid , cleanser composition of ingredients comprising ( 1 ) between about 2 - 60 weight percent of surfactant ; ( 2 ) between about 5 - 50 weight percent of alkali metal bicarbonate or carbonate ; ( 3 ) between about 1 - 10 weight percent of suspending agent ; and ( 4 ) between about 10 - 60 weight percent of water ; wherein the composition has a ph between about 7 - 10 . 5 , and a viscosity in the range between about 1000 - 145 , 000 centipoises . the surfactant ingredient of a present invention fluid cleanser composition can be selected from the group consisting of anionic , cationic , amphoteric and alkylglycosidic surface active agents . suitable surfactants for purposes of the present invention are elaborated in references such as u . s . pat . nos . 4 , 902 , 499 , 4 , 948 , 576 , and 5 , 514 , 369 ; incorporated by reference . a preferred content of surfactant ingredient is between about 2 - 30 weight percent . one class of anionic surfactants are alkyl and alkyl ether sulfates , such as sodium cocoalkyl triethylene glycol ether sulfate . another class of anionic surfactants are the water - soluble salts corresponding to the formula r 1 -- so 3 -- m , where r 1 is a c 8 - c 24 aliphatic group , and m is a cation . another class of anionic surfactants are the reaction products of fatty acids esterified with isethionic acid and neutralized with an alkaline reagent . another class of anionic surfactants are sulfosuccinate salts such as disodium n - octadecylsulfosuccinamate and sodium dioctyl sulfosuccinate . another class of anionic surfactants are olefin sulfonates , such as those described in u . s . pat . no . 3 , 332 , 880 ; incorporated by reference . suitable nonionic surfactants broadly include compounds produced by the condensation of alkylene oxide with an organic hydrophobic compound which can be either aliphatic , alicyclic or aromatic in structure . nonionic surfactants are illustrated by polyethylene oxide condensates of c 6 - c 12 alkylphenols ; condensates of ethylene oxide with the reaction product of propylene oxide and ethylenediamine ; long chain tertiary amine oxides ; long chain tertiary phosphine oxides ; long chain dialkyl sulfoxides ; and the like . suitable cationic surfactants are compounds containing positively charged amine or quaternary ammonium groups , such as those described in u . s . pat . nos . 3 , 155 , 591 , 3 , 929 , 678 , 3 , 959 , 461 , 4 , 387 , 090 , and the like ; incorporated by reference . suitable amphoteric surfactants include derivatives of aliphatic quaternary ammonium , phosphonium and sulfonium compounds . one class of amphoteric surfactants are zwitterionic compounds such as betaines , sultaines and phosphobetaines . illustrative of a betaine is cocoamidopropyl betaine . another class of amphoteric surfactants are compounds containing an amine group and an anionic group such as carboxylate , sulfonate , sulfate , phosphate or phosphonate , as illustrated by sodium 3 - dodecylaminopropionate and sodium 3 - dodecylaminopropane sulfonate . another class of suitable surfactants are alkyl polyglycosides , such as apg 25 , apg 300 , glucopon 600 and plantaren 2000 , which are tradename products sold by the henkel corporation , ambler , pa . the bicarbonate or carbonate ingredient of a present invention fluid cleanser composition can be selected from the group consisting of sodium bicarbonate , potassium bicarbonate , sodium carbonate and potassium carbonate , and mixtures thereof . typically , the bicarbonate or carbonate ingredient of the fluid cleanser composition has an average particle size between about 10 - 250 microns . the average particle size preferably is between about 10 - 200 microns , and most preferably between about 20 - 50 microns . a preferred content of bicarbonate or carbonate ingredient is between about 7 - 40 weight percent . because the particulate bicarbonate or carbonate salt ingredient is in a suspension phase , a large proportion can be incorporated without the limitation of solubility in the fluid medium . the particulate bicarbonate or carbonate salt also serves as a mild exfoliant when in contact with a skin surface . sodium bicarbonate is sold by church & amp ; dwight co ., inc . ( princeton , n . j .) with different average particle sizes , such as grade 1 ( about 55 microns ) and grade 3 ( about 25 microns ). the suspending agent ingredient of a present invention fluid cleanser composition preferably is selected from long chain acyl derivatives such as a glycol ester , which also can contribute a pearlescence effect to the composition . illustrative of suitable suspending agents are ethylene glycol monostearate and distearate . other useful suspending agents include fatty acid alkanol amides such as stearic monoethanolamide ; c 16 - c 22 alkyl dimethylamine oxides such as stearyl dimethylamine oxide , fatty amides such as dihydrogenated tallow phthalic acid amide ; and the like . suspending agents are described in u . s . pat . no . 5 , 439 , 682 ; incorporated by reference . up to about 3 weight percent of auxiliary thickeners can be added to supplement suspending power . in another embodiment this invention provides a fluid cleanser composition of ingredients comprising ( 1 ) between about 2 - 60 weight percent of surfactant ; ( 2 ) between about 5 - 50 weight percent of alkali metal bicarbonate or carbonate ; ( 3 ) between about 1 - 10 weight percent of suspending agent ; ( 4 ) between about 10 - 60 weight percent of water ; and ( 5 ) between about 0 . 05 - 3 weight percent of thickening agent ; wherein the composition has a ph between about 7 - 10 . 5 , and a viscosity in the range between about 1000 - 145 , 000 centipoises . the thickening agent ingredient of a present invention liquid cleanser composition is selected from anionic , cationic and nonionic compounds which provide the desired viscosity , such as cellulosic derivatives and hydrocolloid gums . suitable thickening agents include hydroxymethyl cellulose , hydroxybutyl methyl cellulose , carboxymethyl cellulose , acrylated steareth - 20 methacrylate copolymer ( acrysol ics - 1 ; rohm and haas ), xanthan gum , guar gum , guar hydroxypropyltrimonium chloride ( jaguar c series , rhone - poulenc ), and the like . thickening agents are described in u . s . pat . no . 5 , 439 , 682 ; incorporated by reference . in another embodiment this invention provides a fluid cleanser composition of ingredients comprising ( 1 ) between about 2 - 60 weight percent of a surfactant ; ( 2 ) between about 5 - 50 weight percent of alkali metal bicarbonate or carbonate ; ( 3 ) between about 1 - 10 weight percent of suspending agent ; ( 4 ) between about 10 - 60 weight percent of water ; and ( 5 ) between about 0 . 1 - 5 weight percent of hydrophilic silicone - polymer ; wherein the composition has a ph between about 7 - 10 . 5 , and a viscosity in the range between about 1000 - 145 , 000 centipoises . the hydrophilic silicone - polymer ingredient of a present invention fluid cleanser composition is selected from a specific structural type of silicone nonionic surfactant polymers , having multiple polyoxyalkylene sidechains which impart hydrophilic properties to the silicone - polymer ingredient . the term &# 34 ; hydrophilic &# 34 ; as employed herein refers to a water - dispersible silicone - polymer ingredient which has a water - solubility of at least about two grams per one hundred grams of water at 25 ° c . illustrative of hydrophilic silicone - polymer ingredients are dimethicone copolyol type of polymers , which include commercial products such as dow corning 193 , ge sf - 1288 , abil b 8847 ( goldschmidt ), alkasil ne 58 - 50 ( rhone - poulenc ), amersil dmc - 287 ( americol ), kf 353a ( shin etsu ), masil 1066d ( ppg / mazer ), silicone copolymer f - 754 ( wacker ), sibwet l - 7000 ( union carbide ), and the like , and similar hydrophilic silicone - polymers as listed in the cfta international cosmetic ingredient dictionary ( fourth edition ); incorporated by reference . other suitable hydrophilic silicone - polymers are exemplified by dihydroxy - endcapped polydimethylsiloxanes such as dimethacanol ( ge silicone sm 2725 ), and amine functionalized silicones such as ge silicone sm 2658 . the hydrophilic silicone - polymer ingredient has a gelling effect , and increases the viscosity of the emulsified aqueous medium . additionally , the hydrophilic silicone - polymer ingredient functions as a detackifier when the cleanser composition is applied to a skin surface , and it is a foam modifier and contributes to a smooth skin - feel . a present invention fluid cleanser composition can include between about 0 . 1 - 5 weight percent of moisturizer as an additional ingredient . an ingredient such as propylene glycol , glycerol , dipropylene glycol or polyvinyl alcohol can function as a humectant when the cleanser composition is applied to a skin surface . a present invention fluid cleanser composition also can include optional ingredients such as between about 0 . 1 - 3 weight percent of preservative , and between about 0 . 1 - 2 weight percent of fragrance . suitable preservatives include benzyl alcohol , methyl paraben , ethyl paraben , propyl paraben , imidazolidinyl urea , n -( 3 - chloroallyl )- hexaminium chloride ( dowicil 200 , dow chemical company ), methylchloroisothiazolinone , benzalkonium chloride , and the like . suitable fragrances are exemplified by synthetic compounds and natural oils as described in u . s . pat . nos . 4 , 314 , 915 ; 4 , 411 , 829 ; and 4 , 434 , 306 ; incorporated by reference . synthetic fragrances include geraniol , eugenol , linalool , phenethyl acetate , isobornyl acetate , and the like . other optional ingredients can be included in an invention fluid cleanser composition , such as colorant , pearlescent agent , anti - acne medicament ( resorcinol ), antioxidant , skin healing agent ( allantoin ), sequestrant , vitamin e , antidandruff agent ( zinc pyridinethione ), protein , foam booster , and the like . depending on the intended product end - use , a present invention cleanser composition can vary in rheology , from a relatively low viscosity liquid to a soft gel - like consistency . a present invention cleanser composition can be prepared by standard procedures employed for liquid soap and shampoo product manufacture . as illustrated in the examples , there is a preferred order of organic and inorganic ingredient blending to achieve stable and homogeneous fluid cleanser products . the products of the present invention can be formulated as free - flowing liquids , dilatant liquids , thixotropic liquids , creams , pastes , and the like . the following examples are further illustrative of the present invention . the components and specific ingredients are presented as being typical , and various modifications can be derived in view of the foregoing disclosure within the scope of the invention . this example illustrates the preparation of a fluid cleanser composition in accordance with the present invention . ______________________________________ weight percent______________________________________steol cs 230 . sup . ( 1 ) 50 . 0velvetex ba - 35 . sup . ( 2 ) 10 . 0ge silicone 407 - 2418 . sup . ( 3 ) 1 . 0water ( a ) 2 . 0sodium bicarbonate . sup . ( 4 ) 12 . 0methocel j75ms . sup . ( 5 ) 0 . 5ethylene glycol distearate 3 . 4water ( b ) 20 . 5fragrance . sup . ( 6 ) 0 . 6______________________________________ . sup . ( 1 ) sodium laureth sulfate ( 2 ethoxylates ); 24 . 5 - 26 . 5 % active ; stepan . . sup . ( 2 ) cocamidopropyl betaine ; 30 % active ; henkel . . sup . ( 3 ) dimethicone copolyol . . sup . ( 4 ) grade 3 ( 25 micron average ); church & amp ; dwight . . sup . ( 5 ) hydroxypropyl methylcellulose ; dow chemical . . sup . ( 6 ) bythe - sea rh2771 ; takasago . water ( a ) and silicone are admixed and stirred at room temperature until the silicone is dissolved . water ( b ), methocel and one - half of the sodium bicarbonate are admixed in a reactor and heated to 80 ° c . the ethylene glycol distearate is added to the admixture with stirring until it is blended . the temperature of the admixture in the reactor is lowered to 65 ° c . the remaining sodium bicarbonate , velvetex and the separately prepared aqueous silicone solution are added to the reactor contents , followed by the addition of the steol ingredient with stirring until the admixture is homogeneous . the resultant mixture is cooled to 30 ° c ., and the fragrance ingredient is added with stirring . the product has a ph of 8 . 93 , and a viscosity of 64 , 800 centipoises . sup . ( 7 ). this example illustrates the preparation of a fluid cleanser composition in accordance with the present invention . ______________________________________ weight percent______________________________________steol cs 230 50 . 00velvetex ba - 35 10 . 00ge silicone 288 . sup . ( 1 ) 1 . 00sodium bicarbonate 20 . 00methocel j75ms 0 . 25ethylene glycol distearate 3 . 40water 13 . 85fragrance . sup . ( 3 ) 1 . 50______________________________________ . sup . ( 1 ) sodium laureth sulfate ( 2 ethoxylates ); 24 . 5 - 26 . 5 % active ; stepan . . sup . ( 2 ) cocamidopropyl betaine ; 30 % active ; henkel . . sup . ( 3 ) dimethicone copolyol . the water , methocel and one - half of the sodium bicarbonate are admixed in a reactor and heated to 80 ° c . the ethylene glycol distearate is added to the admixture with stirring until it is blended . the temperature of the admixture in the reactor is lowered to 65 ° c . the velvetex and silicone are added to the reactor contents . the temperature of the admixture is lowered to 50 ° c ., and the remaining sodium bicarbonate is added , followed by the addition of the steol ingredient with stirring until the admixture is homogeneous . the resultant emulsion medium is cooled to 30 ° c ., and the fragrance ingredient is added with stirring . the product has a ph of 8 . 5 , and a viscosity of 18 , 720 centipoises . sup . ( 4 ).

this invention provides a fluid detergent formulation which is particularly suitable for application as a personal cleanser for bath or shower usage . an invention fluid cleanser composition is an aqueous formulation which can be utilized as a mild body shampoo with skin cleansing and skin conditioning benefits . an important feature of an invention fluid cleanser composition is a stable suspension phase of particulate alkali metal bicarbonate which functions as a buffering agent , and which provides deodorizing , exfoliating and water - softening benefits for skin conditioning .

fig1 shows a plan view of a pacing lead 20 according to the present invention . the lead 20 is provided with an elongated lead body 22 which includes one or more electrical conductors ( fig3 ) covered with an insulation sheath 24 . the insulation sheath is preferably fabricated of silicone rubber , polyurethane or other suitable plastic . at a proximal end 26 of the pacing lead 20 is a connector assembly 28 , which is provided with sealing rings 30 and which carries at least one electrical connector pin 32 . the connector assembly 28 is constructed using known techniques and is preferably fabricated of silicone rubber , polyurethane or other suitable plastic . connector pin ( or pins ) 32 is preferably fabricated of stainless steel or other suitable conductive material . at a distal end 34 of the pacing lead 20 is an electrode assembly 36 . the electrical conductors extend from the proximal end 26 to the distal end 34 of the pacing lead 20 , thereby the electrical conductors have a proximal end and a distal end . immediately behind the distal end of the electrode assembly 36 is a tine sheath 38 which includes a plurality of individual tines 40 . tines 40 engage endocardial tissue and urge the electrode assembly 36 to maintain contact with the endocardium . tines 40 are more fully described in u . s . pat . no . 3 , 902 , 501 , issued to citron et al ., incorporated herein by reference . a reinforcing means such as a reinforced fixation sleeve 42 , which may be either fixed or slidably mounted around lead body 22 , serves to stabilize the pacing lead 20 at the site of venous insertion and provide structural support against crushing or constrictive stresses . accordingly , the relative length of the reinforced fixation sleeve 42 should be long enough to permit fixation by suturing at special fixation areas 66 and 68 near the proximal end 26 of the connector assembly 28 and to extend through and beyond the rib - clavicle area . the positioning of the fixation sleeve 42 is illustrated in fig2 wherein the length of the fixation sleeve 42 is d1 . in the preferred embodiment , the length of d1 is in the range of approximately ten to thirteen ( 10 - 13 ) centimeters , but could be adjusted to account for different body sizes without departing from the spirit of the invention . it should be noted that the reinforced fixation sleeve 42 may be slidably mounted around the lead body 22 . an enlarged partially cross - sectional , partially cutaway view of a portion of the pacing lead in the area of the reinforced fixation sleeve 42 is illustrated in fig3 . the lead body 22 includes at least one electrical conductor 46 which preferably is spiral wound and encased in the insulation sheath 24 . the spiral winding of the conductor ( s ) 46 results in a hollow central area 48 , and allows the lead body 22 to remain quite flexible , resulting in a high flexure fatigue resistance . also , the hollow central area 48 receives an insertion guidewire ( not shown ) which is relatively stiff and which allows the doctor to guide and control the implantation of the pacing lead 20 . where multiple conductors are required , they may be either coaxially disposed one about the other , or in a side - by - side multi - lumen arrangement . the construction of the reinforced fixation sleeve 42 is more readily understood upon consideration of fig3 . the reinforced fixation sleeve 42 includes a spiral wound ribbon or flat wire 50 . the flat wire 50 is encased in a biocompatible polymer covering 52 , preferably of similar composition as the insulation sheath 24 . the flat wire 50 is not electrically connected to a conductor 46 or electrode of the pacing lead 20 . preferably , the flat wire 50 has a flexural rigidity and tensile strength substantially greater than that of the spiral wound conductor 46 . the reinforced fixation sleeve 42 thereby has a higher resistance to compressive or constrictive stresses . fig4 illustrates the right side neck - shoulder area of a patient . in fig4 the first rib 70 and right clavicle 72 of the skeletal structure are illustrated . as can be seen , the subclavian vein 74 passes between the first rib 70 and right clavicle 72 before merging with the internal jugular vein 76 and proceeding to the heart ( not shown ). the pacing lead is inserted into the subclavian vein 74 , extends through the rib 70 - clavicle 72 crossing point and down the jugular vein to the heart ( not shown ). the reinforced fixation sleeve 42 is not introduced into the percutaneous lead introducer . however , the reinforced fixation sleeve 42 is long enough to be ultimately implanted and positioned to extend through and beyond the rib - clavicle area in a subclavian vein transvenous implant ( see fig4 ). the reinforced fixation sleeve 42 also extends to the point of and may provide a special fixation area 66 ( fig3 ) for suture tie down anchoring . alternatively , the reinforced fixation sleeve 42 may be configured to cover the lead body 22 at and around the portion which courses through the ribs in a transthoracic - myocardial lead . in the preferred embodiment , the diameter of the lead body is in the range of between about 1 . 50 mm and 2 . 50 mm and preferably about 2 . 0 mm , while the diameter of the reinforced fixation sleeve 42 is in the range of 2 . 0 mm to 5 . 0 mm and preferably about 3 . 0 mm to 4 . 0 mm . when the flat wire 50 has a flattened oval cross - sectional shape , as illustrated at the right in fig3 the flat wire 50 preferably has a minor diameter in the range of between about 0 . 05 mm and 1 . 0 mm and a major diameter in the range of between about 0 . 2 mm and 5 . 0 mm , preferably having the dimensions of 0 . 25 mm by 0 . 75 mm . alternatively , where the flat wire 50 has a rectangular ribbon configuration as shown at the left of fig3 the thickness would be in the range of between about 0 . 05 mm and 1 . 0 mm , while the width would be in the range of between about 0 . 2 mm and 5 . 0 mm , preferably having the dimensions 0 . 25 mm by 0 . 75 mm . the flat wire 50 is preferably a material selected from such materials as : a nickel - cobalt - molybdenum alloy , an iron - nickel - cobalt - molybdenum alloy , titanium , and other similar metals , or alloys including additional minor components . it may also be made up of composites , for example , nickel - cobalt - molybdenum alloy in combination with titanium or silver or other suitable materials in the core or on the surface to add strength or other desirable attributes . materials for the flat wire 50 are selected based on their high tensile strength , fatigue and corrosion resistance and resistivity . it should be evident from the foregoing description that the present invention provide advantages over pacing leads of the prior art . although preferred embodiments are specifically illustrated and described herein , it will be appreciated that many modifications and variations of the present invention are possible in light of the above teaching to those skilled in the art . it is preferred , therefore , that the present invention be limited not by the specific disclosure herein , but only by the appended claims .

an implantable pacing lead with a reinforcing sheath covering a portion of the lead body to prevent physical stress damage to the lead body . the reinforcing sheath includes a metal coil or ribbon encased in a biocompatible polymer which is positioned about a portion of the lead body .

in an embodiment of the present method the determination of the liver performance of a human occurs according to a scheme as shown in fig2 . during this measurement course the metabolization is started by the intravenous administering of the substrate to be metabolized , in particular 13 c methacetin 1 in combination with an isotonic sodium chloride solution 1a . due to the intravenous administration the fast substrate inundation and the fast initiation of the substrate metabolization , which is required for the analysis , is guaranteed . the initiation of the substrate metabolization caused by the enzymatic conversion of the substrate in the liver is thereby faster than the breathing rhythm . the transport of the administered substrate into the liver and the conversion or degradation of the substrate taking place there is schematically clarified in fig7 . the administered substrate ( double cross - hatched circles ) as for instance 13 c methacetin is transported by a specific transport constant into the liver cells , is there converted by the respective enzymes ( single cross - hatched six membered hexagons ), in particular p450 oxygenases , for instance by the means of dealkylation with a specific reaction constant and the dealkylated product ( single cross hatched circles ), for instance paracetamol is transported with a specific transport constant and the 13 c labelled metabolization product ( single cross hatched circle ) for instance 13 co 2 with a specific transport constant out of the liver cells into the blood . beside an enzymatic activation of the substrate in particular by the p450 oxygenases also a release or activation of the substrate by the means of radiation or other fast processes is conceivable . the released metabolization product for instance 13 co 2 is transported via the blood into the lung and is there exhaled . the exhalation air is continuously transported into the measuring device 2 , e . g ., via a breathing mask and a connecting tube and is analyzed by the means of a computer 3 ( stockmann et al ., annals of surgery , 2009 , 250 : col . 119 - 125 ). a measuring device suitable for the present method is for instance described in wo 2007 / 107366 a1 . due to the specific measuring device being applied it is possible to follow the metabolization of the substrate in each breath in real time . this is emphasized in fig3 . the diagram of fig3 shows an increase of the 13 co 2 concentration by the way of the dob value in the exhalation air wherein the increase corresponds to a differential equation of first order . thereby 1 dob indicates a change of the 13 co 2 to 12 co 2 ratio at about thousandth part over the natural ratio . as described before , a max or dob max as well as the time constant tau are deducible from said slope . after the 13 co 2 increase has reached a maximum a decrease of the 13 co 2 concentration occurs what can be attributed to further dynamic processes in the body which contribute to the degradation of the measured signal . described metabolization dynamics it is possible to follow directly and immediately the metabolization of the administered substrate by the enzymes present in the liver . if methacetin is administered as substrate , it is demethylated by the enzyme cyp1a2 . when analysing the slope kinetics of the administered methacetin which corresponds to a differential equation of first order and the parameters a max and tau derived from it , it is now possible to directly determine the liver performance . thereby the maximum value a max allows a statement about the number of healthy liver cells and the liver volume being available for metabolization , while the slope in form of the time constant tau allows statements of the access rate of the substrate into the liver cell . thus , in particular , the time constant tau allows statements if the liver is actually able to take up the substrate . fig7 shows by the means of an example the determination of the relevant parameters on the basis of a curve , which illustrates the increase of the 13 co2 in the breathing air after taking 13 c labelled methacetin , see here also the explanations to fig3 . based on the determined data points ( curve a ) with a measured maximum value a of 22 , 01 dob an adaptation ( fitting ) with one solution of a differential equation of first order ( curve b ) is carried out as described above . based on the solution of the differential equation according to the determination of the amplitude a max of the fitted function with 22 , 09 dob and a time constant tau for the conversion of 2 . 42 minutes occurs . a small time constant of 2 . 42 minutes indicates thereby a good liver permeability while a slow increase of a curve based on the measuring points indicates time constants in the area of over five minutes and therefore a hardening of the liver tissue and the worsened liver permeability connected therewith . beside or additionally to the determination of the amount of a 13 c labelled metabolization product as for instance 13 co 2 in the exhalation air for estimating the liver performance it is also conceivable to follow the concentration decrease of the dealkylated product in the blood and to deduce from the corresponding slope kinetics a time constant tau . this method variant is shown in fig8 . the concentration changes of the administered 13 c labelled substrate , for instance 13 c methacetin and of the dealkylation product formed in the liver , for instance paracetamol , are followed by the means of a suitable analytical method , for instance hplc . the concentration of the 13 c methacetin decreases due to the metabolization ( exponentially decreasing curve starts at an initial concentration of 20 μg / ml 13 c methacetin ) while the concentration of the paracetamol increases in return ( lower curve in fig8 ). the initial concentration changes can also be described here with a differential equation of first order . by the means of the described solution for a differential equation of first order the respective time constants are deducible , wherein the time constant τ1 for the initial fast concentration increase of the paracetamol is 1 . 3 min while the time constant τ2 for the subsequent decelerated concentration increase due to a further distribution in the blood is 16 min . the present method for determining the liver performance is applicable for a multitude of usages . thus , the method allows an estimation of the general health status of a patient , in particular an estimation of the liver performance of a patient . in fig4 a - d the increase of the metabolization is shown as function of time . thereby , different slope kinetics are obtained for different clinical pictures with different maximum values a and different time constants τ . as described , the value a allows the determination of the maximum conversion limax which is directly proportional to the liver performance . fig4 a shows a normal liver performance with a maximum conversion limax of 504 μg / h / kg while in fig4 b - 4 d different clinical pictures are emphasized . in case of cirrhosis of the liver , the metabolization of the administered substrate is reduced so that the maximum conversion limax only reaches a value of 307 μg / h / kg . in case of further liver damages up to a liver failure the maximum conversion of the administered substrate is reduced accordingly to a value of 144 μg / h / kg ( fig4 c ) or 55 μg / h / kg ( fig4 d ). the present method allows also the prediction or tracing of the liver generation and examination of the liver status after an operation as for instance after a liver resection . thus , it is possible by the means of the present method to examine already a few minutes after a liver operation or even already during the operation if and to which extend the liver is efficient . in fig5 the liver performances after a liver operation are shown . the maximum conversion limax differs significantly between a healthy regular liver , a weakened liver or a strongly damaged liver . it usually takes a few days after an operation until the liver is regenerated . if the maximum conversion limax and therefore , the liver performance after an operation has already been very low it can be predicted that the liver of the patient won &# 39 ; t recover and the patient will die with high probability . by the means of the present method , however , a fast recognition of such critical cases is possible so that the affected patients can be alternatively treated for instance by a liver transplantation and can be rescued thereby . the present method allows also a prediction of the operation result before an operation and therefore a suitable operation planning . thus , for instance in combination with a ct volumetry not only the damaged tissue as for instance tumour tissue , but also the tissue which has to necessarily be removed can be determined before a liver operation . this is necessary since in case of a tumour treatment as much tissue around the tumour as possible has to be removed in order to minimize the risk of spreading of a tumour . if thereby , however , too much liver volume is removed , the possibility exists that the patient deceases . the size of the liver volume to be removed depends on the liver performance of the remaining liver volume . due to the exact determination of the liver performance of the existing liver volume an operation can be planned with utmost precision so that the patient has optimal chances for surviving and regenerating . this is shown by the means of the following example . if the tumour volume is for instance 153 ml then it is reasonable to remove a total of ca . 599 ml liver volume . in case of a total liver volume of 1450 ml thus a residual volume of 698 ml would remain what would ensure a survival of the patient . the maximum conversion limax of the administered 13 c methacetin is before the operation 307 μg / h / kg . the aspired residual volume of 698 ml would correspond to a maximum conversion limax of 165 μg / h / kg . the conversion can continuously be determined already during the operation by the means of the present method so that it is guaranteed that the residual volume of 698 ml required for survival is reached . in the present case the residual volume of the liver after the operation is 625 ml and has a maximum conversion of 169 μg / h / kg . due to a direct comparison of the healthy liver volume with the limax value the liver volume to be resized can be determined via the rule of three in order to obtain an aimed limax value . the present method allows also for the determination of the function or the post operative non - function ( pns ) of a transplanted liver . in about 5 % of the cases it happens after a liver transplantation that the transplanted liver for instance due to an insufficient blood circulation does not function . until now , this can only be detected after several days . by the means of the present method it is however possible to detect the malfunction of the liver already after a few minutes since the time constant τ provides information about the accessibility of the administered substrate to the liver . the patient can be treated accordingly and for instance a new transplantation can be carried out . the measurement of the operational success after a liver transplantation and the planning of further treatment steps are possible by the means of the present method . thus , after a liver transplantation the performance of the liver can be determined immediately and directly by the present method and the further treatment of the patient can be optimized individually . the present method allows furthermore the evaluation of the risk of sepsis for intensive care patients . it is known that the risk to die due to a sepsis is very high in the intensive care medicine . it is now possible by the means of the present measuring method to determine directly during admission and treatment a liver damage or a normal function of the liver cells . the determination of the liver damage is also of importance in particular during approval of medicaments and drugs . therefore , one of the most important applications of the present method is the use of the method for examining liver damages caused by medicaments and drugs in the course of a drug approval . during the drug approval it has to be shown in a toxicology test that the drugs to be approved do not damage the liver . such risk estimation is usually deduced from a series of different animal tests . however , unexpected side effects occur often in humans , which are only difficult to detect in animal tests . in contrast , by the means of the present method a toxic effect to animals and humans can be determined exactly and quantitatively . due to the present method which allows for a reliable quantitative determination of the liver performance it is now possible to carry out tests for drug dosages faster and more exactly . long term damages combined with a rearrangement of the liver caused by medicaments as for instance contraceptives , can also be followed by the means of the present method . if medicaments are taken regularly , as for instance in case of contraceptives , changes of the liver can occur which influence at first the accessibility of the liver cells and cause later a reduction of the liver performance . these changes of the liver can be determined by the slope times τ , via which the access rate of the substance into the liver cells can be determined and the maximum value a , which allows statements about the number of healthy liver cells . regular tests with the present measuring method allow therefore the detection of such liver changes . based on the determined data the doctor can carry out a change of administering the medicament so that no further liver changes occur . the influence of genetically modified substances and food on living organisms , in particular human , is currently only difficult to detect . this is in particular due to the fact that the concentration of harmful biological substance is often below or just under the detection limit or the harmfulness of said substance is not known until now . the present method allows the clear detection of the damaging of the liver by genetically modified food . influences of chemicals in the chemical industry or the pharmaceutical industry can also be followed , monitored and identified by the means of the present method . this allows for a reliable examination of the human health in the working place . further applications of the present method are in the area of occupational medicine for estimating health risks , in screening liver cancer , monitoring liver illnesses , as for instance hepatitis , detecting liver damages in animals as for instance caused by the plant senecio jacobaea i . in horses , poisoning and in the environmental medicine in the search for live damaging substances in soil , food and / or drinking water . a well suited application of the present method is the adjustment of medicaments . since the liver metabolizes the plurality of all administered drugs , a majority of the drugs is accordingly metabolized in case of a high liver performance ; while in case of a bad liver performance a low amount of the drugs is metabolized . this however means for a patient that depending on liver performance the dosage of the drugs in the body is different and can therefore also unfold a different effectiveness . therefore , an optimal effect of the drug should be adapted to the liver performance . as an example the administration of tacrolimus , an immunosuppressant against rejection reactions after organ transplantation is being pointed out . the exact adjustment of the dosage of tacrolimus is of high importance since a high dosage of tacrolimus is toxic and if the dosage is too small it has no effect . if the liver performance is now exactly known , the dosage can be adjusted exactly and the effect of the drug can be optimized . the present method can also be used by a family doctor for liver check - ups due to its simplicity and fastness in order to request the liver performance as part of the health status .

a method for determining the liver performance of a living organism , in particular a human , comprising administering at least one 13 c labelled substrate , which is converted by the liver by releasing at least one 13 c labelled metabolization product , and determining the amount of the at least one 13 c labelled metabolization product in the exhalation air over a definite time interval by the means of at least one measuring device with at least one evaluation unit is disclosed . using this method , it is possible to describe the measured initial increase of the amount of the at least one 13 c labelled metabolization product in the exhalation air using a differential equation of first order and to determine a value a max and a time constant tau of the increase of the amount of 13 c labelled metabolization product from the solution of the differential equation of first order .

small animals generally used for experiments are also usable in the method of the present invention . the animals are , for example , small laboratory animals such as mice , rats , guinea pigs and hamsters . in these animals , mice are the most suitable . small animals having glabrous skin are used in the present invention . the term “ glabrous skin ” herein indicates the skin of a hereditary hairless animal and also the skin of a small laboratory animal from which hair was artificially removed by shaving or with a depilatory drug . small animals having the skin from which hair was removed with a razor or the like or those having the glabrous skin realized with a depilatory drug or the like are preferably used because the location in which the barrier function is destroyed can be easily specified in the observation . the small laboratory animals can be controlled by an ordinary breeding method . it is preferred that they get used to the behavioral observation environment , such as the presence of a video camera used in the present invention , before the experiments . the location in which the barrier function is destroyed is preferably such that the small laboratory animal can scratch with his hind limbs so that the effect of the treatment can be easily observed in the method of the present invention . the location is particularly preferably around rostral back , flank or ventral part . although the area to be treated is not particularly limited , it is desirably about 40 to 80 % based on the width or height of the small laboratory animal . in case of mice , the area is about 2 cm × 2 cm . the organic solvent used for the treatment is not particularly limited so far as the solvent per se does not have a strong corroding effect on the skin . the organic solvents include alcohols , ketones , ethers and esters , preferably aliphatic hydrocarbons and dmso , more preferably , acetone or mixtures of acetone and an ether , and particularly preferably a mixture of acetone and diethylether in a ratio of 1 : 1 . in the treatment with the organic solvent or water , the part to be treated is covered with an absorbent cotton containing it , and then the superfluous solvent or water is wiped off or dripped off . preferably , the part is covered with the absorbent cotton containing the solvent or water and then the superfluous solvent or water is wiped off . the time required of the treatment is not strictly limited and is variable depending on the kind of the small animals and the organic solvent used . the time required of the treatment with the organic solvent is generally at least several seconds , preferably about several seconds to several minutes , and particularly about 10 to 60 seconds . the time required of the treatment with water is at least 30 seconds , preferably about 30 seconds to several minutes , and particularly about 30 to 60 seconds . the treatment is repeated until the corneal layer of epidermis has become whity and powder - coated or , in other words , until wrinkle formation or squamae is observed on the skin . the intervals between the treatment with the organic solvent and the subsequent treatment with water are shorter than a period in which the barrier function is completely recovered . the treatments are desirably continuously repeated with such a frequency that the inflammatory stimulation is not given to the skin until at least skin manifestations caused by drying such as scales have become to be observed . the frequency of the treatments varies depending on the kind of the small animals . usually , the treatments are repeated with a frequency of 1 to 3 times in daily for several days ( preferably at least 3 days ). the onset of the dermatoses caused by the disruption of the barrier function can be confirmed by the visual observation of the appearance of the skin , and the determination of hydration of the stratum corneum and transepidermal water loss according to the present invention . a combination of two or more methods is desirable . the formation of wrinkles and scales are apparently observed on the skin after the disruption of the barrier function by , for example , the method of the present invention . therefore , these symptoms can be employed as the index at first . the hydration of the stratum corneum can be determined by a technique of conductimetry , determination of electrostatic capacitance or ft - ir method . water loss through the epidermis can be noninvasively determined with an electric measuring instrument or the like so as not to affect the scratching action . the water loss through the epidermis is desirably still increasing one day after the barrier disrupting treatment , unlike the untreated animals . preferably , the transepidermal water loss in the treated animals is at least 2 - fold much as that of the untreated animals . on the other hand , hydration of the stratum corneum of the treated animals is desirably lower than that of the untreated animals one day after the barrier disruption treatment . namely , hydration of the treated animals determined on the basis of the electrostatic capacitance is preferably less than ½ of that of the untreated animals one day after the barrier disruption treatment . on the other hand , the small test animals having the xeroderma - like lesion caused by the treatment for disrupting the barrier function of the skin according to the present invention show spontaneous behaviour of scratching to the lesional skin with their hind limbs . accordingly , the degree of itchiness induced by the dermatosis can be determined on the basis of the change in the state of the skin by the scratching action and also number of the scratching action . although the number of scratching action can be directly visually observed , it is preferred to observe and to record the animals in an unattended environment . concretely , for example , the observation and recording are desirably carried out by recording the action of the animals in a cage having an open or transparent top with a video camera placed above the cage . as for the observation of the action , the small test animals desirably get used to the behavioral observation environment before counting the number of times of the scratching action . one scratching action means a series of action beginning when the small animal raises its hind limb for starting the scratching and ending when the animal lowers its hind limb . the scratching action is determined by counting the number of the scratching of the region of the disrupted barrier function and surrounding parts with hind limbs . the determination period for each animal is at least 30 minutes , preferably 30 to 150 minutes . several small animals , usually about 4 to 12 small animals , are used for each test and the results are statistically calculated . the effect of a medicine on suppressing the itching according to the present invention can be determined as follows : the effect of such a medicine can be evaluated on the basis of the number of the scratching of an itchy region caused by the disruption of the barrier function of the model animals obtained by the method of the present invention and also degree of the reduction of the number . for example , when a specified test medicine is administered to model animals produced by the present invention by a specified administration method and the number of the scratching action of the model animals is judged to be statistically significantly reduced ( significant level : 5 %), it can be concluded that the medicine is effective . the administration method can be selected from among intravenous injunction , subcutaneous injection , intradermal injection , oral administration , percutaneous administration and pernasal administration depending on the properties of the test medicine . in the percutaneous administration , a medicine to be tested is applied to the skin having a barrier function disrupted by the method of the present invention . in a control group , animals to which the medicine was not administered are used . in a comparative group , animals to which a histamine h 1 receptor antagonist used for suppression of the itching caused by the degranulation of intracutaneous mast cells was administered can be used . further , the degrees of reduction in the number of scratching action obtained by using medicines can be directly compared with each other for the relative evaluation . in the diagnosis of the skin appearance , the control of the formation of scales or the like or disappearance thereof is employed as the index . when no abnormal finding is obtained at all , the medicine can be determined to have a remarkable effect . as for hydration of the stratum corneum , the effect of a medicine is determined on the basis of the protection from lowering of hydration by the barrier - disruption process or degree of the recovery , and the medicine can be determined to have a remarkable effect when the hydration after the completion of the administration is substantially equal to that determined before the cutaneous barrier disrupting treatment . particularly for the evaluation of the effect of a medicine , quasi drug or cosmetic composition for improving the general skin manifestations , it is desirable to evaluate the combination of indexes of skin lesions caused by the disruption of the cutaneous barrier function thereof such as hydration of the stratum corneum , transdermal water loss and diagnosis of appearance of the skin with the number of scratching action . for example , both of ( 1 ) inhibition of formation of scales or the like or disappearance of scales in the diagnosis of the skin appearance and ( 2 ) degree of inhibition of reduction in hydration by the cutaneous barrier disruption or degree of recovery therefrom in the determination of hydration in the stratum corneum , are employed as the indexes . when no abnormality is found in the diagnosis ( 1 ) and the results of ( 2 ) after the completion of the administration are similar to those of animals which were free from the barrier destruction treatment , the medicine can be judged to be remarkably effective . the following examples will further illustrate the method of the present invention for producing the itching model animals , and method of evaluating the effect of a medicine for suppressing the itching of the model animals . a rostral part ( 4 cm 2 , i . e . 2 cm × 2 cm ) of the back skin in each of 10 male icr mice was shaved . four days after the shaving , the following test was started : the skin was covered with a 2 cm × 2 cm absorbent cotton impregnated with a mixture of acetone and diethylether ( 1 : 1 ) for 15 seconds . the skin was wiped to remove superfluous solvent , then covered with an absorbent cotton impregnated with distilled water for 30 seconds , and wiped in the same manner as that described above . this treatment for disrupting the cutaneous barrier function of the skin was conducted twice in daily at intervals of at least 8 hours for 5 days . in a control group , only the shaving was conducted . on the next day after the completion of the 5 days treatment for disrupting the skin barrier function , each mouse was placed in each section of an acrylic acid resin cage ( 26 × 18 × 33 cm ) divided into four sections ( each section : 13 × 9 × 33 cm ). after the mice was acclimatized to the cage in unmanned environment for 60 minutes , the action of each mouse was recorded for 120 minutes with a 8 mm video camera placed above the cage in such a manner that the 4 sections are in one scene . the scratching action was observed by playing back the video tape . the number of the scratching action by which the tip of a toe of a hind limb of the mouse touched the shaved part of the skin in 120 minutes was counted by the visual observation . one scratching action was a series of action beginning when the mouse raised its hind limb for starting the scratching and ending when the animal lowers its hind limb . separately , a rostral part ( 4 cm 2 , i . e . 2 × 2 cm ) on the back of each of 10 male icr mice in another group was shaved . four days after the shaving , a tape stripping test started . in this test , an adhesive cellophane tape was continuously 4 times applied to and peeled the stratum corneum from the rostral part on the back of each mouse . this series of the test was conducted once a day for 5 days . the scratching action of the animals thus treated in a control group was also observed in the same manner as that described above . in still another group , it was begun to cover the skin with a 2 cm × 2 cm absorbent cotton impregnated with a mixture of acetone and diethylether ( 1 : 1 ) for 15 seconds 4 days after the shaving . the skin was wiped to remove superfluous solvent . this treatment for disrupting the cutaneous barrier function of the skin was conducted twice in daily at intervals of at least 8 hours for 5 days . then the scratching action of the mice was observed . namely , the action of each mouse was recorded for 120 minutes with a 8 mm video camera in he same manner as that described above . the number of the scratching action bouts per 120 minutes was counted by the visual observation . the results are shown in fig1 . the number of times of the scratching action of the group of mice which were shaved but not subjected to the barrier disrupting treatment ( int , fig1 ) was 34 . 4 ± 9 . 8 times / 120 minutes , that of the group of mice ( aew ) treated with the mixture of acetone and ether ( 1 : 1 ) and then with distilled water was 156 . 9 ± 32 . 3 times / 120 minutes , that of the group of mice treated with the mixture of acetone and ether was 51 . 7 ± 7 . 5 times / 120 minutes , and that of the group of mice subjected to the tape stripping treatment for 5 days was 52 . 5 ± 12 . 7 times / 120 minutes . thus , the number of the scratching action in the mice treated with the mixture of acetone and diethylether ( 1 : 1 ) and then with distilled water was far larger than the numbers in other treated and untreated groups . it is apparent from the results obtained above that the treatment of the shaved rostral part on the back of each mouse with the acetone / ether mixture followed by the treatment with distilled water more easily induces the skin region which easily causes the scratching action , than the known methods of the physical barrier function - disrupting treatment by the tape stripping and the barrier function - disrupting treatment by only the degreasing with the organic solvent . the effect of terfenadine , which is a histamine h 1 receptor antagonist , and that of naloxone , which is an opioid antagonist , for relieving the itching were determined with the same test materials as those in example 1 . the barrier function - disrupting treatment was conducted in the same manner as that of example 1 . on the next day after the completion of the 5 days barrier function disrupting treatment , the scratching action of mice was recorded for 120 minutes in the same manner as that of example 1 . the observation of the behavior of the mice and the counting of the number of times of the scratching action were conducted in the same manner as that of example 1 . 10 mg / kg of terfenadine which is the histamine h 1 receptor antagonist , was perorally administered at 30 minutes before the starting to record the scratching action , or 1 mg / kg of naloxone , which is an opioid receptor antagonist , was subcutaneously injected at 15 minutes before the starting to record the scratching action . the inhibitory effect of each medicine on itching was represented by the relative number of scratching action , while the average of the number of scratching action in the control group to which no medicine was given was represented as 100 %. the test results were as follows : the number of the scratching action induced by the disruption of the cutaneous barrier function of mice which were administrated terfenadine , a histamine h 1 receptor antagonist , was 124 . 2 ± 49 . 3 % based on that of the control group . thus , no suppressing effect was recognized . on the other hand , the number of the scratching action induced by the disruption of the cutaneous barrier function of mice which naloxone were injected , an opioid receptor antagonist , was reduced to 42 . 5 ± 13 . 1 % based on that of the control group . the difference from the control group was statistically significant ( level of significance : 5 %). ( see fig2 ). it was thus proved that the histamine h 1 receptor antagonist which is clinically ineffective against itching caused by the hypofunction of cutaneous barrier is also ineffective against the scratching action in the present invention . it was also proved that the opioid receptor antagonist clinically effective against itching induced by hypofunction of cutaneous barrier is also effective against the scratching action in the present invention . the effect of glycerol ( humectant ) on the skin manifestations and itching induced by the barrier disruption treatment of the present invention was determined by using the test animals similar to those used in example 1 . the barrier function - disrupting treatment was conducted twice in daily in the same manner as that of example 1 continuously for 5 days . the skin manifestations were examined by the visual observation and the determination of hydration of the stratum corneum based on the relative electrostatic capacitance determined with corneometer cm 825 ( courage + khazaka electronics , cologne , germany ). hydration of the stratum corneum was determined before starting the first barrier disrupting treatment every day and on the next day after the completion of the five days barrier disruption treatment . as for the scratching action , the scratching action of each mouse was filmed and recorded for 120 minutes in the same manner as that in example 1 on next day after the completion of the five days barrier disruption treatment . the observation of the action and counting of the number of the scratching action were conducted in the same manner as that of example 1 . glycerol was used in the form of 10 % aqueous solution thereof . in the group of 5 days application , 50 μl of glycerol was applied to the part of the barrier disruption in open method one hour after the barrier disruption treatment each time . in the group of 1 day application , 50 μl of glycerol was applied to the part of the barrier destruction in open method one hour after the barrier destruction treatment conducted twice on the fifth day . the results of the test were as follows : hydration of the stratum corneum in the control group was 44 . 5 ± 1 . 9 before starting the treatment of cutaneous barrier disruption , which was reduced to 15 . 5 ± 2 . 1 on the next day after the completion of the 5 days barrier disruption treatment . in the group in which 10 % aqueous glycerol solution was applied , the formation of scales and wrinkles induced by the cutaneous barrier disruption was completely inhibited . in this group , hydration of the stratum corneum , which was 40 . 0 ± 1 . 2 before starting the treatment of cutaneous barrier disruption , was not lowered and it was 44 . 7 ± 3 . 0 on the next day after the completion of the 5 days barrier disrupting treatment . the number of the scratching action bouts per 120 minutes was 126 . 5 ± 20 . 8 in the control group , and it was 42 . 5 ± 10 . 0 in the group in which 10 % aqueous glycerol solution was applied for 5 days . the difference between the two groups was statistically significant . on the other hand , in the group wherein 10 % aqueous glycerol solution was applied for one day , hydration of the stratum corneum once reduced to 20 . 5 ± 1 . 3 from 43 . 5 ± 1 . 3 by the 4 days barrier function disrupting treatment was recovered to 41 . 3 ± 2 . 6 ( close to the hydration before starting the treatment of cutaneous barrier disruption ), but slight scales and wrinkle formation was observed . the number of the scratching action bouts per 120 minutes was 76 . 5 ± 14 . 6 . thus , the difference from the control group was statistically significant , though the effect of suppressing the itching was incomplete . it was understood from these results that when glycerol , clinically effective in improving the skin manifestations induced by hypofunction of cutaneous barrier , is applied to the models of this experiment for 5 days starting in the initial stage of the barrier disrupting treatment , the appearance of all the skin manifestations of the model was controlled . however , when glycerol was applied for one day after the appearance of the skin manifestations induced by the disruption of the barrier function , it was remarkably effective on hydration of the stratum corneum but other properties of the skin such as protection from scale and wrinkle formation were not improved . glycerol was partially effective in removing the itching . namely , when the skin care is started before the onset of the skin manifestations , a remarkable effect on inhibiting the barrier disruption treatment is obtained . after the onset of the skin manifestations , a remarkable effect was obtained only on the hydration of the stratum corneum probably because of the improvement of the barrier function . accordingly , it is estimated that the onset of the skin manifestations induced by the barrier disrupting treatment of the present invention can be prevented or the symptoms can be improved by the humectant skin care effective for human beings . the suppressing effect of a medicine which can be determined by the present invention is considered to be parallel with the suppressing effect thereof on the dermatoses . also , the effect of a humectant skin care component evaluated on the basis of the scratching action as the index according to the present invention is considered to be parallel with the effect on the itching induced by the disruption of the barrier function . the results are shown in fig3 . the present invention provides animal models capable of efficiently realizing the scratching action related to the itching , while the onset of the itching could not be clearly recognized in animal models having disrupted barrier function in the prior art . namely , the animal models obtained by the present invention have an itchy sensation close to the itchy sensation of most patients with dermatoses who are characterized by a hypofunction of cutaneous barrier . therefore , when the animal models obtained by the present invention are used , test results close to those obtained by clinical tests of human beings can be obtained in the treatment of itching and also in the determination of effectiveness of a preventive drug . the model animals of the present invention can contribute to the reduction in unpleasant feeling of patients with dermatoses and also to the removal of aggravating factors from the patients . according to the present invention , model animals of a dermatosis suffering from itching for unknown causes can be produced . further , according to the present invention , effects of a therapeutic agent on itching induced by hypofunction of cutaneous barrier can be determined , while the evaluation of such effects was difficult in the prior art .

the present invention provides itching model animals usable for evaluating the therapeutic effect of medicines , medicinal compositions , external preparations for the skin , etc . on itching induced by hypofunction of cutaneous barrier and also for evaluating the effect in improving the barrier function of the skin weakened and converted to be itchy by an external preparation for the skin or a cosmetic . the present invention also provides a method for producing such animals . itching symptoms are realized by degreasing the glabrous skin of each of small test animals with an organic solvent and then treating the skin with water to induce a lesion of the skin by the disruptions of the barrier function without inflammation .

the elements or parts of elements common to the forms of embodiment described below will be denoted using the same reference numeral . with reference to the aforesaid figures , reference numeral 4 globally denotes a bandage for horses &# 39 ; legs , suitable for wrapping around the legs of the horse . according to one form of embodiment , said bandage 4 comprises a first bandage strip 8 suitable for winding directly onto the horse &# 39 ; s coat , and to be covered by a second covering bandage strip 12 . preferably , the first strip 8 is made from a silicone gel able to adhere to the horse &# 39 ; s leg so as to conform to the morphology of the said limb . preferably , the first strip 8 has a number of holes 16 able to permit the transpiration of the horse &# 39 ; s coat . advantageously , said holes 16 are of such a size as to improve the deformation capacity of the first strip 8 and the adaptation of the same to the morphology of the horse &# 39 ; s leg . preferably , said holes 16 are evenly distributed over said first strip and contribute to lightening the weight of the first strip 8 . according to one form of embodiment , the bandage 4 comprises a first bandage strip 8 suitable for winding directly onto the horse &# 39 ; s coat and a second bandage strip 12 suitable for covering and strengthening the compression of said first strip 8 . advantageously , the first and second strips 8 , 12 are joined to each other at their respective first and second upper extremities 20 , 24 . advantageously , the joining of said upper extremities 20 , 24 is made so as to be seamless . according to one form of embodiment , the joining of said extremities 20 , 24 is performed by means of a co - molding technique . preferably , said first and second upper extremities 20 , 24 overlay at least partially with the first and the second strip 12 , 8 respectively so that at the point of a hooking portion 28 of the strips 8 , 12 , said strips are at least partially overlaid . preferably , the second upper extremity 24 of the second strip 12 is positioned on the part opposite the part of the strip placed against the horse &# 39 ; s coat . preferably , the first upper extremity 20 comprises a pair of slots 32 , on the side of the bandage suitable for placing directly against the horse &# 39 ; s coat . according to one form of embodiment , the first upper extremity 20 , at the point of attachment with the second strip 12 , comprises a pair of tabs 36 , able to overlay at least partially the second strip 12 , on the side opposite the part of the strip placed against the horse &# 39 ; s coat . preferably , the width of the first strip 8 is greater or the same as the width of the second strip 12 . advantageously , the second bandage strip 12 is an elastic strip . for example , the second strip 12 is a strip of medical sheepskin , or wool or acrylic , or fleece , lycra or similar . the method of producing a bandage according to the present invention will now be described . the method of making comprises the phases of predisposing a strip in silicone gel suitable for winding directly onto the horse &# 39 ; s coat and making a number of holes in said strip in silicone gel so as to permit transpiration from the horse &# 39 ; s coat . the first strip 8 is then laid over the second strip 12 in elastic material with the relative upper extremities 20 , 24 laid directly against each other . said upper extremities 20 , 24 are then joined so as to create a seamless joint . preferably , the assembly phase of the strips 8 , 12 is performed by means of a co - molding technique of the said upper extremities 20 , 24 , so as to incorporate at least partially a portion of the second strip inside the first strip in silicone gel . as may be appreciated from this description , the bandage according to this invention makes it possible to overcome the drawbacks presented in the technical note . in fact , the first strip in silicone gel means that the bandage can be perfectly adapted to the morphology of the horse &# 39 ; s leg . in addition , the presence of the holes limits the sweating of the horse and encourages transpiration from the leg . moreover , the holes help to reduce the total weight of the bandage so as to reduce to a minimum the limitation of the movements of the horse . in addition , the holes increase the elasticity of the bandage and make it easier to deform so as to mold perfectly to the morphology of the horse &# 39 ; s leg . in addition , the use of a seamless joint between the first and second strips prevents any rubbing or abrasion of the horse &# 39 ; s leg . in addition , thanks to the fact that the first and second bandage strips are in a single piece , the chances of the covering strip loosening are reduced . according to a further advantage the bandage is easier to fit onto the leg than known state - of - the - art bandages , given that it is a single piece . a technician skilled in this area , may make numerous modifications and adjustments to the bandages described above so as to satisfy contingent and specific requirements , all contained within the sphere of the invention as defined by the following claims .

an elastic bandage for horses &# 39 ; legs particularly suitable for protecting horses &# 39 ; legs without limiting their movement and without preventing transpiration . the application of the bandage does not cause rubbing or abrasion of the horses &# 39 ; legs .

fig1 - 7 show apparatus 10 and its various features . apparatus 10 has a frame 12 with two longitudinal sidebars 14 which form longitudinal sides of the frame . cross - bars of a shoulder bar 16 and a hip bar 18 tie the two sidebars 14 together . a horizontal rectangular supporting surface 24 is shown with a covering 26 supports reclining patient 30 . the length of sidebars 14 , shoulder bar 16 , and hip bar 18 are made such that frame 12 will closely enclose supporting surface 24 . the length of legs 20 are equal and of a length such that support frame 12 will be essentially horizontal and be positioned immediately above supporting surface 28 when apparatus 10 is supported by an essentially horizontal floor . legs 20 can either be made integral with other elements of frame 12 , can be attached separately , and can be made adjustable in length whether made integral to the frame or not . in fig4 leg 20 is shown integral with sidebar 14 . in fig1 and 2 legs 20 are integral with sidebar 14 on both sides of frame 12 . the arrangement of leg 20 can be changed depending upon the type of support provided . in fig3 , leg 20 is shown secured within an end of sidebar 14 . fig4 also shows one means of attaching one end of hip bar 18 to sidebar 14 . this also applies to attaching the opposite end of hip bar 18 to the opposite sidebar 14 , and to attaching both ends of shoulder bar to both sidebars . a female connector 32 is secured to the inner side of sidebar 14 by two bolts 32 a through mating threaded holes in sidebar 14 , not shown . female connector part 32 has a generally trapezoid shaped opening 32 b on the exposed side , is secured to sidebar 14 with the widest part of the trapezoid upward and has a upward extending lip from the lower edge . male connector part 34 has a trapezoidal shaped extension 34 b sized to fit within part 32 b . part 34 is secured to the end of hip bar 18 by two bolts 32 a through mating threaded holes , not shown . hip bar 18 is secured to sidebar 14 by dropping extension 34 b into receptacle 32 b from above where the weight of the sidebar will assist in holding it in position within the upward extending lip . the opposite end of hip bar 18 and both ends of shoulder bar 16 are attached to sidebars 14 using identical parts attached in the same manner . as shown in fig1 and 3 , hip bar 18 can be further secured in place by an elastic bungee 12 a which encircles the hip bar and is attached to leg 20 by a end fastener 12 b , which is secured through hole by a bolt 12 c . both ends of shoulder bar 16 and hip bar 18 are secured to legs 20 by a bungee 12 a in the same manner . fig5 and 7 show another and preferred means of attaching both ends of shoulder bars and hip bars between both sidebars 14 . shoulder bar 17 and hip bar 19 are substituted respectively for shoulder bar 16 and hip bar 18 in this second means , and are attached to the sidebars 14 using a different fastener permitted by their different construction . shoulder bars 17 and hip bars 19 are both made from two tubes 42 which are the same length as shoulder bars 16 and hip bars 18 . the two tubes 42 have a rectangular shaped connection 42 a welded between the tubes at both ends on both sides to secure them together . a nut 42 b is welded between tubes 42 and connection 42 a at both ends of the bars and the nut is secured in place with the threaded opening aligned with the centerline of tubes 42 . extensions 14 d from sidebar 14 mate with the interior of tubes 42 . threaded rod 14 e mate with nut 42 b on the interior end and has an attached knob 14 f to rotate the rod for attaching and detaching the hip bar 19 . the opposite end of hip bar 19 and both ends of shoulder bar 17 have similar arrangements as do the adjoining interior portions of sidebars 14 for attaching the parts together . to provide for different height and different spacings between the shoulder and hips of patients , using the first or second connection means with either shoulder sidebar 14 and hip bar 16 or using shoulder sidebar 17 and hip bar 19 , provides a plurality of locations for both the shoulder bars and the hip bars . this arrangement permits the bars to support the shoulder and the hip of any patient regardless of their height or their hip and shoulder spacing . a flexible spinal strap 36 of flexible material extends longitudinally across the center of frame 12 . strap 36 has a loop 36 a formed on one end and a loop 36 b formed on the opposite end . loop 36 a encircles shoulder bar 16 and loop 36 b encircles a tension bar 38 . tension bar 38 extends completely across frame 12 opposite sidebars 14 and is secured in place by threaded shafts 40 extending through the center of sidebars 14 through mating holes at the ends of the sidebars 14 . the threaded shafts 40 engage mating threaded holes in tension bar 38 , not shown , and are secured in place by bolts 38 a threaded into mating holes . wing nuts 40 a , engage shafts 40 having threads which mate with the threads on the shafts . changing the position of the wing nuts 40 a on shafts 40 provides a means for adjusting the position of tension bar 38 , which is mounted between the ends of shafts 40 , and change the amount of tension provided by strap 36 . in operation , patient 30 is lying on his back on the supporting surface 28 , shoulder bar 16 with integral legs 10 , and hip bar 18 or shoulder bar 17 and hip bar 10 are connected to sidebars 14 . the parts are assembled with shoulder bar 16 or 17 , hip bar 18 or 19 and strap 36 beneath the patient , and with loop 36 a of strap 36 engaging shoulder bar 16 or 17 . shafts 40 engaged by wing nuts 40 a are threaded into the ends of sidebars 14 . tension bar 38 is extended through loop 36 b of strap 36 and connected to the ends of threaded shafts 40 . wing nuts 40 a are then rotated to obtain the desired tension . supporting surface 28 can then be removed leaving patient 30 supported by appliance 10 . as described above , sidebars 14 can be integral with legs 20 , however the legs can be separable from the sidebars so that the frame 12 , when not in use , can be fully disassembled . in either case , sidebars 14 are connected by either shoulder bar 16 or 17 and hip bar 18 or 19 respectively using either the first or second means described above . as can be seen , with patient 30 positioned over spinal strap 36 with shoulders and hips supported by either shoulder bar 16 and hip bar 18 or by shoulder bar 17 and hi bar 19 , the supporting surface can be lowered to afford more full access to the patient &# 39 ; s torso . the clearance and access thus afforded can allow for bed cleaning , the taking of measurements and / or molding of the torso of the patient . the above are just a few examples of the modifications and changes that are possible , and would readily occur to one skilled in the art , therefore it is contemplated that the appended claims will cover any such modifications or embodiments as fall within the true scope of the invention .

an appliance provides a pair of sidebars and a pair of cross - bars which are assembled around a patient reclining upon a supporting surface . the appliance has legs which support the appliance at the level of the patient . the cross - bars are positioned under the hips and shoulders of the patient . a flexible strap , which has tension adjustment apparatus , extends between the cross - bars under the patient &# 39 ; s spine to assist in supporting the patient . after the appliance is assembled the supporting surface can be removed to provide complete access around the periphery of the patient for examination and treatment .

referring now more particularly to the drawings , and those embodiments of the invention here presented by way of illustration , fig1 shows a stent generally indicated at 15 , the stent 15 being carried by a catheter 16 . the catheter 16 is one of two coaxial catheters , the other catheter 18 being a generally conventional balloon catheter having the balloon 19 at its distal end . it will be understood by those skilled in the art that , in conventional , balloon angioplastiy , a catheter such as the catheter 18 is threaded through the arterial system to place the balloon at the location of the stenosis . the balloon 19 is then inflated to urge the arterial wall outwardly and open the lumen in the artery . this same technique will be utilized with the arrangement shown in fig1 of the drawings , the balloon 19 acting to perform the angioplasty ; however , after the vessel is sufficiently open by means of the balloon 19 , the coaxial catheter 16 will be manipulated to urge the stent 15 in place over the balloon 19 . after the stent 15 is over the balloon 19 , the balloon 19 will be inflated to urge the stent outwardly to its opened condition . referring to fig2 of the drawings , it will be seen that the stent 15 includes a wall 20 , the wall 20 having sufficient memory that the stent as a whole tends to maintain its collapsed condition . one end of the wall 20 is provided with a hook for engagement with one of a plurality of complementary hook means 22 . the hook 21 will necessarily be biased outwardly sufficiently that , as the hook 21 is urged past the plurality of hook means 22 , the hook 21 will engage each of the hooks 22 . because of this arrangement , when the balloon 19 is not further inflated , the hook 21 will remain engaged with one of the hooks 22 to prevent collapse of the stent 15 . it will also be noticed that the stent 15 contains a plurality of generally circumferential ribs 24 . it is contemplated that the ribs 24 will engage the arterial walls sufficiently to prevent inadvertent movement of the stent after placement and removal of the catheter 16 . as will be discussed hereinafter , the stent 15 may also contain a plurality of openings to allow tissue to grow therethrough and further hold the stent 15 in place . looking now at fig3 and 4 of the drawings , it will be seen that the stent 25 is a slightly modified form of the stent 15 . the stent 25 includes the wall 26 which will be biased towards collapse as is the wall 20 of the stent 15 . once the stent 25 is urged to its expanded condition , the interlocking hook means 28 will become engaged as shown in fig3 to prevent collapse of the stent 25 and maintain the stent in its maximum , open condition . it will be understood that there may be times when the stent is improperly placed , or for other reasons must be removed . with the stent 25 , the ends 29 and 30 of the wall 26 are so biased that , when the stent 25 is expanded so far that the ends 29 and 30 are released from engagement , the end 29 will move inwardly and the end 30 will move outwardly . on subsequent release of the stent 25 , the walls 29 and 30 have exchanged places so that the hook means 28 cannot now engage . as a result , the stent 25 will collapse to its minimum external diameter . though many different materials may be utilized in forming the stents of the present invention , one form of material is illustrated in fig5 of the drawings . in fig5 there is a woven network indicated at 31 . this woven network may be metal such as stainless steel or the like , or may be a knit or woven plastic material such as polyester filaments . if the network 31 is made of metal , the intersection can be sonically welded or otherwise heat sealed to one another . following provision of the network 31 , the network 31 is covered by a plastic material indicated at 32 . the material 32 can again be any of numerous materials , so long as the material is implantable . nevertheless , numerous plastic materials including polyethylene , polyester , polytetrafluoroethylene and others can be utilized . as illustrated in fig5 the network 32 is simply coated with the material 32 so that openings 34 are distributed throughout the material . while the openings 34 are not necessarily so uniformly distributed , it will be understood that the use of a plurality of openings 34 promotes epithelialization to promote incorporation of the stent into the vessel wall . turning now to fig6 of the drawings , there is a stent indicated at 35 carried at the end of a catheter 36 . the catheter 36 includes a balloon 38 as is known in the art . while the above described stents have been biased inwardly and have been forced outwardly , the stent 35 is biased outwardly and is forced inwardly and retained by means of a pin 39 . for a full understanding of the stent 35 , attention is directed to fig6 and 8 of the drawings which show both plan view and cross - sectional views of the stent 35 . the stent 35 is here shown as having a generally smooth wall 40 having a plurality of openings 43 in accordance with the foregoing discussion . the wall 40 is biased outwardly towards it maximum diameter ; however , for placement by means of the catheter 36 , the stent 35 is urged inwardly to its minimum diameter ; and the stent is provided with a first pair of lugs 41 carried on the end 42 of the wall 40 , and second pair of lugs 44 carried generally towards the opposite end 45 of the wall 40 . when the wall 40 is urged inwardly to collapse the stent 35 , appropriate openings in the lugs 41 and 44 are aligned , and the pin 39 is placed therethrough to hold the stent 35 in its collapsed position . as shown in fig6 of the drawings , it is contemplated that the pin 39 will be in the form of a wire that extends along the catheter 36 , contained within a channel 46 . with this arrangement , the pin 39 will extend to the lug 44 at the distal end of the stent 35 , and it will be understood that the distal end lug 44 may have a hole that does not extend completely through the lug in order to cover the end of the pin 39 . the pin 39 then extends the full length of the stent 35 and into the channel 46 . while not here illustrated , it will be understood that the pin 39 extends completely along the length of the catheter 36 so the pin 39 can be manipulated externally of the body so that , at the appropriate moment , the pin 39 can be removed from the lugs 41 and 44 and allow the stent 35 to expand . as here shown , when the stent 35 expands , the ends 42 and 45 will remain overlapped to some extent . if desired , interlocking grooves 48 and 49 can be provided so the stent 35 has a relatively fixed expanded diameter . attention is next directed to fig9 - 12 of the drawings which show another modified form of stent . the stent 50 is similar to the stent 35 in that it is biased outwardly and is forcibly held inward by a pin ; however , the stent 50 is considerably different from the stent 35 in that the stent 50 is of a somewhat segmented construction to allow longitudinal flexibility . in the top plan view shown in fig9 of the drawings , it will be seen that the stent 50 includes a plurality of segments 51 , each segment 51 having a lug 52 thereon for receipt of a pin 54 . the segments 51 are interspersed with segments 56 on the opposite side of the pin 54 , the segments 56 having lugs 58 thereon . as is better shown in fig1 of the drawings , there is a generally continuous spine 59 extending along the bottom of the stent 50 and interconnecting all of the segments 51 and 56 . because of this construction , it will be seen that the stent 50 will be readily bendable along its longitudinal axis , the bending being resisted only by the relatively narrow spine 59 . furthermore , it will be understood that the individual segments 51 and 56 can be made much shorter to provide the tighter radii , or relatively long in the event the stent is not intended to be very flexible . though the stent 50 in fig9 - 12 of the drawings is not shown in conjunction with a catheter , it will be understood by those skilled in the art that the stent will be put into place using an arrangement such as that shown in fig6 of the drawings . the catheter 36 and wire channel 46 would be the same , the specific stent being the only difference . fig1 of the drawings shows the cross - sectional shape of the stent 50 while the stent is held in its closed , or collapsed , condition by the pin 54 . when the pin 54 is removed , the stent 50 will expand to the condition shown in fig1 of the drawings . it vill of course be recognized that a balloon , such as the balloon 38 , may be utilized to assist in urging the walls of the stent outwardly to the desired position . the material from which the stent 50 is made may be of any of the numerous materials previously mentioned , including the material shown in fig5 of the drawings . because the stent 50 is made up of a plurality of individual segments 51 and 56 , there is no particular need for additional openings in the wall of the stent , the spaces between the segments providing adequate openings for initial fluid drainage and subsequent epithelialization . simply by way of example , fig1 and 12 illustrate the inclusion of a filament 60 in the wall of the stent . the purpose of the filament 60 is to show that stent 50 can be made of a plastic material having sufficient memory to be urged to the open condition as shown in fig1 ; or , the stent 50 can be made of a relatively flaccid fabric or the like having spring filaments 60 embedded therein for urging the stent 50 its open position . also , the stent 50 can be made entirely of metal , including well known alloys of platinum and gold , or chromium and cobalt . attention is now directed to fig1 to 16 for a review of the fabric liner 70 . it will be noted that the liner is in the shape of a tube which has a longitudinal fold or folds 71 to give a smaller diameter so that it fits axially into the stent . the liner has approximately the same linear dimensions as the stent when said stent and said liner are both in an expanded condition . the liner is fabricated from polyester fabric material having substantially large interstices between the weave whereby epithelialization may occur therethrough to achieve good anchoring . in another embodiment , the liner is a non - woven polytetrafluoroethylene ( goretex ) fabric . the liner is suitably adhered at spaced points along the inner wall except , of course , where the stent overlaps the stent at its opposite edge of the stent as by adhesives or sonic welding when the stent is of polymeric material . the spots of adherence is chosen whereby when the stent is permitted to expand the liner will unfurl and eliminate the fold or folds 71 . other woven fabric materials are contemplated from which the liner is constructed . fig1 is a cross - sectional view of the stent with the liner 70 in a furled or folded condition in the stent of the present invention . fig1 , is then , the same cross - section showing the lines 70 in an unfurled condition . attention is now directed to fig1 - 18 , wherein the lugs 52 as seen in fig1 have oval openings 81 . the end of the pin 54 has a flattened portion 82 whereby it must be suitably keyed through the openings thereby controlling longitudinal movement of the stent when locked into the oval opening 81 . from the foregoing discussion it will be understood that the present invention provides an arterial stent and a method for placing the stent for preventing restenosis following angioplasty or other mechanical opening of the lumen in an artery . while several specific designs and materials have been disclosed , those skilled in the art will recognize that the materials must be implantable , and all portions of the stent must be sufficiently smooth to prevent trauma during placement . further , all comers and the like should be will rounded to promote epithelialization without subsequent trauma due to the presence of sharp edges during natural body motions . it will of course be understood by those skilled in the art that the particular embodiments of the invention here presented are by way of illustration only ; and are meant to be in no way restrictive ; therefore , numerous changes and modifications may be made , and the full use of equivalents resorted to , without departing from the spirit or scope of the invention as outlined in the appended claims .

a prosthesis for use in preventing restenosis after angioplasty is formed of plastic or sheet metal , and is expandable and contractible for placement . the prosthesis can be inserted while in a collapsed position , then expanded and locked at the larger diameter . spring force can be provided by the material itself , or metal springs can be embedded within the walls of the prosthesis . preferably , the walls have holes therethrough to promote tissue growth ; and , in one embodiment , the holes are in the form of slots so that the prosthesis is segmented and can bend longitudinally . in a further embodiment the angioplasty stent is fitted with an internal fabric liner of substantially the same longitudinal dimensions as the stent . it is adhesively secured to the internal wall of the stent at selected points whereby the liner may have longitudinal fold or folds and may then be expanded as the stent is expanded after being positioned .

referring to the drawings in detail , wherein like numerals indicate like elements , there is shown in fig1 a line metering apparatus in accordance with the present invention designated generally as 10 . the line metering apparatus 10 is used on a flexible filament vegetation cutting device 12 . a portion of a lawn mower 14 , with which the cutting device 12 is preferably used , is shown in fig1 . the lawn mower 14 includes an outer housing 16 which is carried out a ground surface by a plurality of wheels , one of which is shown as 18 . a cross member 20 is attached within the housing 16 . the cutting device 12 including the line metering apparatus 10 , are attached to the cross member 20 . a generally cylindrical shroud 22 extends downwardly from the cross member 20 and has a central opening 24 for receiving portions of the cutting device 12 . a flange 26 is attached to the cross member 20 adjacent to the shroud 22 . an electric motor 28 is attached to the flange 26 by conventional means , such as nuts and bolts 30 . a drive shaft 32 is drivingly coupled to the electric motor 28 and is rotatably driven thereby . a fan member 34 is fixedly attached to the drive shaft 32 to draw air over the motor 28 for cooling purposes . the electric motor 28 is connected to a source of electric current in any suitable conventional manner . a spool means 36 is removably attached to the drive shaft 32 by a nut 38 . the spool means has a centrally located hole 33 . the hole 33 has a pair of opposed flat surfaces 35 . a pair of opposed flat surfaces on the drive shaft 32 mates or keys with the surfaces 35 . the nut 38 securely fastens the spool means 36 to the drive shaft 32 . since the spool means 36 and the drive shaft 32 are keyed to one another , the spool means 36 rotates together with the drive shaft 32 whenever the drive shaft 32 is rotated . as is best seen in fig4 the spool member 36 is made up of a central cylindrical section 40 , a medial section 42 , and an outer circumferential section 44 . the spool means 36 is preferably formed of an integral piece of hard plastic material . the central cylindrical section 40 takes the form of a longitudinally extended cylinder 46 which is received about the drive shaft 32 . the medial section 42 extends radially outward from a lower end 48 of the cylinder 46 . the medial section 42 includes a set or plurality of first teeth 50 extending upwardly and spaced at generally equiangular distances . in the embodiment shown , six teeth 60 are spaced at approximately 60 ° intervals . each of the teeth 50 has a generally vertically extending engaging surface 52 . an upwardly extending surface 54 forms a ramp means which extends upwardly from adjacent engaging surface 52 in the direction of rotation of the spool means 36 , that is , to the right in fig8 - 11 . a plurality of strengthening ribs 56 extend between the teeth 50 and the cylinder 46 . the ribs 56 provide additional structural integrity to the spool means 36 . the outer circumferential section 44 includes a cylindrical wall 58 , a bottom flange 60 , and a top flange 62 . a filament receiving area 64 is formed between the flanges 60 , 62 and the wall 58 . one or more lengths of a flexible filament 66 are wound within the area 64 . a plurality of first stop members 68 , whose function will be explained more fully hereinafter , are connected to and extend upwardly from the cylindrical wall 58 and top flange 62 . the stop members 68 are equal in number to the teeth 50 and are also spaced at equiangular 60 ° intervals . each of the first stop members 68 has an abutment section 70 , a downwardly sloping ramp section 72 extending from one side of the abutment section 70 , and a connecting section 74 which connects the stop member 68 to the top flange 62 and the cylindrical wall 58 . a slit 76 extends radially inward from the outer edge of the bottom flange 60 . a second slit 78 extends radially inward of the outer edge of the bottom flange 60 at a location disposed 180 ° from the first slit 76 . a slot 80 is formed through the bottom of flange a short distance radially inward of the slit 76 and along a radial line in alignment with the slit 76 . a corresponding slot 82 is formed through the bottom flange 60 adjacent the slit 78 . an innermost end of the filament 66 is passed through the slot 80 to aid in the attachment of the filament 66 to the spool means 36 . another length of filament 66 can be attached through the slot 82 . a guide drum 84 is disposed in a generally overlying relationship about the spool means 36 . the guide drum 84 is preferably formed of a hard plastic material and includes a central cylindrical section 86 , a medial section 88 , and an outer downwardly sloping guide section 90 . the central section 86 is formed of a cylinder 100 which has an inner surface 102 . the inner surface 102 has a diameter slightly larger than the outer diameter of the cylinder 46 . in this manner , the guide drum 84 is free to rotate relative to the support means 36 . the medial section 88 includes an inner annular disc portion 104 , an inner cylindrical portion 106 , a frusto - conical portion 108 , an outer annular disc portion 110 , and an outer cylindrical portion 112 . the inner annular disc portion 104 extends generally radially outward and perpendicularly from the cylinder 100 . the inner cylindrical portion 106 extends upwardly from an outer edge of the disc portion 104 . the frusto - conical portion 108 extends generally upwardly and outwardly from an upper edge of the cylindrical portion 106 . the outer annular disc portion 110 extends outwardly from an upper edge of the frusto - conical portion 108 and the outer cylindrical portion 112 extends generally downwardly from an outer edge of the disc portion 110 . in this manner , the portions 106 , 108 , 110 , 112 form a receiving area for the top flange 62 and the first stop members 68 . as best seen in fig1 the cross sectional configuration of the portions 106 - 112 has a mating contour to that of the top flange 62 and first top members 68 . also , as seen in fig1 , the outer cylindrical portion 112 extends downwardly below the top flange 62 and terminates adjacent to the lower flange 60 . the lower flange 60 has a larger diameter than the top flange 62 . the bottom flange 60 extends radially outward to the outer cylindrical portion 112 in order to prevent the entry of dirt , grass particles and the like into the filament receiving area 64 . the guide section 90 of the guide drum 86 includes a frusto - conical portion 114 which extends downwardly and outwardly from an outer surface of the cylindrical portion 112 and an upwardly curved lip portion 116 at the lower outer circumferential edge of the guide drum 84 . a pair of gaps or line outlets 118 are formed through the outer cylindrical portion 112 . a pair of line guide walls 120 , 122 extend from the cylindrical portion 112 on either side of each gap 118 . a curved guide member 124 extends from the radial outward end of each guide wall 120 and a curved guide member 126 extends from each guide wall 122 . the guide members 124 , 126 serve as curved bearing points for filament 66 exiting the guide drum 84 . to prevent premature wear of the guide drum 84 at the points of contact between the filament 66 and the drum 84 , a wear plate 128 is attached to a bottom surface of the guide drum 84 adjacent the guide members 124 , 126 . only a single wear plate 128 is shown on the left side of fig6 . a recess 130 which has the general shape of the bottom of the wear plate 128 is shown on the right side of fig6 . each wear plate 128 is received within a recess 130 . the recesses 130 have sufficient depth so that each wear plate 128 fits flush to remainder of the bottom surface of the guide drum 84 . each wear plate 128 has a base which lies flush within one of the recesses 130 and a pair of curved uprights . each curved upright fits flush around one of the guide members 124 , 126 . each wear plate 128 is secured in position by a line retainer 132 . each line retainer 132 has a generally inverted u - shaped configuration . a pair of legs or attachment plates 134 forms the base of the retainers 132 . a peg or post 136 extends from the bottom surface of the frusto - conical portion 114 and passes through a hole in each of the legs 134 to stake the line retainer 132 to the guide drum 84 . the line retainer 132 serves to secure the wear plate 128 to the guide drum 84 and also to hold the line 66 between the guide members 124 , 126 . a pair of strenghtening ribs 137 extend between the cylindrical portion 112 and the bottom surface of the frusto - conical portion of 114 in order to give additional strength to the guide drum 84 . a plurality of second teeth 138 extends downwardly from the inner annular disc portion 104 of the medial section 88 . each of the teeth 138 has an engagement or abutment surface 140 and a ramp or guide surface 142 . as seen in fig1 the abutment surface 140 of the second teeth 138 engages the engaging surface 52 of the first teeth 50 when the guide drum 84 is driven . the guide surface 142 slants upwardly away from the abutment surface 140 in the direction of rotation of the guide drum 84 . the slant of the guide surface 142 is approximately the same as the slant of the upwardly extending surface 54 . as will be explained more fully hereinafter , the surface 54 serves to guide the second teeth 138 upwardly out of engagement with the first teeth 50 . a plurality of second stop members 144 extends radially inward from an inner surface of the cylindrical wall 112 . as seen in fig8 - 11 , each first stop member 68 has a bottom surface 146 . the bottom surface 146 is slanted upwardly in the direction of rotation of the support means 36 and the guide drum 84 . the second stop members 144 similarly have top surfaces 148 slanged upwardly . the support means 36 and the guide drum 84 are so disposed that the top surface 148 passes below the bottom surface 146 during relative rotation between the support means 36 and the guide drum 84 . a generally frusto - conical shaped ring 152 is secured to a top surface of the portion 114 of the guide drum 84 . a plurality of pegs or posts 150 extends upwardly from a top surface of the frusto - conical portion 114 . the ring 152 has a plurality of holes extending through it for receiving the posts 150 . in this manner the ring 152 is secured or staked to the guide drum 84 . the ring 152 is preferably made of a metal material to add mass to the guide drum 84 . the purpose of providing additional mass will be explained more fully in the description of the operation of the apparatus . a guide drum 84 &# 39 ; is shown in fig1 . the guide drum 84 &# 39 ; has a number of alternate parts , which will be identified by new numerals . parts of the guide drum 84 &# 39 ; which are similar to the guide drum 84 will be indicated by primed numerals . a generally flat annular ring 154 is attached along the bottom surface of the guide drum 84 &# 39 ;. the ring 154 is utilized in place of the ring 152 to increase the mass of the guide drum 84 &# 39 ;. an outer cylindrical portion 156 forms a portion of the medial section of the guide drum 84 &# 39 ; and has a pair of gaps or line outlets 158 formed in it at 180 ° intervals . no line guide walls extend radially outward from the cylindrical portion 156 . a pair of curved guide members 160 , 162 are formed integral with the guide drum 84 &# 39 ; and extend downwardly from the bottom surface of the frusto - conical portion 114 &# 39 ;. a recess 164 is formed adjacent to each pair of guide members 160 , 162 . a wear plate 166 is received within each of the recesses 164 and is secured thereto by a line retainer 165 which is held in position by staking upon a pair of posts 168 that extend downwardly from the frusto - conical portion 114 &# 39 ;. as seen in fig1 and 15 , the wear plate 166 has a base 167 and a pair of curved uprights 169 , 171 . the guide members 160 , 162 , the wear plate 166 , and the line retainer 165 perform the same function as the corresponding parts in the drum 84 . each of the various alternate parts shown with the guide drum 84 &# 39 ; can be substituted for the corresponding portions in the guide drum 84 , without changing the other portions of the guide drum 84 . for instance , the guide walls 120 , 122 may be omitted from the guide drum 84 which still utilizing the frusto - conical ring 152 , or the guide walls 120 , 122 can be retained in the guide drum 84 while the ring 154 can be substituted for the ring 152 . the guide drum 84 is generally received about the support means 36 . a spring 170 is received about the drive shaft 32 and the inner cylindrical portion 106 . a top end of the spring 170 contacts a bottom surface of the fan member 34 and a bottom end of the spring 170 contacts a top surface of the inner annular disc portion 104 of the guide drum 84 . in this manner , the spring 170 biases the guide drum 84 downwardly against the spool means 36 . the first and second set of teeth 50 , 138 are thus biased into engagement as shown in fig1 . a braking or decelerating means is shown diagramatically as 172 . upon actuation , the decelerating means 172 rapidly decelerates the drive shaft 32 , and hence , the spool means 36 . the deceleration caused by the decelerating means 62 is at a rate much more rapid than the normal deceleration of the drive shaft 32 when the motor 28 is turned off . for example , the decelerating means 172 can bring the drive shaft 32 to a complete stop within approximately 0 . 3 seconds . the braking means 172 can be any conventional electric motor braking mechanism . a number of braking mechanisms are known in the art and , hence , the braking means 172 will not be described in detail . also shown diagramatically is an actuator switch 174 for activating the decelerating means 172 . the actuator switch 174 may be attached to an accessible portion 178 of the lawn mower 14 and connected to the decelerating means 172 by conductors 180 . when the filament lawn mower 14 is performing a cutting operation , the drive shaft 32 is rotated at a high speed , for example 8 , 000 rpm , by the electric motor 28 . during the cutting operation , the first and second sets of teeth 50 , 138 engage one another as shown in fig1 and in phantom line in fig1 . the portions of the apparatus 10 are moving from left to right in fig1 . assuming that an additional line filament is not needed and the motor 28 is merely shut off , the shaft 32 decelerates at a rate less than would be caused by the decelerating means 172 . during such an operation , the spring 170 maintains the guide drum 84 and the spool means 36 in the engaged driving condition shown in fig1 . when an additional length of the filament 66 is required , the decelerating means 172 is activated by the switch 174 while the shaft 32 is rotating . the shaft 32 and the spool means 36 are thus rapidly decelerated . however , the guide drum 84 is keyed for rotation with the spool means only by the engagement of the first and second teeth 50 , 138 . the guide drum 84 is thus free to continue rotation in the driving direction . the inertia of the guide drum 84 causes the guide drum 84 to continue rotation during the rapid deceleration . it has been found that when the guide drum 84 is constructed of plastic , rings 152 or 154 are desirable to increase the mass of the guide drum 84 in order to assure that the guide drum 84 has sufficient inertia to continue rotation during the rapid deceleration of the spool means 36 . the surface 54 guides the guide drum 84 upwardly during the continued rotation . the first and second teeth 50 , 138 thus disengage from one another and the second stop members 144 rotate and move upwardly below the lower surface 146 of the first stop members . see fig8 . the relative rotation between the guide drum 84 and the support means 36 continues until the second stop member 144 engages the abutment section 70 of the first stop member 68 . the guide drum 84 at this point has rotated a sufficient amount for the teeth 138 to be over the next successive teeth 50 . see fig9 and the full line of fig1 . thereafter , the guide drum 84 is forced downwardly and guided by the ramp section 72 so that the teeth 138 engage the next successive teeth 50 . see the phantom line of fig1 . fig1 illustrates the relative positioning of the teeth 50 , 138 and the stop members 68 , 144 at various points of relative rotation between the spool means 36 and the guide drum 84 . in this manner , the guide drum 84 is rotated a discrete amount relative to the support means 36 and a discrete amount of filament 66 is played out . as is obvious from the above description the amount of biasing force supplied by the spring 170 must be sufficient to keep the guide drum 84 in engagement with the spool means 36 during the normal deceleration of the drive shaft 32 but must be light enough to permit relative rotation between the guide drum 84 and the spool means 36 during rapid deceleration caused by the decelerating means 172 . while preferred embodiments of the present invention have been described above , certain variations should be considered within the scope of the invention . for example , while the guide drum 84 has been illustrated as the driven means and the spool means has been illustrated as a driving means , these functions could be reversed . also , while in the preferred embodiment , the apparatus 10 has been illustrated in use with a lawn mower , it should be obvious that the apparatus 10 could be used in other types of line filament vegetation cutters . also , the spring 170 could be precisely selected so that the biasing force of the spring 170 would return the first and second teeth 50 , 138 into engagement after the relative rotation of the guide drum 84 and the spool means 36 without the use of the first and second stop members 68 , 144 . numerous characteristics and advantages of the invention have been set forth in the foregoing description , together with details of the structure and function of the invention , and the novel features thereof are pointed out in the appended claims . the disclosure , however , is illustrative only , and changes may be made in detail , especially in matters of shape , size and arrangement of parts , within the principle of the invention , to the full extent extended by the broad general meaning of the terms in which the appended claims are expressed .

a device for metering discrete lengths of filament utilized in a flexible filament vegetation cutting device is disclosed . the line metering device is preferably used in flexible filament lawn mowers . an electric motor rotatively drives a drive shaft about its axis . a driving mechanism , preferably a spool is coupled to the drive shaft for rotation therewith whenever the drive shaft is rotated . a driven mechanism , preferably a guide drum , is selectively coupled for rotation to the driving mechanism . the spool has the flexible filament wound about it and is coupled to one of the driven and driving mechanisms for rotation therewith . the metering mechanism includes a device for rapidly decelerating the rotating drive shaft and driving mechanism , together with a device for disengaging the guide drum mechanism from the spool during the rapid deceleration whereby the guide drum is free to rotate a discrete amount relative to the spool . in this manner a length of filament is metered from the spool .

for purposes of this disclosure , the term “ aligned ” means parallel , substantially parallel , or forming an angle of less than 35 . 0 degrees . for purposes of this disclosure , the term “ transverse ” means perpendicular , substantially perpendicular , or forming an angle between 55 . 0 and 125 . 0 degrees . also , for purposes of this disclosure , the term “ length ” means the longest dimension of an object . also , for purposes of this disclosure , the term “ width ” means the dimension of an object from side to side . for the purposes of this disclosure , the term “ above ” generally means superjacent , substantially superjacent , or higher than another object although not directly overlying the object . further , for purposes of this disclosure , the term “ mechanical communication ” generally refers to components being in direct physical contact with each other or being in indirect physical contact with each other movement of one component affect the position of the other . particularly , with reference to the figures , fig1 depicts an example of a wrist band 100 connected to a wrist watch 102 . in this example , the wrist band has a first section 104 that is connected to a first side 106 of the wrist watch 102 at a first end 108 with a rod ( not shown ). the first section 104 includes multiple adjustment holes 110 and a display 112 . in this example , the electrical components of the display 112 are contained within an increased cross sectional thickness 114 of the wrist band 100 . in some cases , the increased cross sectional thickness 114 exists because the display 112 is part of a replaceable module that can be detached from the wrist band 100 . this replaceable module may be snapped into place on the wrist band 100 or otherwise attached to the wrist band 100 . in some cases , the replaceable module includes components associated with the display , such as a processing unit , a transmitter , memory , input mechanisms , a speaker , a microphone , sensors , other types of components , or combinations thereof . but , some of these components may be integrated into other portions of the wrist band 100 . when the replaceable module is connected to the wrist band 100 , electrical leads and / or wires may electrical connect the replaceable module with the other electrical components of the wrist band 100 . the wrist band 100 also includes a second section 116 that is attached to a second side 118 of the wrist watch 102 . the second section of the wrist band 100 includes a buckle 120 and loops 122 . while this example has the display 112 on a different section of the wrist band 100 than the buckle 120 and the loops 122 , the buckle 120 and the display 112 may be incorporated into the same section . any appropriate type of wrist watch 102 may be attached to the wrist band 100 . in this example , a wrist watch 102 with a mechanical time tracking mechanism is attached to the wrist band 100 . fig2 depicts an example of the wrist band 200 . in this example , the display 202 has a curved outer surface 204 . also , the display 202 is connected proximate the wrist watch 206 . the wrist band 200 increases in thickness where the display 202 is attached . in this example , at least some of the electronics associated with gathering information to be presented in the display 202 are housed in the increased thickness . fig3 depicts an example of the wrist band 300 with the wrist watch removed for illustrative purposes . in this example , a protrusion 302 extends from an inside surface 304 of the wrist band 300 . the protrusion 302 forms a shelf . on one side of the protrusion 302 , the protrusion 302 includes an electrically conductive material that can make contact with the user &# 39 ; s skin when the user is wearing the wrist band 300 . the other side of the protrusion may receive the wrist watch . in some cases , the other side of the protrusion includes an electrically insulating material to avoid interfering with the electrical signals that are sensed in the user &# 39 ; s skin through the electrically conductive side of the protrusion . the electrically conductive material may be in communication with a processing unit in another portion of the wrist band 300 . the electrical signals sensed with the protrusion may be processed in the processing unit to determine physiological information about the user . for example , this kind of information may be used to determine the user &# 39 ; s heart rate . in some cases , the bottom side of the protrusion includes multiple regions of electrically conductive materials that are spaced apart from each other to provide two different electrical contact points . this example allows the protrusion to sense an electrical potential . in other examples , the electrically conductive surface is a first skin contact that the user makes with an electrically conductive circuit incorporated into the wrist band 300 . another skin contact can be the user &# 39 ; s finger that is pressed against another electrode elsewhere in the wrist band , completing the circuit . in yet another example , a second electrode may be incorporated into another portion of the wrist band 300 . in some cases , there is just one skin contact in an electrical circuit with the wrist band and the user . fig4 is an example of the wrist band 400 without the wrist watch attached for illustrative purposes . in this example , no protrusions exists . however , the wrist band 300 may still acquire heart rate information to present in the display 402 . for example , the wrist band 400 may be in communication with a remote heart rate monitoring device worn by the user during a workout . in other examples , electrodes are incorporated into the inside surface 404 of the wrist band 400 that sense the electrical properties of the user &# 39 ; s skin . fig5 is an example of the wrist band 500 where the first and second sections 502 , 504 are attached . in this example , the buckle 506 of the second section 504 is fastened through the adjustment holes 508 in the first section 502 . fig6 depicts an example of a wrist band 600 that includes multiple links 602 . at least some of the links 602 are removable and / or replaceable . at least some of the links 602 may include electronic components that can be used to gather , process , or present information to the user through the display or another communication mechanism . for example , at least one of the links may include a transmitter , a processing unit , memory , a sensor , an electrode , a battery , a charging port , a speaker , a microphone , an optical sensor , an audio sensor , a chemical sensor , a pressure gauge , another type of sensor , another type of device , or combinations thereof . a first link and a second link may be connected to each other through a pin 604 . in those situations where the first and second link include electronics , the pin 604 may be used to transmit power and / or data between the first and second links . in one embodiment , the pin 604 includes an electrically conductive material that is surrounded by an electrically insulating material . signals ( e . g . power and / or data ) can be sent through the electrically conductive material while the outer electrically conductive material prevents the pin 604 from shorting out . the ends of the pin 604 may include regions that expose the electrically conductive material to the outside of the pin so that the electrically conductive material can make electrical connections with circuitry within the first and second links . fig7 depicts an example of a wrist band 700 that includes multiple links 702 . a display 704 is attached to the links 702 . in this example , each of the links 702 have a width that is shorter than the entire width of the wrist band 700 . fig8 depicts an example of the wrist band 800 made of links 802 where the links 802 are as wide as the width of the wrist band 800 . fig9 depicts an example of a system 900 incorporated into the wrist band . in this example , the system includes processing resources 902 in communication with memory resources 904 . the memory resources 904 include a movement type determiner 906 , a step counter 908 , an arm movement counter 910 , a calorie counter 912 , a distance determiner 914 , a heart rate determiner 916 , a respiration rate determiner 918 , a time displayer 920 , a stopwatch 922 , another type of programmed instruction , or combinations thereof . while the illustrated figure depicts the memory resources including specific types of programmed instructions , the memory resources may include any appropriate amount of programmed instructions and any appropriate type of programmed instructions . for example , the memory resources may include more or less programmed instructions than depicted in the illustrated figure . in other examples , the memory resources include more than just what is depicted in the illustrated example . in yet further examples , the memory resources may not include some of the programmed instructions depicted in the illustrated figure . the processing resources 902 are also in communication with i / o resources 924 . the i / o resources 924 may be in communication with a mobile device 926 , a phone 928 , a heart rate monitor 930 , a physiological sensor 932 , another type of remote device , or combinations thereof . while the illustrated figure depicts the i / o resources in communication with specific types of device , the i / o resources may be in communication with any appropriate number of device and any appropriate type of device . for example , the i / o resources may be in communication with more or fewer devices than depicted in the illustrated figure . in other examples , the i / o resources may be in communication with more than just what is depicted in the illustrated example . in yet further examples , the i / o resources may not be in communication with some of the devices depicted in the illustrated figure . also , the processing resources 902 may be in communication with components that are incorporated into the wrist band . these devices may include an electrode 934 , an accelerometer 936 , a display 938 , a global positioning unit 940 , other types of devices , or combinations thereof . while the illustrated figure depicts the processing resources in communication with specific types of devices , the processing resources may be in communication with any appropriate number of devices and any appropriate type of device . for example , the processing resources may be in communication with more or fewer devices than depicted in the illustrated figure . in other examples , the processing resources may be in communication with more than just what is depicted in the illustrated example . in yet further examples , the processing resources may not be in communication with some of the devices depicted in the illustrated figure . fig1 depicts an example of a watch band 1000 where the band is made of multiple links 1002 . displays 1004 are incorporated into the band 1000 . additional modules can be added to the band by replacing at least one of the links with a module . the module may communicate with the display &# 39 ; s memory , batteries , and processing resources through wireless communication protocols . in other examples , the chain links include electrical contacts where power and / or data is transferred through the chain links between the display modules 1004 and the additional modules . these modules may provide additional functionality , such as modules for determining heart rate , blood oxygen levels , temperature , glucose levels , acceleration , location , movements , and so forth . fig1 depicts an example of a pin 1100 that connects links , such as the links depicted in fig6 - 7 . in this example , the pin 1100 includes multiple electrical conductors 1104 housed in an electrical insulator 1102 . the electrical insulator 1102 may be a plastic or another type of insulator , that prevents the conductors 1104 from shorting to one another . the conductors may transmit power and / or data between links . in some cases , one of the conductors may transmit power , another may transmit data , and another may provide a return path to complete the circuit . while this example is depicted with just three conductors 1104 , any appropriate number of conductors may be incorporated into the pin 1100 . fig1 depicts another example of a pin 1200 that connects links , such as the links depicted in fig6 - 7 . in this example , the pin 1200 includes multiple electrical conductors 1202 , 1204 , 1206 that can transmit power and / or data between the links . in this example , the electrical conductors 1202 , 1204 , 1206 are concentric to one another and are separated a distance from each other with a dielectric material . the ends of the electrical conductors 1202 , 1204 , 1206 may be received in the links in a circular receptacle that makes an electrical connection between the electrical conductors 1202 , 1204 , 1206 and the receptacles . in some examples , the pin 1200 rotates with respect to one of the link and remains stationary with respect to the other link as the watch band moves . but , in other examples , the pin 1200 can move relative to each of the links as the watch band moves . in those examples where there is rotational movement between an end of the electrical conductors and the link &# 39 ; s receptacle , the circular ends of the electrical conductors can rotate within the receptacles without breaking the electrical connection . fig1 depicts a system 1300 where the band 1302 is in communication with remote devices 1304 , 1306 located in a shoe . the remote devices 1304 , 1306 in the user &# 39 ; s shoe may include an accelerometer , a sensor , or another type of device that counts the number of steps that the user takes . this remote device 1304 , 1306 may send and receive messages from the band 1302 . in general , the invention disclosed herein may provide a wrist band that includes electronic features . this wrist band may be worn in conjunction with a wrist watch that also includes electronic features . in this example , the wrist watch and the wrist band may communicate with each other and coordinate with each other to present features in either the wrist watch &# 39 ; s display or the band &# 39 ; s display . in other examples , the wrist band is connected to a mechanical watch or another type of watch that does not have the ability to communicate information gathered through the wrist band . in this example , the information gathered with the wrist band may be presented in the display incorporated into the wrist band or that information may be sent to a remote device where the information is presented , stored , and / or further processed . the display integrated into the wrist band may provide the user with helpful information that allows the user to make decisions about how active the user ought to be to reach fitness goals . the wrist watch display may show information like the estimated number of calories burned or other types of energy units intended to measure energy consumption . the wrist band may track the calories burned during the course of a workout and / or track the calories burned over a longer period of time . the wrist band may include an accelerometer which can measure movements of the user &# 39 ; s body to determine the number of steps taken by the user or measure other types of movement performed by the user . in some examples , the accelerometer is a multi - axis accelerometer that has the capability of distinguishing between stepping movements of the user , arm movements of the user , or other movements of the user . this type of accelerometer may record a pattern of vertical movements that occur at a substantially regular rate . the accelerometer or a processing device in communication with the accelerometer may determine that the recorded pattern corresponds with walking movements and that each of the vertical changes corresponds with a step . further , the accelerometer or a processing device in communication with the accelerometer may have an ability to recognize patterns that correspond to arm movements or other types of body movements . as a result , the wrist band may have the capability of recognizing different types of body movements that can be used to determine the type of exercise performed by the user , the number of repetitions performed by the user , the calorie burn associated with these body movements , other data , and combinations thereof . in some cases , the accelerometer may be used to determine the speed at which the user is moving . this may assist in determining the distance that the user is traveling during a workout or throughout the day . in other examples , the wrist band includes a global positioning system that identifies the user &# 39 ; s location , which assists the wrist band in determining the speed and distance traveled by the user . the global positioning system may also assist the user in determining directions to desired locations . the user &# 39 ; s stride length may also be determined with the accelerometer and / or the global positioning system . in some examples , the wrist band can detect the user &# 39 ; s heart rate . this may be accomplished by incorporating an electrode into the wrist band . the electrode may be located in any appropriate location along the wrist band . in one example , the electrode is incorporated into the band at the clasp that joins both sides of the wrist band together . in another example , the electrode is positioned adjacent an end of the band where the wrist band attaches to the wrist watch . in this example , the electrode may be incorporated into a protrusion that extends away from the wrist band . the protrusion may form a shelf with a first side that has an electrically conductive material . the electrically conductive material may be positioned against the user &# 39 ; s skin so that protrusion can sense the electrical pulses transmitted through the user &# 39 ; s body that regulate the user &# 39 ; s heart rate . a second side of the protrusion may be opposite the first side and may be adjacent to the back side of the wrist watch . in some cases , the wrist watch may be detachable from the protrusion . in some cases , more than one electrode is attached and / or incorporated into the wrist band . having at least two electrodes allows the wrist band to detect voltage differences , which can be used to assist in determining the heart rate . in some cases , the user can contact the electrode with his or her fingertip at a different location than where the electrode is contacting the skin about the user &# 39 ; s wrist . any appropriate type of electrical measurement may be read off of the internal electrically conductive pathway , such as a voltage differential , an electrical current , a resistance , or another type of electrical characteristic , or combinations thereof . while the above examples use the user &# 39 ; s electrical characteristics to determine the user &# 39 ; s heart rate , the user &# 39 ; s heart rate may be determined using other types of physiological characteristics , such as capillary exchange , bioelectrical signals , blood pressure changes , blood volume change , acoustic signals , other types of signals , or combinations . these types of physiological characteristics may be measured with sensors that are incorporated into the user &# 39 ; s wrist band . the data gathered with the wrist band may be used to determine the number of calories burned by the user . the calorie count may be at least partially based on the body movements of the user that are track with the accelerometer . in this example , the wrist band may use any appropriate calculation to estimate a number of calories burned by the user in response to body movements . for example , the wrist band may assume that each movement of the user is a predetermined fraction of a calorie . in other examples , the wrist band associates a higher calorie count to certain kinds of movements , speeds , and repetitions . in this example , the wrist band may associate a higher calorie burn for leg movements than arm movements because leg movements move the entire weight of the body while arm movements may be moving just the weight of the arm . other sensors may be incorporated into the wrist band to aid in determining the number of calories burned by the user . for example , a heart rate monitor may be incorporated into the wrist band to determine how hard the user is working . further , the wrist band may analyze the patterns from the accelerometer to determine how fast a user is walking . if the pattern reveals that a person is taking steps at a faster rate , the wrist band may associate a greater intensity of work being performed by the user and adjust the calorie count estimate accordingly . further , the wrist band may be in communication with other devices that are intended to measure other physiological parameters of the user that can be used as factors for determining the calorie count . for example , a thermometer may be positioned on the user to determine a temperature of the user . likewise , an oxygen analyzer that measures the user &# 39 ; s oxygen consumption may also be in communication with the wrist band . while these examples have been described with reference to specific devices and mechanisms that may be used in whole or in part for determining a calorie count , any appropriate mechanism for determining and / or estimating the user &# 39 ; s calorie count may be used in accordance with the principles described in the present disclosure . in some embodiments , the calorie count includes an estimated basal metabolic calorie count and an activity calorie count . to determine the basal metabolic calorie count , the wrist band may use information about the user . for example , the wrist band may request from the user information such as age , gender , height , weight , and other types of information that may be useful for determining the user &# 39 ; s basal metabolic calorie count . this information may be gathered from other devices that store the user &# 39 ; s personal information , such as a device that includes the user &# 39 ; s profile . in other examples , this information may be retrieved from another type of remote storage device . other types of parameters may be tracked with the wrist band and / or presented in the display of the wrist band . in some examples , remote devices may gather physiological information about the user , which can be transmitted to the user . other types of parameters that may be gathered and / or displayed with the wrist band include , but are not limited to , a breath rate , a distance traveled , a stopwatch , an arm movement count , another type of body movement count , a body temperature , a thermal characteristic of the body , a nutritional characteristic of the body , an electrical property of the body , a magnetic property of the body , a chemical property of the body , a pressure characteristic of the body , an average heart rate , a measured high heart rate , a measured low heart rate , a blood oxygen level , an ambient temperature , an atmospheric pressure , an ambient humidity , another atmospheric condition , an altitude , a current speed , a maximum measured speed , a sleep parameter , a fat loss parameter , a heart rate zone parameter , another type of characteristic of the body , or combinations thereof . sensors for determining these types of parameters may be incorporated directly into the wrist band or these sensors may be in remote communication with the wrist band . some of these remote sensors may be placed in the user &# 39 ; s shoe , clothing , sport bra , chest strap , other wrist , hat , ear , leg , upper arm , another location in the clothing , another location on the user , or combinations thereof . further , the wrist band may include other features , such as email features , texting features , calendar feature , contact features , alarm features , camera features , weather features , alert features , map features , direction features , compass features , location features , social media features , fitness trainer features , other types of features , or combinations thereof . in some examples , the wrist band can track at least one aspect about the user &# 39 ; s sleep . for example , the wrist band may track the user &# 39 ; s movements during sleep . the movements during sleep may be correlated with the sleep cycle in which the user is sleeping or be used to determine how deep the user is sleeping . the wrist band may use this information to determine how many calories the user is burning during sleep . additionally or alternatively , the sleep information may be used to analyze sleep patterns of the user . for example , the sleep information can be used to inform the user that the user experiences a deeper sleep at certain times at night , which may help the user determine when to go to bed . information collected by the wrist band during sleep may also be used to determine if the user snores , how hard the user snores , or determine another parameter about snoring . this information may be correlated with the user &# 39 ; s activity during the day . in some cases , the wrist band may find a relationship between the amount of energy expended by the user during the day and the amount of snoring done by the user at night . in these examples , the wrist band may make a recommendation to the user for making changes to the user &# 39 ; s sleep . in some examples , the wrist band can detect the time that is takes a user to fall asleep , the duration of the user &# 39 ; s sleep , the time that the user was in each sleep cycle , the time that the user was awake , the time that the user was restless , amount of oxygen consumed during sleep , oxygen saturation levels during sleep , other sleep parameters , or combinations thereof . these determinations may be made based on the user &# 39 ; s movements , heart rate , respiratory rate , location , information detected with a microphone incorporated into the wrist band , other types of measurements , or combinations thereof . further , the wrist band may recognize associations between the user &# 39 ; s daily activity , the user &# 39 ; s diet , other information recorded with the wrist band , or combinations thereof and the user &# 39 ; s sleep . for example , the wrist band may recognize patterns that when the user drinks a stimulate ( e . g . caffeine ) before bed that the user &# 39 ; s sleep experience changes . further , the wrist band may analyze the physiological results of the user &# 39 ; s sleep throughout the day or another time period following the user &# 39 ; s sleep . for example , the user &# 39 ; s heart rate , blood pressure , respiration , ability to lift heavy loads , other physiological results may be compared to the user &# 39 ; s sleep the night before or the sleep history of the user over a time period including multiple nights to determine physiological changes / responses to the user &# 39 ; s sleep experience . the wrist band may include a combination of hardware and programmed instructions for executing the functions of the wrist band . in this example , the wrist band includes processing resources that are in communication with memory resources . processing resources include at least one processor and other resources used to process the programmed instructions . the memory resources represent generally any memory capable of storing data such as programmed instructions or data structures used by the tracking system . programmed instructions that may be stored in the memory resources include a movement type determiner , a step counter , an arm movement counter , a calorie counter , a distance determiner , a heart rate determiner , a respiration rate determiner , a time displayer , a stop watch , other programmed instructions , or combinations thereof . while this example has been described with specific types of programmed instructions , any appropriate type of programmed instructions may be used , which may be more or less than the programmed instructions listed above . the memory resources include a computer readable storage medium that contains computer readable program code to cause tasks to be executed by the processing resources . the computer readable storage medium may be tangible and / or non - transitory storage medium . the computer readable storage medium may be any appropriate storage medium that is not a transmission storage medium . a non - exhaustive list of computer readable storage medium types includes non - volatile memory , volatile memory , random access memory , write only memory , flash memory , electrically erasable program read only memory , magnetic storage media , other types of memory , or combinations thereof . the movement type determiner represents programmed instructions that , when executed , cause the processing resources to determine the type of movement executed by the user based on the outputs from the accelerometer . if the movement type determiner classifies a movement as a stepping movement , the processing resources can cause the step counter to increase to reflect the number of steps taken by the user . likewise , if the movement type determiner classifies a movement as an arm movement , the processing resources can cause the arm movement counter to increase to reflect the number of arm movements executed by the user . in some examples , the movement type determiner can classify the movements as other types of movements , such as back movements , jumping movements , abdominal movements , core movements , other types of movements , or combinations thereof . the calorie counter represents programmed instructions that , when executed , cause the processing resources to count the number of calories burned by the user . the calories counter may draw from the step counter , the arm movement counter , or another type of counter to determine the calorie count . additionally , the calorie counter may also draw from a library to ascertain some of the variables used to calculate the calories burned , such as an age parameter , a weight parameter a gender parameter , another type of parameter , or combinations thereof . further , the calorie counter may also draw from an output of the pulse rate determiner . the distance determiner represents programmed instructions that , when executed , cause the processing resources to determine a distance traveled by the user . in some examples , the distance determiner obtains information from a global positioning unit to determine , at least in part , the distance traveled by the user . in other examples , the distance determiner obtains information from the step counter and information from a local or remote library . this information from the library may include a walking stride parameter and / or a running stride parameter specific to the user . the distance determiner may determine , based on output from the accelerometer , whether the user is running or walking and collect the steps taken by the user . in this example , the distance determiner may multiply the appropriate stride with the number of counts to determine a distance traveled . the heart rate determiner represents programmed instructions that , when executed , cause the processing resources to count the number of beats measured from the user &# 39 ; s pulse over a predetermined period of time with a pulse detector . the pulse rate determiner represents programmed instructions that , when executed , cause the processing resources to determine the pulse rate based on the pulse count measured with the pulse counter . the respiration rate determiner may represent programmed instructions that , when executed , cause the processing resources to determine the respiration rate of the user . in some examples , the respiration rate is determined by receiving a signal from a remote device that records the user &# 39 ; s respirations . the remote device may include a device that measures the user &# 39 ; s diaphragm movements or measures the user &# 39 ; s gas exchange during the user &# 39 ; s breaths . the wrist band may also include a time display that the user can view from the side of the user &# 39 ; s wrist . additionally , the wrist band can include a stopwatch function that allows the user to measure specific time periods associated with his or her workout or another type of event . further , the memory resources may be part of an installation package to be downloaded to the wrist band . in response to installing the installation package , the programmed instructions of the memory resources may be downloaded from the installation package &# 39 ; s source , such as a portable medium , a server , a remote network location , another location , or combinations thereof . portable memory media that are compatible with the principles described herein include dvds , cds , flash memory , portable disks , magnetic disks , optical disks , other forms of portable memory , or combinations thereof . in other examples , the program instructions are already installed in the wrist band . here , the memory resources can include integrated memory such as a hard drive , a solid state hard drive , or the like . the processing resources may be in communication with input / output ( i / o ) resources . such i / o resources may include a transmitter that communicates with remote computing devices . in some examples , the remote computing devices send information to the i / o resources . but , in other examples , the i / o resources send information to the remote computing devices . any appropriate type of transmitter may be used in accordance with the principles described in the present disclosure . for example , the transmitter may be a radio transmitter , an optical transmitter , an acoustic transmitter , an antenna , another type of transmitter , or combinations thereof . additional , any appropriate type of remote computing device may be in communication with the i / o resources , such as a mobile device , a phone , a wearable computing device , a heart rate monitor , a physiological sensor , a global positioning unit , a fitness tracking device , a fitness accessory , a digital device , another type of remote computing device , or combinations thereof . the fitness tracking device may be a remote server or a cloud based device that stores fitness data about the user . for example , the fitness tracking device may include a user profile that includes the user &# 39 ; s age , weight , height , gender , running stride , walking stride , other types of personal data , or combinations thereof . further , the fitness tracking device may include the historical activities of the user . for example , the fitness tracking device may include data about the workouts that the user has performed over time , the number of calories burned , the distance run , the user &# 39 ; s movement count , the user &# 39 ; s historical heart rate , the amount of weight lifted , the number of lift repetitions , other types of fitness data , sleep data , nutrition data , medical condition data , other types of data , or combinations thereof . the fitness tracking device may be wired or wirelessly accessible to the user over the internet . as a result , the user may access this information through his or her mobile device , electronic tablet , laptop , desktop , smart phone , other type of device , or combinations thereof . in this manner , the user can retrieve historical information about his or her workout . in some examples , the user has an option to share at least some of his or her fitness data with friends that also use a fitness tracking program associated with the fitness tracking device . in this example , the user can remotely compete with friends and family in athletic activities . an example of a fitness tracking program that may be associated with the fitness tracking device is the ifit program , which can be found at www . ifit . com ( last visited apr . 25 , 2014 ). the ifit program is available through icon health and fitness , inc . located in logan , utah , u . s . a . in some examples , the processing resources and the memory resources are located within the wrist band . the memory resources may be part of the band &# 39 ; s main memory , caches , registers , non - volatile memory , or elsewhere in the band &# 39 ; s memory hierarchy . alternatively , the memory resources may be in communication with the processing resources over a network . in this example , some of the memory resources may be located in one of the remote computing devices . further , the data structures , such as the library , may be accessed from a remote location over a network connection while the programmed instructions are located locally . the band may be in communication with an accessory . examples of these accessories may include pedometers , motion detectors , speedometers , blood pressure monitors , electrocardiogram electrodes , other types of electrodes , global positioning units , mobiles devices , smart phones , other watches worn by other users , cpap machines , other types of sensors that measures a physiological parameter of a user , other types of accessories , or combinations thereof . this accessories may be used to communicate data to the wrist band that can be used to at least assist with determining the appropriate measurement to display . further , the accessories may track information obtained from the wrist band . in some cases , this obtained information may transmit the data to a central location storage device , perform calculations , perform another task with the data , or combinations thereof . in some cases , the user &# 39 ; s personal information can be stored locally on the wrist band . in these examples , the information may be inputted into the band through an input mechanism ( e . g . touch screen , button , dial , switch , microphone , etc .). in other examples , the information is inputted into another device and sent to the band . in this example , the user can input information into the mobile device and send it to the wrist band . the user can input the user &# 39 ; s age , gender , weight , height , preferences , body composition , other types of user information , or combinations thereof . further , the user may input user activity that was not recorded with the wrist band . for example , if the user ran for twenty minutes without wearing the wrist band , the user may input that activity into the mobile device and communicate that information to the wrist band . also , the user may input the number of calories that he or she consumed and send that to the wrist band . in those examples where the wrist band tracks the number of calories burned by the user , the wrist band can track the net amount of calories based on the calories consumed by the user and the amount of energy expended by the user . to make this calculation , the wrist band may determine the number of calories that the user needs to maintain his or her body at rest . in some examples , the user inputs the number of calories that the user calculates that he or she consumed into the mobile device . in other examples , the user inputs the types of food and their corresponding amounts to into the mobile device . in this situation , the mobile device may calculate , based on the user &# 39 ; s input , the number of calories that the user consumed . alternatively , the mobile device may send the user &# 39 ; s eating information to the wrist band to determine the number of calories consumed . the user may also view information collected by the wrist band or view calculations performed by the wrist band on the mobile device . in some examples , the screen of the mobile device is larger than the either of the first or second displays of the wrist band , so the user may desire to view at least some of the information collected and / or calculated by the wrist band on the mobile device &# 39 ; s screen . in other examples , the mobile device may include a key pad that has more features or that are easier to manipulate than the input mechanisms of the wrist band , so the user may prefer to input data or otherwise modify data with the mobile device . also , in the illustrated example , the wrist band is a metal wrist band . but , any appropriate type of wrist band may be used in accordance with the principles described in the present disclosure . for example , a non - exhaustive list of wrist bands that may be used include leather bands , stainless steel bands , titanium bands , caoutchouc bands , textile bands , nylon bands , synthetic bands , gold bands , metal bands , silver bands , aluminum bands , mesh bands , expansion bands , silicone bands , velcro bands , clasp bands , strap bands , other types of bands , or combinations thereof . in one example , the wrist band may include multiple chain links that are connected to one another . such a chain may have the appearance of charm bracelet . one of the chain links may include a display , processing resources , and the battery . the band may receive additional functionality by added chain links that include sensors , transmitters , and other types of modules with different types of functionality . these additional modules may replace at least some of the current links in the band . examples of sensors may that may added in this style of bracelet include radiofrequency functionality , an ability to identify blood sugar levels , temperature , heart rate , acceleration , movement , oxygen level sensor , blood - pressure , location detection , global positioning systems , secondary three axis gyroscope , glucose monitoring , and so forth . these sensors or other types of sensors may be used to determine the user &# 39 ; s activities , like eating , sleeping , exercising , and so forth . knowing the user &# 39 ; s activity may help the processing resources interpret the readings that the sensors are measuring . in other examples , the added modules may resemble charms that hang from the bracelet . in some situations , the user may initially purchase the bracelet with standard features . but , later on , the user may purchase additional link modules that increase the bracelet &# 39 ; s functionality . in some examples , the modules in the chain bracelet models may be in wireless communication with each other . in yet other examples , the chain links provide an electrical contact for data and / or power transmission . any appropriate type of wrist watch may be connected to the wrist band . thus , the wrist watch may be a digital wrist watch , a mechanical wrist watch , or combinations thereof . the wrist watch may include a mechanical counting mechanism , an electronic counting mechanism , or another type of counting mechanism . in some examples , the wrist watch is in communication with a remote computing device that tracks the time of day and conveys time information to the wrist watch . one benefit of the present wrist band system is that a user may use their current wrist watch , and incorporate the present wrist band to convert their wrist watch to a smart wrist watch , merely by changing out the wrist band . further , the wrist watch may be any appropriate size and / or shape . compatible shapes may include generally circular shapes , generally rectangular shapes , generally square shapes , generally triangular shapes , generally star shapes , generally polygonal shapes , other shapes , or combinations thereof . in some cases , the wrist band includes a first display that may be viewed at a different angle than the display of the wrist watch . this display may be secured to the portion of the wrist band that faces the user when the wrist band is secured to the user &# 39 ; s wrist . the wrist band display may have a different look and feel than the display of the wrist watch . in some examples , the wrist band is connected to the wrist watch at an end of the band with a rod , however any appropriate alternative connection system may also be used . the orientation of the band &# 39 ; s display may align with the rod &# 39 ; s length . but , in other examples , the orientation of the band &# 39 ; s display is transverse the rod &# 39 ; s length . in yet other examples , the orientation of the screen changes based on input from the wrist band &# 39 ; s accelerometer . for example , as the user changes the orientation of his or her arm , the orientation of the display screen may change so that the display appears in an orientation that is convenient for the user . the band &# 39 ; s display may turn off due to lack of interaction by the user . in some examples , the band may determine , based on accelerometer input or input from other sensors , that the user &# 39 ; s arm that carries the watch is at the user &# 39 ; s side . in this situation , the display screen may turn off to conserve the band &# 39 ; s energy . the wrist band may include removable modules . for example , the display screen may be held in a housing forming part of the wrist band , and be detachable from the wrist band . as the display screen is attached to the wrist band , the display electrical connects with the other components of the wrist band so that the display can receive instructions from the processing resources . in some examples , the display can be snap into and out of the wrist band . circuit connectors may be incorporated into the back side of the display that make an electrical connection with wires or leads in the wrist band . the removable display screen may be attached to the wrist band using any attachment system including , but in no way limited to , a rod , screw , or other fastener ; an adhesive ; magnetic attachment ; an interference fit with the wrist band housing ; and the like . the other components of the wrist band may also be part of replaceable and / or removable modules . for example , processing resources , memory , a battery , another type of power source , a transmitter , an input mechanism , a microphone , a speaker , an accelerometer , a global positioning system , an electrode , a sensor , another component of the wrist band , or combinations thereof may be part of a removable and / or replaceable module . these modules may snap into the wrist band . in other examples , these modules may be screwed or otherwise fastened to the wrist band . in some cases , the modules may be secured to the wrist band with a pin , fastener , magnetic attraction , and the like . any appropriate type of removable module may be used . in some cases , the removable modules are links in the wrist band . the links may be secured to one another with pins . in these embodiments , the links may house different components of the wrist band &# 39 ; s electrical components . for example , one of the links may be dedicated to memory , a processing unit , a microphone , an input mechanism , a transmitter , a battery , a speaker , an accelerometer , another type of sensor , an electrode , or combinations thereof . in some cases , more than one link may be dedicated to each of the above mentioned devices . for example , more than one of the links may be dedicated to memory or processing resources . in other examples , at least one of the links is dedicated to more than one function . pins that connect the links to each other may include an electrically conductive material that may complete an electrical circuit when the pins are secured to both links . in one example , the outside of the pin includes an electrical insulator , which prevents the electrical circuit from shorting out if the outside of the pin comes into electrical contact with another electrical conductor . the inside of the pin may include an electrically conductive material that becomes part of the electrical circuit when securing both the pins to each other . the pin may include an exposed region , where the electrical insulator is removed and the pin &# 39 ; s electrically conductive material is exposed . the exposed region may touch electrical contacts in the links establishing an electrical connection between the pin and the internal components of the link . in an alternative example , the electrically conductive material is not exposed to the outside of the pin . in this example , the exposed region is replaced with an inductive coupling . the inductive coupling may include an electrically insulating , but magnetically conductive material , such as ferrite . in this example , the inductive coupling converts the electrical signal from the links into a magnetic signal , which passes down the pin &# 39 ; s internal electrically conductive material . at the other end of the pin , the electrical signal is again converted into a magnetic signal and passed to the link , where the signal is converted back into an electrical signal . while the electrical connection between the pins and the links has been described above with reference to specific types of connections , any appropriate type of electrical connection may be used in accordance to the principles described in the present disclosure . in some situations , the pins include multiple conductors . in one example , the pin is hollow and houses a pair of twisted wires in the hollow cavity of the pin . in other examples , the pin includes an electrically insulating material in its center which holds the twisted pair in place . in alternative examples , the multiple conductors may be parallel conductors where one of the conductors carries power , another of the conductors is the return , and the remaining conductor is for carrying data . the pin may also include a coaxial cable . one benefit of a coaxial cable is that the ends of the coaxial cable can be rotary contact with receptacles in the links on both sides . thus , the as links rotate as the watch band is moved , the electrical connections at the ends of the pin can be maintain without imparting fatigue into the conductors . in a similar example , the conductors may be incorporated into a tri - axial cable . the triaxle cable may include an electrically conducting core , with two electrically conductive and concentric shield spaced apart from each other and the core with a dielectric materials . one of these conductors may carry power , another one of the conductors may be a return line , and the final conductor may be for carrying data . the wrist band may include an operating system that sends and receives text messages , phone calls , alerts , timers , calendaring events , emails , workout instructions , and so forth . also , the wrist band may have the ability to play music or other types of downloadable programs , connect to the internet , recognize audio commands , covert speech to text , establish a wireless connection with other devices , control other devices through the wireless connection , provide real time directions and other types of navigation features , support other features , or combinations thereof . further , the wrist band may have the ability to download applications , such as from the apple store or another type of repository . in some cases , the battery may be a rechargeable battery . in this situation , the battery module may be removed from the wrist band and placed in a charger . in yet other examples , the battery module may be charged by induction or may include a receptacle that receives at least one prong of a plug - in . in this case , the rechargeable battery may be recharged without removing the battery module from the wrist band . while the examples above have been described with reference to the band being a wrist watch , the band may be attached to any appropriate location on the user . for example , the band may be worn on the user &# 39 ; s forearm , upper arm , neck , ankle , leg , forehead , other portion of the user &# 39 ; s body , or combinations thereof . the principles described in the present disclosure may be applied to necklaces , bracelets , ankle bracelets , chains , other types of jewelry , other types of bands , or combinations thereof .

a replacement wrist band may include a display and at least one replaceable module formed on the wrist band itself .

multiple embodiments of the disclosed devices , kits and methods are described with reference to only a few exemplary drawings . although a particular embodiment may be illustrated and described herein as including particular components in a particular configuration , such components and configuration are for exemplary purposes only . the figures and descriptions of the embodiments described herein are not intended to limit the breadth or the scope of the inventive concepts or the appended claims . rather , the figures and detailed descriptions are provided to illustrate the inventive concepts to a person of ordinary skill in the art and to enable such person to make and use the inventive concepts . with reference to fig1 - 2 , exemplary reinforcement device 10 is shown . reinforcement device 10 comprises a sheet of biocompatible material which is exemplified as mesh sheet 12 . the biocompatible material may be bioabsorbable , non - bioabsorbable , partially bioabsorbable , or some combination of one or more of these . the biocompatible material may comprise any of a number of materials . by way of non - limiting examples , bioabsorbable materials may comprise polyhydroxy acids , polylactides , polyglycolides , polyhydroybutyrates , polyhydroxyvaleriates , polycaprolactones , polydioxanones , synthetic and natural oligo - and polyaminoacids , polyphosphazenes , polyanhydrides , polyorthoesters , polyphosphates , polyphosphonates , polyalcohols , polysaccharides , and polyethers . by way of non - limiting examples , mon - bioabsorbable materials may comprise polyalkenes , polyethylene , fluorinated polyolefins , polytetrafluoroethylene , polyvinylidenefluoride , polyamides , polyurethanes , polyisoprenes , polystryrenes , polysilicones , polycarbonates , polyaryletherketones , polymetacrylates , polyacrylates , aromatic polyesters , and polyimides . mesh sheet 12 may comprise a single layer of material , or it may comprise two or more layers of material . separate layers of material may or may not be co - extensive in length and / or width . mesh sheet 12 may be at least partially woven or knitted . mesh sheet 12 have a reinforcing material 14 in or on at least a portion of the mesh sheet 12 . reinforcing material may comprise any of a number of biocompatible materials , including but not limited to synthetic composite materials such as polyglactin and / or poly p - dioxane undyed yarn . the reinforcing material can be applied to the mesh sheet 12 using any of a number of impregnating or application techniques . reinforcing material 14 may be in the form of ribs or strips on at least a portion of the periphery of mesh sheet 12 . reinforcing material 14 may also be applied in the horizontal direction as a plurality of spaced apart rows . although the strips of reinforcing material depicted in the drawings run the entire periphery of the reinforcing device 10 and include a plurality of spaced apart rows at a common length distance between adjacent rows , other configurations are contemplated . mesh sheet 12 also is equipped with two or more columns of hooks 16 a , 16 b that run parallel or substantially parallel to a longitudinal axis l of reinforcement device 10 . the hooks depicted are shaped like inverted u &# 39 ; s , which are similar to wickets used in croquet . other shapes and configurations of hooks are contemplated ; the hooks are structures though which suture may pass in sewing the reinforcement device 10 to the patient . these hooks 16 a , 16 b may be integrally formed with the mesh sheet 12 or added on or to the mesh sheet 12 using any of a number of methods . in the depicted embodiment , the common longitudinal distance between hooks within a spaced apart column is d 1 . one or more of hooks 16 a , 16 b may also be affiliated with an aperture 17 a , 17 b . in the depicted embodiment , each of hooks 16 a , 16 b is affiliated with an aperture 17 a , 17 b . the apertures 17 a , 17 b are sized and shaped so that a marking end of a marking device may mark a patient &# 39 ; s fascia where a needle and suture are to pierce a patient &# 39 ; s fascia to attach the reinforcement device 10 to the patient . the ability to mark fascia may provide guidance in the form of a template to a surgeon for precision of location in a suturing process . placement of apertures 17 a and 17 b is sufficiently distant from an incision point to avoid wound dehiscence . in the depicted embodiment of fig1 and 2 , the column with hooks 16 a and the column with hooks 16 b are on opposite sides of a longitudinal center region 18 that is substantially rectangular and encompasses center line 18 ′. center region 18 falls between the spaced apart columns of hooks . center region 18 extends from opposite ends of the mesh sheet 12 , top edge to bottom edge . the top edge and bottom edge are opposite each other and are perpendicular to or substantially perpendicular to the longitudinal axis of mesh sheet 12 . within this center region 18 , there is a reinforcing column of hooks 20 . hooks 20 may be of the same or a different material and / or configuration than the hooks 16 a , 16 b . hooks 20 may be supported by reinforcing material 14 . the longitudinal distance between hooks 20 is d 2 . in the depicted embodiment , d 2 is greater than d 1 . different configurations and variations between the length d 1 and d 2 are contemplated . for example , d 2 may be 1 . 5 × greater , 2 × greater , 2 . 5 × greater , 3 × greater , 3 . 5 × greater or 4 × greater than d 1 . different ratios may also be suitable . generally , reinforcement devices 10 may have a number of shapes and dimensions . in one non - limiting exemplary embodiment of a rectangular reinforcement device 10 , a horizontal width of mesh sheet 12 is about 5 cm , a longitudinal length is about 15 cm or about 30 cm , d 1 is about 1 cm , and d 2 is about 3 cm . the length of reinforcement device 10 depends upon the length of incision , and a surgeon may cut a commercially available reinforcement device 10 to fit the size of a particular incision . the about 5 cm width overlap of the incision may add tensile strength to the wound to assist in reducing the incidence of incisional hernias . generally , for about every 1 cm of d 1 required to close a particular incision , about 4 cm of suture may be used . stated another way , an exemplary ratio of suture length to wound length of 4 is one embodiment suited for prevention or reduction of incidence of incisional hernias . different dimensions and different ratios are contemplated ; those identified in this paragraph are merely exemplary teachings . referring to fig3 - 5 , examples are shown where a reinforcement device 10 is used in connection with the closing of an abdominal incision . the surgeon places the reinforcement device 10 over the fascia , attempting to align the center region 18 , and the center line 18 ′ with the incision itself . the surgeon may then mark a patient &# 39 ; s fascia through the apertures 17 a and 17 b to indicate where the needle and suture are to pierce fascia to sew the reinforcement device 10 to the patient . in one non - limiting embodiment , the apertures 17 a and 17 b are about 1 cm in horizontal distance from the center line 18 ′. the particular suture 22 and / or needle ( s ) ( not shown ) for use with the reinforcement device 10 may be provided in a surgical kit including the reinforcement device 10 , along with other medicaments , sterilizers , marking devices , cutting tools , and other medical devices and equipment . any of a number of commercially available sutures 22 may be used with the reinforcement device 10 . the suture 22 may , for example , be bioabsorbable or non - bioabsorbable . when the fascia is marked , a surgeon may position reinforcement device 10 in a position to commence suturing . such position may be intra - peritoneal or extra - peritoneal , depending upon the materials of the reinforcement device 10 . for example , non - bioabsorbable materials may be positioned to avoid potential for adhesion to internal organs . generally , the suturing involves inserting the sutures 22 through the fascia , then looping the suture through hooks 16 a to fascia to 16 b to fascia to 16 a to fascia to 16 b , etc . in a series of generally z - shaped formations or a series of generally x - shaped formations , possibly using a double needled suturing technique . eventually , as a suturing pattern encounters a hook 20 in its general path , the surgeon may gain additional reinforcement by passing the suture 22 at least once through and / or around hook 20 before completing the connection between a hook 16 a and a hook 16 b . an exemplary non - limiting suturing pattern is indicated in fig4 , and another in fig5 . other suturing patterns are contemplated . with regard to the devices , kits , methods , etc . described herein , it should be understood that , although the steps of such methods , etc . have been described as occurring according to a certain ordered sequence , such methods could be practiced in an order other than the order described . it should also be understood that certain steps could be performed simultaneously , that other steps could be added , or that certain steps could be omitted . the above description is intended to be illustrative , not restrictive . the scope of the invention should be determined with reference to the appended claims along with the full scope of equivalents . it is anticipated and intended that future developments will occur in the art , and that the disclosed devices , kits and methods will be incorporated into such future embodiments . thus , the invention is capable of modification and variation and is limited only by the following claims .

a reinforcement device comprises a sheet of biocompatible material equipped with a plurality of hooks for reinforcing the closure of a surgical incision , including elongated abdominal incisions . the reinforcement device , when implanted through surgery , reduces the likelihood of and / or prevents incisional hernias . the reinforcement device may be included in a surgical kit .

referring to the drawings in detail , reference character 10 generally indicates a paste dispensing toothbrush comprising an elongated shank member 12 and an elongated hollow cylindrical handle member 14 . the shank member 12 is provided with a plurality of bristles 16 near one end thereof and is also provided with an elongated longitudinal passageway 18 extending from an open end 20 of the shank member to and into communication with a plurality of ports 22 provided at the base of the bristles 16 . tooth cleaning and polishing paste material indicated by reference character 24 may be forced along the passageway 18 , through the ports 22 and into communication with the bristles 16 as will be hereafter set forth . the outer periphery of the end of the shank member is provided with a plurality of threads 26 for threadably receiving one end of the handle member 14 which is also provided with matching threads 28 . the open end 20 of the shank member 12 is provided with a centrally disposed recess 30 surrounding the end of the passageway 18 . the handle member 14 is provided with an elongated paste compartment 32 which typically extends through approximately one - half of the length of the handle and is in open communication with the shank passageway 18 when the handle 14 is attached to the shank member 12 . the outer end portion of the handle member 14 is provided with internal helical threads 32 which extend from the outer end of the paste compartment 32 to the outer end of the handle member . a rotary drive knob 36 is rotatably secured to the outer end of the handle member by means of a flange member 38 carried by the drive knob 36 and an annular groove 40 provided on the inside wall of the handle member adjacent the end thereof . an elongated drive rod 42 has one end thereof secured to the drive knob 36 , extends into the threaded drive compartment 34 and terminates adjacent the paste containing compartment 32 . the cross - sectional shape of the drive rod 42 is shown as being square in fig3 but may take on any polygonal shape or any other suitable shape to serve as a wrenching element for a purpose that will be hereinafter set forth . a drive disc 44 is threaded around the outer periphery thereof and is threadably disposed within threaded drive compartment 34 . the disc 44 is provided with a polygonal shaped aperture 46 for slidably receiving the drive rod 42 therethrough . the shape of the drive rod 42 and the cooperating shape of the aperture 46 of the disc serve to allow the disc 44 to slide along the rod 42 but to rotate therewith . hence , it can be seen that rotation of the knob 36 and associated drive rod 42 causes the disc 44 to be threadably moved along the drive compartment 34 in a direction determined by the direction of rotation of the knob 36 . a toothpaste carrying cartridge member generally indicated by reference member 48 is carryable within the paste compartment 32 of the handle 14 as shown in fig1 and 2 . the cartridge 48 generally comprises a cylindrical body portion 50 which is necked down to form a nozzle 52 at one end thereof and which is receivable within the open end 20 and recess 30 of the shank member 12 . a plunger or piston member 54 is slidably carried within the body portion 50 of the cartridge whereby the paste material 24 is carried between the piston member and the nozzle 52 . an elongated hollow piston rod 56 is secured to the piston 54 and extends outwardly from the cartridge body 50 for loosely receiving the drive rod 42 therein . the outer end 58 of the piston rod is engagable with the drive disc 44 . it is noted that the cartridge member 48 may be a disposable cartridge that is marketed as a pre - loaded toothpaste carrying cartridge for use with the toothbrush described herein . it is further noted at this point that the relative dimensions of the paste compartment 32 may be varied from the size shown in the drawings , taking up approximately half of the inner end of the toothbrush handle down to a smaller size if it is desired to provide a smaller amount of paste within the cartridge . the internally threaded drive compartment 34 simply needs to extend far enough into the handle member so that the paste may be substantially completely dispensed into the shank passageway of the toothbrush . it can be seen in operation that the shank member 12 and handle member 14 may be disengaged to dispose of a spent cartridge . after disposing of the spent cartridge , the knob 36 is rotated in a direction to move the drive disc 44 back up to a position adjacent the drive knob 36 . the device is now ready to receive another cartridge 48 therein . a new cartridge 48 , is then installed having its piston member 54 and associated piston rod 56 attached . the drive knob 36 and drive rod 42 may then be rotated along with the drive disc 44 . as the disc 44 rotates , it slidably moves along the rod 42 into contact with the outer end 58 of the piston rod 56 . further rotation of the drive knob 36 thereby pushes the piston rod 56 and associated piston member 54 through the cartridge body 50 thereby forcing paste out of the cartridge , through the passageway 18 , through the ports 22 and into communication with the brushing elements or bristles 16 . it is noted that it is entirely up to the user as to how much paste is disposed by simply rotating the knob 36 until the desired amount of paste appears at or around the bristles 16 . after brushing , the user may simply unscrew the shank member 12 and completely wash the bristles and the passageway 18 and then resecure the shank member 12 to the handle 14 with the cartridge still intact . the brush is now ready for subsequent usage . it is also noted that the entire device may serve as a cartridge whereby the entire toothbrush is a throw - away item and comes with the paste compartment 32 prefilled with paste 24 . however , at this point it is felt that such usage would not be economically feasible . referring now to fig4 reference character 48a generally represents a second embodiment of the cartridge having an identical body portion 50 and associated nozzle member 52 which is pre - filled with paste 24 . in this case , the piston and piston rod are formed as one single piece indicated by reference character 60 . a removable cap member 62 is placed over the open end of the nozzle 52 . upon use with the toothbrush hereinbefore described , the cap member 62 is simply removed from the nozzle and the cartridge then is inserted within the toothbrush handle and the shank member of the toothbrush as hereinbefore described . from the foregoing it is apparent that the present invention provides a toothpaste dispensing toothbrush apparatus having a positive drive system carried within the handle member . the apparatus also provides a disposable cartridge member which is simple and efficient in construction and operation for use with a toothbrush hereinbefore described . whereas , the present invention has been described in relation to the drawings attached hereto , other and further modifications apart from those shown or suggested herein may be made within the spirit and scope of the invention .

a toothbrush having a polishing paste compartment and a plunger apparatus for forcing paste through a passageway into communication with the bristles of the toothbrush . the compartment for containing the paste may be either a refillable container or cartridge or a disposable cartridge . the plunger is operated by a thumb wheel drive located at the end of the toothbrush handle .

the apparatus in fig1 includes a necked cylindrical roller 10 known as permanent wave rod , which may comprise lightweight plastic material , and may have reduced diameter extend 10a between somewhat enlarged flaring ends 10b to provide wound hair storage space . in each of fig1 , 5 and 8 the roller is shown as including a row of perforations 14 which serve to drain any excess liquid reagent . attached to one end 11 of the roller is one end 21 of a differential hair roller engaging and retaining band 20 . the other end 12 of the roller 10 may incorporate a removeably fitting plastic plug 30 , to which the opposite end 22 of the retaining band 20 is attached . fig4 shows the configuration of the apparatus as it would be in use , with hair wound in place . the retaining band 20 is of such a length that it is in a somewhat stretched condition when it is both attached to the end of the roller 11 and to the plug 30 , when the plug is fitted to the other end 12 of the roller 10 . as is shown in fig2 and 3 , the stretchable retaining band means 20 is comprised of stretchable material , rubber or other elastomer for example , that consists of a series of first portions 23 and second portions 24 . in this example , the first portions 23 are rod - like cylinders which , in the absence of the second portions 24 would comprise a band or cord of uniform cross sectional area with respect to the longitudinal axis 25 . the second portions 24 typically consist of generally spherical beads of larger cross sectional area than the portions 23 . an alternative second portion , in place of the spherical construction , shown in fig9 uses a beadlike portion that has a generally oval shaped cross section 26 in all planes that intersect the longitudinal axis 25 of the retainer 20 . the incorporation of second portions 24 on an otherwise uniform band 20 creates multiple spaces 15 between portions 24 , the band serving to retain hair 16 in a wound condition about the roller 10 . the creation of such multiple spaces 15 allows the hair to be retained in a wound condition with the additional advantages of the capability of hair treating lotion to pass freely about hair 16 that is retained in those spaces 15 irrespective of the closeness of the band to the roller . the non - uniform cross section of the retainer along its length with respect to its longitudinal axis 25 provides for , at most , local convex contact at 18 between multiple second portions 24 and the roller 10 or hair 16 . the elimination of line contact where the otherwise uniform bands contacts the hair 16 allows lotion to freely pass along the hair , and minimizes kinks and lines in the resulting curled hair . for simplicity of manufacture , the band end portions 21 and 22 referred to above may have generally spherical beadlike construction similar to that of the second portions 24 , described above , and are attached or molded integrally with respective first portions 23 . further , the end portions 21 and 22 are compatible with the typical attachment means depicted in fig4 and 7 . the construction shown in fig6 consists of a recess 41 extending radially inward with respect to the longitudinal axis 42 of the roller , partially into the roller from the surface 17 of the end portion 11 of the roller 10 . the recess 41 is sized to accommodate the end portion 21 of the retainer band 20 , and has a slit 43 extending from the recess 41 to the end face 44 of the end portion 11 . slit 43 is sized to accommodate a retainer first portion 23 while restricting passage therethrough of a retainer beadlike end portion 21 , integral with said first portion 23 . the construction shown in fig7 has similar attaching means as that shown in fig6 except that it is included in the plug 30 . as shown , a recess 31 extends partially into the cap 32 of the plug 30 from the end face 33 and parallel to the longitudinal axis 42 of the roller 10 and plug 30 combination . that recess 31 is sized to accommodate the other beadlike end portion 22 of the retainer 20 , and has a slit 34 extending from the recess 31 to the radially outwardly edge 35 of the plug 30 . slit 34 and recess 31 are sized and function with similarity to the recess 41 and slit 43 described above , to accommodate end portion 22 of the retainer and its respective integral first portion 23 . it is intended that the invention be capable of being used in conjunction with both a permanent wave rod type of hair roller 10 shown in fig1 - 7 and a generally cylindrical hair roller . the typically tubular roller 50 shown in fig8 includes end means 51 adapted for use with the end portions 21 and 22 of a retainer band 20 . said means 51 consists of a slit 52 extending from the end face 53 partially into the roller 50 . slit 52 is sized to accommodate a first portion 23 of a retaining band 20 while restricting passage therethrough of a retainer end portion 21 or 22 integral with said first portion 23 , such that end portion 21 or 22 is retained generally interiorly of the tubular roller 50 . one considered variation of the invention shown in fig1 incorporates beadlike second portions 24 of varying cross sectional area with respect to the longitudinal axis 25 so that localized convex contact 18 is maintained between multiple second portions 24 of the band 20 and the concave surface 17 of the permanent wave rod 10 . it should be noted that the above is a description of only certain preferred embodiments of the invention and that the scope of the invention is more accurately specified as in the following claims .

a differential hair engaging retainer to be used in combination with a hair roller , and comprised of stretchable means extending lengthwise of the hair roller for retainer hair about said roller and forming multiple spaces between said means and said roller , with or without hair extending therethrough , to permit lotions to pass therethrough in all positions of proximity of said stretchable means to said roller .

embodiments of the present invention will be described in detail with reference to the accompanying drawings . as shown in fig1 to fig5 , there is illustrated a side - pressing and casing self - locking type of automatic safe disposable blood sampling device , comprising a casing 1 , a lancet needle 2 , an elongated lancet needle cap 6 and a spring 3 . the casing 1 comprises an upper part and a lower part which are connected into an integral structure by using holes and pins provided on contacting surfaces thereof respectively . a launching chamber 4 is formed inside the casing 1 , and the lancet needle 2 and the spring 3 are arranged in the launching chamber 4 . the spring 3 is located behind the lancet needle 2 wherein the head of the spring 3 is caught in a catching groove 10 , and the tail of the spring 3 is caught on the catching plate 9 , thus forming an elastic sliding structure in a launching direction . a lancet needle - exiting hole 5 is provided at one end of the casing 1 in a direction consistent with the launching chamber direction . a cylindrical boss 7 is provided at the head of the lancet needle 2 , and a lancet needle tip 8 is extended centrally out of the boss 7 . further , a protruding ring 11 is provided circumferentially on the boss 7 . an elongated lancet needle cap 6 has a rod structure and is provided with a deep hole in a front portion thereof and a tail wing at a rear end thereof . the front portion of the elongated lancet needle cap 6 passes through the lancet needle - exiting hole 5 so as to fit over the boss 7 , and the elongated lancet needle cap 6 can be prevented from retracting accidentally from the boss 7 through engagement of the protruding ring 11 with the deep hole . a catch - launching mechanism and a self - locking mechanism are provided between the lancet needle 2 and a side of the casing 1 along a compression path of the spring 3 . as shown fig6 to 9 , the catch - launching mechanism comprises a second elastic arm 12 extended from a side of the casing 1 , a first elastic arm 13 extended from another side of the casing 1 , and a blocking notch 14 provided in the lancet needle 2 . the second elastic arm 12 and the blocking notch 14 are located at a bottom side of the casing 1 in fig1 to 5 , and the second elastic arm 12 is inclined towards to the inside of the launching chamber 4 . a cantilever end of the second elastic arm 12 is engaged with the blocking notch 14 so as to form a locking structure . the first elastic arm 13 serving as an press button is located at an upper side of the casing 1 in fig1 , and an intermediate section 13 - 1 of the first elastic arm 13 serving as a pressing portion is protruded from the upper side of the casing 1 in fig1 . an extension section 13 - 2 of the first elastic arm 13 has an inversed u - shape , and the lancet needle 12 is located between two legs 13 - 3 of the inversed u - shape extension section 13 - 2 while two legs 13 - 3 extend into holes provided on the casing 1 and pass across the launching chamber 4 respectively . distal ends of the two legs 13 - 3 contact or are close to the cantilever end of the second elastic arm 12 . the self - locking mechanism comprises barbs 15 provided respectively on two outer sides of the inversed u - shape extension section 13 - 2 , and self - locking hooks 16 provided at positions corresponding to the barbs 15 on the inner wall of the casing 1 . the self - locking hooks 16 are located on paths along which the barbs 15 are advanced . in order to protect the self - locking mechanism in a state in which the lancet needle 2 of the blood sampling device is not launched , the lancet needle 2 is provided with a first locking section 2 - 1 and a second locking section 2 - 2 . prior to be locked , the position of the second locking section 2 - 2 corresponds to that of the inversed u - shape extension section 13 - 2 as shown in fig1 , and the bottom side of the second locking section 2 - 2 has the same inclination and inclined direction as that of the second elastic arm 12 . the cross section of the second locking section 2 - 2 has substantially the same width from top to bottom , and widths of gaps formed between the two sides of the second locking section 2 - 2 and the inner walls of the casing 1 are smaller than that of the two legs 13 - 3 of the inversed u - shape extension section 13 - 2 . therefore , at this time , the inversed u - shape extension section 13 - 2 of the first elastic arm 13 can not move downwards . as a result , the barbs 15 on the inversed u - shape extension section 13 - 2 can not engage with the self - locking hooks 16 on the casing 1 so as to lock with each other respectively , as shown in fig7 . when the lancet needle 2 is pushed towards to the rear side ( right side in fig1 ) of the casing 1 , the first locking section 2 - 1 of the lancet needle 2 is moved rearwards so that the position of the first locking section 2 - 1 is brought to gradually come close to the position of the inversed u - shape extension section 13 - 2 of the first elastic arm 13 . the width of the cross - section of the first locking section 2 - 1 is decreased gradually from top to bottom , and the widths of gaps formed between two sides of the first locking section 2 - 1 and the inner walls of the casing 1 are equal to or larger than that of the two legs 13 - 3 of the inversed u - shape extension section 13 - 2 respectively . therefore , the inversed u - shape extension section 13 - 2 can be moved downwards so that the barbs 15 can be moved downwards along with the inversed u - shape extension section 13 - 2 so as to be engaged and locked with the self - locking hooks 16 on the casing 1 . before the cantilever end of the second elastic arm 12 is caught by the blocking notch , since the second locking section 2 - 2 has a larger width in the transverse direction of the cross - section thereof ( the cross - section of the second locking section 2 - 2 has a rectangle shape in the embodiment , as shown in fig7 ), the inversed u - shape extension section 13 - 2 of the first elastic arm 13 can not pass through the gaps formed between the inversed u - shape extension section 13 - 2 and inner walls of the casing 1 even if pressing the inversed u - shape extension section 13 - 2 , thus achieving the self - locking mechanism . the lancet needle 2 is brought into a locking state by pushing the elongated lancet needle cap 6 , at this time , the first locking section 2 - 1 of the lancet needle 2 corresponds to the inversed u - shape extension section 13 - 2 , since the transverse width of the cross - section of the first locking section 2 - 1 is decreased from top to bottom ( the cross - section of the first locking section 2 - 1 has a tapered shape in this embodiment , as shown in fig9 ), the widths of the gaps increase , so that two legs 13 - 3 of the inversed u - shape extension section 13 - 2 of the first elastic arm 13 can be inserted into the gaps formed between the inversed u - shape extension section 13 - 2 and inner walls of the casing 1 by pressing the inversed u - shape extension section 13 - 2 , contact with and act on the cantilever end of the second elastic arm 12 at last , thus causing the cantilever end of the second elastic arm 12 to disengage from the blocking notch 14 . as shown in fig1 , there is illustrated an end - pressing and casing self - locking type of automatic safe disposable blood sampling device , comprising a casing , a lancet needle 2 , an elongated lancet needle cap 6 and a spring 3 . the casing comprises a sliding sleeve 17 and an outer sleeve 20 , and an elastic catching member 19 is provided at a side of the lancet needle 2 . when the elongated lancet needle cap 6 is pushed , the lancet needle 2 presses the spring 3 . while the elastic catching member 19 is caught at an end of the sliding sleeve 17 , thus achieving locking . the self - locking mechanism comprises a barb 15 and a self - locking hook 16 , and the barb 15 is provided on the sliding sleeve 17 while the self - locking hook 16 is provided on the outer sleeve 20 . in operation , the elongated lancet needle cap 6 is first pulled out , then the outer sleeve 20 is held by hand of a user . thereafter , the lancet needle - exiting hole in the casing is directed at a region of a human body to be blood - sampled and the blood sampling device is pressed . at the same time , the sliding sleeve 17 is moved by an external force towards a closed end ( right end in fig1 ) of the outer sleeve 20 ( rightward in the fig1 ) inside an inner chamber formed inside the outer sleeve 20 . the bevel 18 forces the elastic catching member 19 to disengage from the sliding sleeve 17 , and the spring 3 pushes the lancet needle 2 along a guide groove ( not shown ) to launch the lancet needle 2 . then a lancet needle tip of the lancet needle 2 is ejected out of the lancet needle - exiting hole so as to puncture the region of a human body to be blood - sampled . at the same time , since the sliding sleeve 17 is slid towards the closed end of the outer sleeve 20 inside inner chamber of the outer sleeve 20 , the barb 15 is engaged and locked with the self - locking hook 16 . therefore , the sliding sleeve 17 can not further slide inside the inner chamber of the outer sleeve 20 , thus causing the blood sampling device to fail . while the present invention has been described with reference to the specific embodiments thereof , it should be understood by those ordinary skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention . in addition , many modifications may be made to adapt to a particular situation , material , composition of matter , process , process step or steps , to the objective , spirit and scope of the present invention . all such modifications are intended to be within the scope of the claims appended hereto .

an automatic safe disposable blood sampling device includes a casing with a launching chamber formed therein . the launching chamber has a lancet needle - exiting hole at a front end thereof ; a lancet needle arranged inside the launching chamber ; a spring ; a launching mechanism composed of the spring and a catch - launching mechanism ; a press - launching mechanism provided on the casing ; and a self - locking mechanism composed of barbs provided on the press - launching mechanism and self - locking hooks or notches provided on the casing which engage corresponding barbs . when pressed , the press - launching mechanism triggers the catch - launching mechanism , to disengage the lancet needle from the casing . the spring pushes the lancet needle so as to launch the lancet needle . during forward movement of the press - launching mechanism , the barbs pass across the self - locking hooks or notches . in the process of retraction , the barbs are locked with the self - locking hooks or notches and cannot return to their initial states .

referring to fig1 and 2 , a percutaneous needle guide 10 , made in accordance with an example embodiment of the present invention , is shown . the guide 10 includes a housing 12 having an inclinometer 14 , a linear needle measuring device 16 , and an adjustable needle holding device 18 . a percutaneous needle 20 is slidably received in the adjustable needle holding device 18 and is operatively coupled to the linear needle measuring device 16 . the adjustable needle holding device 18 is adapted to slidably hold any of a plurality of different diameter percutaneous needles along a z - axis that is perpendicular to a bottom wall 22 of the housing 12 . the bottom wall 22 of the housing 12 is used as a reference surface for further measurements . the inclinometer 14 , which may also be referred to as a clinometer or a level sensor , can take any of several known forms . the inclinometer 14 measures the inclination of the housing 12 relative to the earth &# 39 ; s gravitational field , and specifically , the position of the reference surface 22 relative to the earth &# 39 ; s gravitational field . in accordance with one example embodiment of the present invention , the inclinometer 14 could include a vessel 30 mounted in a top wall 31 of the housing 12 . the surface of the top wall 31 is parallel to the bottom wall 22 . those skilled in the art will appreciate , that for the purposes of the inclinometer 14 , the surface of the top wall 31 is , in effect , also a reference surface . the vessel 30 is , in accordance with one example embodiment of the present invention , generally circular shape , and includes a liquid 32 and a float 34 . the float 34 includes a centrally positioned indicator portion 36 that extends upward from the float . when the housing 12 has its bottom reference wall 22 perpendicular to the earth &# 39 ; s gravitational field , the indicator portion 36 is centered at the top of the vessel 30 . this is referred to as the zero angle position , i . e ., no inclination of the housing 12 . the vessel 30 includes angle indication markings 44 along an x - axis direction and a y - axis direction so that the position of the indicator portion 36 relative to the markings 44 will provide an indication of the angle of inclination of the housing 12 relative to the earth &# 39 ; s gravitational field . values along the x - axis represent pitch and values along the y - axis represents roll of the housing 12 relative to the earth &# 39 ; s gravitational field . the device 18 includes an adjustable screw 50 threaded into the housing 12 and into a needle receiving passage 52 of the housing 12 . a v - shaped needle holder 54 is slidably mounted in the passage 52 and receives the needle 20 positioned in the passage 52 and slidably holds the needle 20 so that its axis is parallel with the z - axis of the housing 12 . a linear measuring device 16 includes a first wheel 60 mounted for rotation about an axis 62 via an axle 63 . the first wheel 60 is positioned to contact the needle 20 when the screw 50 is turned so as to snug the v - shaped needle holder 54 against the needle 20 . the v - shaped holder 54 has a bearing surface that allows the needle 20 to slide along the z - axis . when the needle 20 is slid in the housing in a z - axis direction , the linear movement of the needle 20 causes the first wheel 60 to rotate about the axis 62 . a measurement tape 64 wraps around the first wheel 60 and a second wheel 66 mounted for rotation about an axis 67 on an axle 68 mounted substantially in parallel to the axis 62 . a measurement viewing window 70 is located in the housing 12 above the measuring tape 64 that allows the user to view a linear position measurement of the needle 20 . the position indication provided by the measurement tape can be calibrated so that a zero position indication can be provided through the window 70 when the needle tip 72 is positioned even with the bottom wall 22 of the housing . this is accomplished by sliding the needle 20 until a zero measurement is indicated in the window 70 , loosening the adjustment screw 50 until the needle 20 no longer contacts the measurement tape , slide the needle until the tip 72 is flush with the bottom wall surface 22 , then re - tightening the adjustment screw . the length of tape needed and the number of internal wheels need can be adjusted so as to permit sufficient linear measurement of needle movement to a selected z - axis depth . referring to fig4 and 5 , another example embodiment of a measuring device is illustrated including a single measurement wheel 80 operatively contacting the needle 20 and mounted for rotation about an axis 81 . the single wheel 80 includes measurement indications 82 . the wheel is mounted below a clear measurement window 84 for providing a measurement indication of linear needle position along the z - axis . the combination of the measurement wheel 80 and needle 20 can be calibrated in a similar manner as with the measurement tape . also , the vessel 30 could be filled with a supermajority of liquid except for a relatively small area of gas that forms a bubble 90 that would float and provide an indication of the inclination of the housing 12 . furthermore , the vessel 30 could be mounted in the housing 12 so that it could rotate about the z - axis of the housing 12 so that the angle indications could be rotated to any desired angle relative to an x and y axis of the housing itself . such an arrangement provides a different zero position option and angle reading option . referring to fig3 , an example use of the percutaneous needle guide 10 of the present invention on a patient 100 ( shown in cross - section ) is illustrated . assume that the patient 100 has a lesion 106 and nearby blood vessels 108 . further , assume that it is desired to biopsy the lesion using a percutaneous needle . it is desirable to have the needle enter the lesion 106 and not hit the blood vessels 108 . the patient 100 is first placed into an imaging gantry such as a ct scanner . images are obtained to identify the actual position of the lesion and blood vessels . the x , y angle θ is determined and the z axis depth is determined along a best path scenario to hit the target . the guide 10 is positioned onto the patient at the determined x , y angle and the needle inserted to the determined depth along the z axis using the guide measuring device . the inclination reading of the guide 10 and the z axis depth measurement are visible to the doctor so that the needle insertion could occur while the patient is in the gantry . also , the variable needle holding arrangement permits all needle sizes needed . referring to fig2 , adhesive mounting devices 110 could be attached to the bottom wall 22 of the housing 12 to aid in securing the housing 12 to the patient 100 during any procedure . in accordance with one embodiment , the adhesive feet 110 could be malleable flaps or other means for allowing the device 10 to adhere to the skin surface of the patient without requiring the device 10 to rest flush with the skin surface . in accordance with one example embodiment , the guide 10 is made of plastic with liquid in the inclinometer 14 . if the guide 10 is to be used with imaging devices other than ct scanners or mri scanners , then the guide 10 could be made with metal parts . for example , if the guide were to be used in a biopsy procedure using ultrasound guidance , the guide could have metal parts . also , under such uses , the inclinometer could be an electronic inclinometer instead of the float arrangement described . also , an electronic needle displacement measuring device could also be used in situations where metal is not a concern . using an electronic inclinometer and an electronic needle displacement measuring device permits use of a computer for monitoring and feedback of the sensor signals . from the above description of the invention , those skilled in the art will perceive improvements , changes and modifications . for example , the adjustable needle holding device 18 could be a different type of slidable securing means such as a tape , string , or plastic strap that fits into a groove in the housing 12 between the needle and the housing . once the needle is placed into the needle receiving passage 52 , the plastic strap is fed through the groove to take up the space between the needle and the housing or the “ v ” shaped member to hold the needle in operative contact with the measuring tape or wheel . also , rather than an inclinometer that uses fluid floats or bubbles , a weighted needle arrangement could be used with one needle for the x - axis and one needle for the y - axis . each x , y needle would pivot about its associated mounting axle with the weighted end below the pivot point . such improvements , changes and modifications within the skill of the art are intended to be covered by the appended claims .

a percutaneous needle guide includes a housing and an inclinometer secured to the housing for sensing a two dimensional inclination of the housing relative to the earth &# 39 ; s gravitational field and for providing an indication thereof . a percutaneous needle is slidably mounting to the housing in a fixed axial orientation relative to the housing . a needle measuring device is mounted in the housing and operative by linear motion of the percutaneous needle so as to measure the linear position of the percutaneous needle relative to the housing and providing a measurement indication .

referring now to the drawings in which like reference numerals refer to like or corresponding elements among the several figures , there is shown in fig1 a front view of a medical instrument 20 , which in this embodiment comprises a modular patient care system having a controller 22 located in the center and three functional clinical devices that are mounted on either side of the controller . in this case , the clinical devices comprise an infusion pump module 24 mounted to the left side of the controller , a syringe pump 23 mounted to the right side of the controller , and an oximetry module 25 mounted to the right side of the syringe pump , also to the right of the controller . the infusion pump and syringe pump provide medical fluids to the circulatory system of a patient while the oximetry module monitors the level of oxygen in the blood of a patient . a system of this sort is more fully described in u . s . pat . no . 5 , 713 , 856 entitled “ modular patient care system ” to eggers et al . incorporated herein by reference . the controller comprises a processor and memory for storing data and programs and for executing those programs . data may be obtained from the clinical devices 23 , 24 , and 25 interacting with the controller and the programs are for controlling the operation of the controller and the clinical devices . while the following embodiments of the present invention will be described in the context of a modular patient care system , various types of medical instruments , including those forming individual standalone units , as well as modular systems , are contemplated . further , when applied to a modular system , the clinical devices interacting with the controller need not be in physical contact with the controller . the infusion pump module 24 depicted in fig1 is a large volume parenteral pump (“ lvp ”) configured to deliver fluid at a controlled rate to a patient ( not shown ). in addition to the infusion pump mounted to the controller 22 and controlled separately by the controller , other functional medical instruments or clinical devices or modules , such as those providing patient monitoring , may be liked together with the infusion pump or other instrument in a practice configuration . for example , the syringe pump 23 may be linked with the oximetry medical instrument 25 to operate in a patient - controlled analgesia (“ pca ”) configuration . in such an arrangement , the syringe pump delivers analgesia to the patient on the command of the patient ; however , the controller may override the patient &# 39 ; s command based on the data concerning the patient &# 39 ; s blood - oxygen saturation provided by the oximetry medical instrument . in such an example , the controller is enabled to provide the features of the infusion pump , the features of the syringe pump , and the features of the oximetry instrument , as well as provide further features in operating the syringe pump and the oximetry instrument in a pca practice configuration . other examples of features that may be provided by the controller and instruments or modules mounted with and under the control of the controller include capnography monitors , invasive or non - invasive blood pressure monitors , and others . in the case of the medical instrument 20 shown in fig1 and in other figures , the clinical devices including the infusion pump 24 , the syringe pump 23 , and the oximetry module 25 can be connected on their left or right sides to the controller 22 or to another clinical device . in the example shown , the right side of the infusion pump is mounted to the left side of the controller and the left side of the syringe pump is mounted to the right side of the controller . other clinical or modules , including another infusion pump or pumps , may be mounted to the existing clinical devices . further details may be found in u . s . pat . no . 5 , 713 , 856 to eggers . in this embodiment , the controller 22 provides a centralized interface for the various attached functional clinical devices 23 , 24 , and 25 , performing various functions for the clinical devices such as programming and communications . in this embodiment , the controller is also used to provide power to the mounted clinical devices , to provide an interface between the patient care system 20 as a whole ( including the attached modules ) and external servers , and other devices , and to provide most of the clinician interface for the pumps and the oximetry module . the controller includes a display 26 for visually communicating various information , such as the operating parameters of the pump , as well as displaying alerting and alarm messages . the controller also includes control keys 28 for programming the attached functional clinical devices . as is further shown in fig1 , the infusion pump 24 also has a display 30 , such as an led display , located in plain view on the door in this embodiment and may also be used to visually communicate various information relevant to the pump , such as the current infusion rate and alarm messages . control keys 32 also located on the front panel of the infusion pump exist for controlling certain operations of the infusion pump , such as pausing or resuming an infusion . both of the other instruments 23 and 25 mounted to the controller have displays 30 and control keys 32 also . referring now to fig2 , a block diagram of components of the controller 22 is shown . the controller includes an audio alarm 36 that may be used in conjunction with the display 26 to alert the operator to various conditions , such as programming or operating errors , alarms , and other advisories . the controller also has external communication ports 38 , such as rs - 232 serial ports , with which it may communicate with a medical facility server or other computer and with a portable processor that a clinician may have to transfer information as well as to download drug libraries or other data and programs . in addition , the controller in one embodiment includes a communications interface 40 which provides a personal computer memory card international association ( pcmcia ) slot for receiving pcmcia cards . the examples presented here are for illustration purposes only , and one skilled in the art could readily select from a variety of commercially available communication means . for instance , the controller may be equipped with various wired systems and with various wireless systems , such as an rf ( radio frequency ) system , an infrared system , a blue tooth system , or other . in the embodiment shown in fig2 , an external communications controller 42 controls the command and data flow through the ports 38 , while the processor 54 of the controller directly controls the communications interface 40 . the external communication ports 38 , communications interface 40 , and control keys 28 may all be used as input devices through which information may be entered to the system 20 . the controller may also include other input devices such as a bar code scanner ( not shown ) for scanning information relating to the infusion or rfid interrogator for reading information from passive or active rfid tags . the controller 22 contains a power input 44 for receiving power from an external power source ( not shown ) and forwarding that power to a power supply 46 . additionally , an internal power source 48 , such as a battery , may be used to maintain power to the system functions , including memory , when the controller is disconnected from an external power source . a power manager 50 controls the switchover between the two power sources , controls the charging of the internal power source and monitors the remaining capacity and power consumption of the internal power source to estimate the remaining system runtime on the internal power source . the power supply also provides power to any attached modules , such as the infusion pump 24 , through power ports 51 and 52 . the processor 54 accesses and executes a computer program or programs 56 that control the operation of the overall medical instrument , i . e . patient care system 20 , including aspects of any attached medical instrument modules . the processor 54 communicates with the attached modules via an internal communications controller 57 that controls the command and data flow to the attached modules through the internal communications ports 58 and 60 . in this embodiment , the computer program 56 is resident in the controller 22 of the patient care system 20 , as shown in fig2 . more particularly , the computer program is stored or embedded in a memory 62 in one embodiment . it is to be understood that the memory 62 as well as other memories in the patient care system 20 , may be any type of memory or any combination of memories that can be erased and / or reprogrammed without having to physically remove the memory from the system . examples of such memories include , but are not limited to , battery - backed random access memory ( ram ) and “ flash ” electronically erasable programmable read only memory ( flash eeprom ). a battery backup 64 provides power to the memory 62 in the event of loss of power from both the external and internal 46 and 48 power supplies . the program 56 provides control over the controller features and the features of the medical instruments mounted to the controller , in this case the infusion pump 24 , the syringe pump 23 , and the oximetry instrument 25 . an example of controller features may be the basic operating controls over certain mounted instruments such as rate , time , and vtbi for the pumps . another example may be the acceptable oxygen saturation settings ( high and low ) for the oximetry module . additional features for the controller may be certain displays of trends for example , or identification of the patient , medication being administered , or drug libraries . in addition , the program may provide for the ability to program practice packages as described above . the features associated with pca may be made available by the program . in such a case , the data of the oximetry instrument is analyzed and used to control the syringe pump . many other features may be made available by the program 56 . the program typically has a main control program with a plurality of subprograms directed to a single feature , multiple features , predetermined combinations of features , or practice packages . additionally , each medical instrument mounted to the controller may have its own resident program that will likewise provide features of operation of the respective instrument . for example , the program in each pump instrument 23 and 24 may have the features of rate , time , and vtbi while the program in the oximetry instrument may provide the features of the acceptable oxygen saturation settings ( high and low ). fig3 is a block diagram that illustrates components of the infusion pump medical instrument 24 . along with the display 30 , an audio alarm 65 serves to alert the operator to certain conditions , such as the completion of an infusion or a downstream or upstream occlusion in a fluid line for example . the display 30 and control keys 32 are controlled by the control key / display controller 66 . the infusion pump 24 receives and processes data and commands from the clinician and communicates with the attached controller 22 through a support processor 68 and an associated memory 70 . as in the controller , the memory has a battery backup 72 that assists in retaining stored data and programs during periods where the main power source is not available . the infusion pump receives power from the controller via one or the other of the power ports 74 and 76 depending upon which side of the controller the infusion pump is mounted . a power manager 78 controls the distribution of the power from the power ports 74 and 76 to the pump . the pump also contains an internal communications controller 82 , which may send or accept data or commands from the controller through the communication ports 84 and 86 , again depending upon which side of the controller 22 the infusion pump is mounted . the infusion pump 24 also contains typical components of commercially available pumps , such as a motor controller 88 for controlling a pump motor 90 and a sensor controller 92 to obtain indications from sensors 94 which illustratively may be used to detect pump mechanism speed and fluid pressure , air - in - line , and flow stoppage . other sensors may exist in other embodiments and may be monitored by the support processor 68 or other devices . the indications received by the sensor controller are monitored by the support processor as well as a safety processor 96 to activate alarms and / or stop the operation of the pump when undesired events are detected . the motor controller 88 and pump motor 90 may be any suitable peristaltic pump motor / motor controller combination . fig4 shows a block diagram generally illustrating an embodiment of the computer program 56 in accordance with principles of the invention . as mentioned above , the computer program is resident in the controller 22 ( fig1 ) in this embodiment and controls the operation of the medical instrument 20 . the resident program provides a plurality of operating features 98 that may be combined in various combinations to form different operating configurations 100 for the system 20 . although the program can provide features of the controller itself , the designation “ controller ” has been left off fig4 . instead , other features related to the pumps and oximetry ( spo 2 ) instrument are discussed . the various operating features of the infusion pump 24 (“ lvp ”) of fig1 and 3 are illustrative of types of operating features 98 the resident computer program 56 may provide a medical instrument . the pump typically provides several basic operating features including flow rate control , control over the infusion time , and control over the volume - to - be - infused . the basic operating features may also include the activation of alarms in response to error conditions detected by the various sensors 94 . features are indicated symbolically through the use of the alphabetical characters “ a through e ” for the infusion pump , “ e through i ” for the syringe pump , and “ j through n ” for the oximetry instrument . in addition to these basic operating features , the infusion pump 24 or syringe pump 23 may include other operating features . whether located in the controller 22 or the pump itself , the feature of a drug library that stores data such as drug names , concentrations , rates , and maximum allowable doses , or other parameters may be provided for operation of the infusion or syringe pump . the feature of a drug infusion rate calculator may also be provided . further , the features of complex drug delivery procedures , such as multiple rate volume infusions and automated ramp up - taper down infusions may be provided . features of multi - channel coordinated infusions , multi - dose infusions , secondary or “ piggyback ” infusions , bolus dosage and delayed start infusions may also be made available by the program . the controller 22 , pumps 23 and 24 , and oximetry instrument 25 , as well as other instruments that may be mounted or connected together , may also support features related to “ practice packages .” operating features tailored for particular practice areas or locations of use in a hospital such as the operating room (“ or ”), oncology (“ onc ”), or pediatrics (“ ped ”) wards or rooms may be made available . these practice packages may provide , for example , the specific operating parameters , alarm thresholds and available overrides appropriate for the designated practice area or hospital location as well as other specific practice - related data , controls , and displays of information . although various operating features 98 have been described with respect to the medical instrument configuration shown in fig1 consisting of two pumps 23 and 24 and a patient monitor ( oximetry ) instrument 25 , a plurality of operating features 98 may similarly be provided for other modules that may be mounted to form a part of a patient care system 20 . in the embodiment shown in fig4 , a pulse oximeter ( spo 2 ) and syringe pump , each having a plurality of operating features 98 , form a part of the patient care system 20 along with the infusion pump . in the case shown and described in fig1 through 4 , the resident program 56 ( fig2 ) is a complete program including all subprograms necessary to operate the controller 22 with any instrument that may be mounted to it directly or indirectly and to provide any and all features that it and such instruments are capable of providing to a clinician or other operator in any combination or practice package . basic operational features included in the program as well as the most advanced and complex features designed . therefore , only one program is needed for any such medical instrument because that program contains all features that exist as of the day the program is installed into a medical instrument . however , in accordance with aspects of the invention , access to those features is controlled , as discussed below . the computer program 56 controls access to the various operating features 98 of the medical instruments with which it is associated . in particular , the operating features 98 may be selectively activated or deactivated to form combinations of operating features to place the instrument in the various operating configurations 100 . the computer program 56 includes a feature access control component 102 that inhibits the use of an operational feature unless it has been activated . in one embodiment , certain basic operational features may be available at all times , regardless of the feature access control component status . for example , the basic features of rate , time , and vtbi may always be available to any operator . however , in another embodiment , no operational feature is available without the respective feature being activated by the feature access control component . in accordance with aspects of the invention , a feature access key 104 may be used with the feature access control component 102 to activate operational features of the medical instrument . the feature access control component will selectively activate and deactivate features depending on the contents of the feature access key 104 . the feature access key may be communicated to the processor 54 ( fig2 ) via any of the input devices of the medical instrument , such as the control keys 28 ( fig1 ) or interface 40 such as by use of a personal digital assistant (“ pda ”) or other device . the key may also be given by remote server in the case where the medical instrument is in contact with it . in another embodiment , the computer program 56 is responsive to the access key 104 to activate a plurality of different features , configurations , and practice packages . additionally in one embodiment , an access key exists that will activate all possible features of the medical instrument . such access key is typically termed a “ master ” access key and is independent of the release number or version number of the program . turning now to fig5 , an embodiment of a feature access key 104 according to aspects of the present invention is shown . in this embodiment , the feature access key is a binary string , although it will be understood by one skilled in the art that the access key may be provided in other forms as well , such as an alphanumeric string . in fig5 , the feature access key 104 includes twelve bytes , with the first two bytes 105 being used to identify the version number of the computer program . in one embodiment , the version number contains two parts , a release number , which is stored in the first byte , and a revision number , which is stored in the second byte . the version number identified by the access key must match the actual version number of the computer program of the medical instrument for the access key to be valid in this embodiment . a data area 106 follows the software version number in the binary string . the data area 106 contains a two - byte section for the ctrlr ( controller ) and each module type supported by the controller , which , in fig5 , includes an lvp ( infusion pump ), an spo 2 ( pulse oximeter ), and a syringe ( syringe pump ). although only three module types are supported in the embodiment of fig5 , the data area 106 may be expanded to support any number of module types that are part of the medical instrument . the first bit in each two - byte section for the modules indicates whether the module is supported by the patient care system . two bits per byte , such as the lowest bit in each nibble , are reserved for use with an integrity check , or an error checking technique , such as cyclical redundancy checking (“ crc ”) or , as in this embodiment , a checksum . the remaining bits in each two - byte section indicate which optional operating features associated with the particular module type are to be activated and deactivated . the last two bytes 107 of the access key 104 in this embodiment are used for a checksum . the checksum provides a security feature against attempts to enter an access key that activates features that have not been authorized for use . the reserved bits in the data area 106 are manipulated to give a desired checksum value that is stored in the last two bytes 107 . the form of the feature access key may vary , only one embodiment is shown and described for purposes of illustration . for example , other data integrity checks or data error checking techniques may be used , such as but not limited to a crc technique or similar data integrity checks . fig6 shows a method 120 for controlling access to features of a medical instrument , according to aspects of the present invention . this particular medical instrument has a plurality of operating features such as shown in fig4 that are combinable in different combinations or usable alone . these features control the operation of the medical instrument . the method is begun at 122 and at step 124 , a program that includes all operating features that may be selectively activated or deactivated in combinations to place the medical instrument in any of a plurality of operating configurations is installed . the entire computer program is installed in the memory of a controller of the medical instrument such that the computer program is resident within the system available to the controller and controls the operation of the medical instrument and the selection of the operating configuration of the system . step 124 may be performed at the manufacturing site for the medical instrument ; installation of the computer program may also occur through flash upgrading in the memory to include new features and combinations of features available for possible selection by the controller . the program inhibits 126 the use or activation of features , combinations of features , and practice packages without an access key . as discussed above , in one embodiment , certain operational features may be available regardless of the existence of an access key and a decision 128 may be made that these are sufficient for the operation of the pump 130 for the present patient . for example , the features of rate , time , and vtbi may be available for use with the pump and this may be sufficient for present purposes . however , if other features are desired 128 , the method now requires the entry of an access key 132 . the access key is checked 134 and if certain information correlates thereby authenticating the access key , the data of the access key is received and is used to activate operational features of the medical instrument 136 . the pump is now operated 130 with the additional features . if the access key cannot be authenticated , the method returns to the decision box of “ other operational features needed ?” 128 . during operation of the medical instrument , such as the pump example used in fig6 , if it is decided that further pump configurations are needed 138 , an access key is entered 132 so that those configurations may be activated . the use of the access key in accordance with aspects of the invention provides for a single program to be validated for all medical instruments instead of multiple programs that have been customized for each customer order . in accordance with the invention , all programs and subprograms necessary to control the medical instrument are resident in the medical instrument and simply need to be activated to be available for use . no further installations of programs are necessary to obtain further features . for example , marketing or sales personnel assisting a customer in the selection and use of the medical instrument features and configurations can identify which operating configurations the customer may find useful and may simply provide the customer with the necessary access key corresponding to that operating configuration or configurations at that time . the customer , or the sales personnel , can then enter the feature access key into the controller of the medical instrument via an appropriate input device to obtain the desired operating configuration . in another embodiment , the access key may be entered into the medical instrument by the manufacturer remotely over the internet or other communication means so that the customer need not become involved in such reprogramming . at step 136 , the feature access control component 102 ( fig4 ) responds to the feature access key 104 to activate and deactivate respective operating features 98 of the medical instrument . as a result , the instrument may be placed in the particular operating configuration or configurations corresponding to the access key data fields . the clinician may then operate the medical instrument accordingly . in one embodiment , operating features that have not been activated or that have been deactivated by the access key are not displayed as options on the display 26 or shown any other way . accordingly , the clinician would not be distracted by options that can be seen but not used . in a further embodiment , attempted use of an incorrect feature access key will result in the medical instrument ignoring the incorrect access key . in another embodiment , the attempted use of an incorrect access key will cause the medical instrument to revert to the basic feature mode where the only features activated are those that do not require the use of an access key . in the case of one embodiment , once activated , the features are not deactivated unless the customer requests such action . however , at the time of upgrade to the program ( including the subprograms ), the customer is once again queried as to any changes he / she desires to available features of the medical instrument . if the customer no longer desires certain features , they are simply not activated during upgrade of the program in the medical instrument . upgrading the computer program can be performed in typical ways , such as through the distribution of any appropriate computer readable medium , such as a pcmcia card or a cd - rom , or may be directly installed through connection with the internet or other data communication means . in the case where a medium is distributed to the customer , a medical instrument technician of the healthcare facility in which the medical instrument is located installs the entire computer program in the memory of the medical instrument . the technician is given an access key accompanying the upgrade medium according to the ordered configurations of the customer and he / she enters the access key to place the instrument in the configuration with the desired features . although primarily discussed in terms of an infusion pump , the system and method in accordance with the invention are usable with other medical instruments . an oximetry instrument was also shown but other monitoring and healthcare instruments can incorporate aspects of the invention . from the foregoing , it will be appreciated that the system and method in accordance with the principles of the invention provide a convenient means to selectively control access to various features in a multi - featured medical instrument to accommodate individual clinicians . a manufacturer can support and validate a single program while still selectively controlling access to features of the computer program . such selective activation may be provided by various manufacturer personnel who can provide each customer with a specific feature access key that corresponds to a particular operating configuration selected by the customer . although specific embodiments of the invention have been described and illustrated , it may be seen that the invention is susceptible to modifications and other embodiments within the ability of those skilled in the art , and without the exercise of the inventive faculty . thus , it should be understood that various changes in form , detail , and application of the present invention may be made without departing from the scope of the invention .

an access key is required for operation of features of a medical instrument . a control program is used to control access to the operating features of the medical instrument . all programs of the medical instrument are validated for operation of any and all of the features of the medical instrument either alone or in any combination . however access to use of those features or combinations of features of the medical instrument requires an access key that is recognized by the control program . the pump may be usable in a basic operational configuration without entry of any access key ; however , more advanced features will be disabled unless the operator enters a correct access key to enable one or more of those features . operator input for enabled features will be accepted by the instrument but operator input for disabled features will not be accepted . disabled features are not displayed , nor is information about them displayed . by means of the invention , the medical instrument and all of its control programs are completely validated for all uses and modes of operation during manufacture ; however , users are restricted from use of certain features by means of the requirement for an access key .

with reference to fig1 to 4 , an outsole for a shoe according to the invention comprises a body 1 with substantially flat development , made of natural or synthetic rubber , shaped in accordance with the outline of the entire shoe sole or of just a portion thereof ( for example the tip ). in this second case , the shoe sole will be provided with two ( or more ) outsole semi - components physically separate from one another . body 1 therefore exhibits a top face 2 , smooth in the schematic representation of fig2 but which could actually be grooved or cut in various ways , intended for the foot &# 39 ; s support with the interposition of an inter - sole and / or insole . body 1 further exhibits a lower face 3 from which a distribution of protrusions projects , adapted for defining the actual sole tread . among these protrusion , protrusions 4 can be noticed arranged in the inner zone of the lower face 3 , that is , in a substantially central position , and peripheral protrusions 5 , arranged along the face peripheral edge . in particular , among the peripheral protrusions 5 , which shall be discussed in detail hereinafter , a tip protrusion 5 a and two side protrusions 5 b can be seen . a leather upper 6 , shown in cross section in the assembled configuration ( that is , of the finished or semi - finished shoe as shown in fig1 ) develops with a base 6 a defined between side vertical walls 6 b . the upper 6 is intended for being assembled with the outsole , to complete the manufacture of the sole and , at the same time , integrate it in the shoe . to this end , as shown in fig4 , in the area intended for forming the base 6 a , windows 7 are formed in upper 6 . the windows 7 have a profile that matches the profile of the central tread protrusions 4 , which are intended for engagement with the same openings 7 . on the upper 6 , in the area of transition between base 6 a and side walls 6 b , there are provided cuts 8 , 9 , formed in correspondence with respective peripheral protrusions 5 b , 5 a . more precisely , cuts 8 , 9 extend so as to be in accordance with the profile of the area of superimposition between the respective peripheral protrusions 5 b , 5 a , and the lower face 3 , an area which , more generally speaking , is in practice defined between the inner edge of the protrusions and the peripheral edge of body 1 ( shown in dotted lines in fig2 ). in fact , with reference again to the peripheral protrusions , and with particular reference to fig1 and 3 , there can be noted that each of them extends beyond the peripheral edge of body 1 , projecting then also upwards and defining respective top abutment surfaces 10 a , 10 b . the latter , along the junction with body 1 , are displaced downwardly relative to top face 2 . the extent of such displacement is preferably equal to , or slightly greater than , the thickness of the leather of the upper 6 . still according to a preferred solution , the abutment surfaces 10 a , 10 b develop according to the imaginary continuation of the lower face 3 beyond the peripheral edge of body 1 . the outsole and the upper are assembled as follows . after having suitably distributed the suitable adhesive substances on the relevant surfaces , the outsole is superimposed to the upper 6 , inserting a peripheral protrusion 5 a in the relevant cut 8 . the central protrusions 4 penetrate windows 7 of base 6 a of the upper . the lower face 3 of body 2 , in the area which is free from protrusions , will abut on base 6 a , thus being coated thereby . the other peripheral protrusions 5 a , 5 b are finally introduced in the respective cuts 8 , 9 . the deformability of both the leather and the rubber of which the upper and the protrusion are respectively formed , assist in allowing such operation . in this way , peripheral protrusions 5 a , 5 b pass below upper 6 ( the term below being referred to the shoe usage position ) through the cuts 8 , 9 , as clearly shown in fig1 . this figure shows how in the practice , due to the particular configuration and position of the peripheral protrusions relative to body 1 , the leather of upper 6 and body 1 itself carry out a superimposition reversal , highlighted at reference index s , with the leather passing from the outside the body ( in the area of base 6 a ) to the inside of the peripheral protrusions 5 a , 5 b , abutting against the relevant top surfaces 10 a , 10 b . if , as mentioned , the displacement of the top surfaces 10 a , 10 b is equal to about the thickness of the leather , the shift from the outsole to the side walls 6 b of the upper will cause no discontinuity , and therefore , no inconveniences to the wearing comfort of the shoe . if the abutment surfaces 10 a , 10 b substantially begin as an imaginary continuation of the lower face 3 , there will be obtained the further advantageous result of minimizing the deformation required to the upper for realising the engagement . accordingly , the forming of wrinkling , chipping or inaccuracies in general will be avoided . with reference now to fig5 , the invention , according to methods similar to those described above , may be applied also in the case of an upper 16 which , on the top side , exhibits a continuous development from the outset . in practice , the side walls 6 b are integrally connected above the foot before the assembly to the outsole , unlike the previous case where the connection occurred thanks to a closing operation following said assembly . in this case , it is the base 6 a which is initially discontinuous — that is , longitudinally divided into two halves — and the procedure to be followed for carrying out the assembly will be therefore slightly different ; the two base halves will be the last to be arranged between the protrusions , after the superimposition reversal between the outsole and the upper has already been carried out . it will then be appreciated that , according to the invention , when at the end of the gluing step the external fastening stitching between the outsole and the upper must be carried out , the same stitching can be applied right over the peripheral protrusions , which in this case are externally superimposed to the upper . the aesthetic result is therefore considerably improved as compared to the conventional solution with stitching running over the upper . the leather cut edges remain fully covered by the relevant protrusions , and therefore invisible . the handmade assembly between the outsole and the upper is very easy , since it is the same and very reversal engagement between the outsole and the upper , along with the particular configuration of the peripheral protrusions , that keeps the superimposition steady and accurate . no additional operations of separate rubber portions to be applied subsequently , nor the use of an internal “ midsole ” are required , so the method is quick and inexpensive and the shoe comfort qualities are not worsened . the method , even though with a less satisfactory result , can be carried out also with an outsole wherein the peripheral protrusions have no top abutment surfaces displaced downwards , since the cuts formed in the upper , possibly with the aid of simple reference signs on the outsole rubber , is sufficient to carry out the superimposition reversal mentioned above . the reversal will clearly exhibit variable dimensional features according to the materials used . obviously , the protrusions , both the peripheral ones 5 a , 5 b and the central ones 4 , can vary in number , shape and arrangement . accordingly , windows 7 and cuts 8 , 9 on the upper will be adapted , as it can be appreciated by a simple comparison between fig1 and fig2 to 4 , wherein different distributions of central protrusions 4 are noticeable . then , as confirmed by the variant proposed in fig5 , it can be seen that the peripheral protrusions can even extend also towards the outsole center , and that therefore actual independent central protrusions may not be present . in this case , the cuts formed in the upper 16 are much more extended as compared to the previous solution , and they become actually window - shaped . even though in the present description reference was made to leather and rubber as materials used respectively for the upper and the outsole , it is clear that the invention may be applied also with different materials , whenever there raises a problem similar to that described in the introduction . in particular , the rubber outsole could also include hide inserts or portions . other variants and / or changes may be brought to the outsole structure for a shoe , to the method of assembling the outsole to an upper , and to the shoe thus obtained , according to the present invention without thus departing from the scope of protection of the invention itself .

a shoe outsole comprising a substantially flat body with a top face and a lower face exhibiting a distribution of tread protrusions . the protrusions include at least one peripheral protrusion extending beyond the peripheral edge and defining a top abutment surface displaced generally downward relative to the top face of the body . in a method of assembling the outsole to a shoe upper , for each peripheral protrusion , a cut is formed in the upper , developing in accordance with the profile of the area of superimposition between the peripheral protrusion and the body &# 39 ; s lower face . the method provides for insertion of the at least one peripheral protrusion into the appropriate cut so as to enable passage of the protrusion below the upper as a superimposition reversal between the upper and the body .

the present invention relates to a torque measuring device for providing an electrical output proportional to torque applied to a shaft thus measuring the rotational force applied to the shaft . the device of the present invention as currently embodied permits measurement of rotational forces applied to a shaft in both shaft stationary and shaft rotating conditions . in one mode of operation the device of the invention can be &# 34 ; locked &# 34 ; so that the amount of work effort expended in turning the rotatable shaft is directly measured . copending , commonly assigned u . s . patent application ser . no . 06 / 099 , 838 filed dec . 3 , 1979 by john engalitcheff , jr . and now u . s . pat . no . 4 , 337 , 050 , the contents of which are incorporated by reference herein , describes a method and apparatus for the rehabilitation of damaged limbs in which a plurality of interchangeable tool simulator accessories are detachably connected to a brake means having a constant , predetermined torque resistance for use in diagnostic and rehabilitation therapy of damaged upper extremities . by simulating the natural movements of common activities under conditions of controlled torque resistance which remains linear rather than increasing with increased load , this device permits a gradual series of progressive exercises which can avoid muscle damage caused by trying to progress too quickly . the electrical brake employed therein has the inherent characteristic that torque is constant for a given voltage setting under therapeutically encountered conditions , unlike most prior art devices in which the torque resistance varies with speed . the device employed torque curves , as measured by a torque wrench , which were related to various voltage settings which produced given torque resistance levels . however , recalibration is required due to mechanical wear of the magnet and armature , and the need to resort to torque curves is inconvenient . accordingly , it is a general object of the present invention to provide a measuring device specially adapted for use in the field of rehabilitation and which will accurately and directly measure the force exerted by the patient . it is another object of the present invention to provide a measuring device which readily causes the brake mounting plate to return to a neutral positon when force has been removed from the shaft . upon study of the specification and appended claims , further objects , features and advantages of the present invention will become more fully apparent to those skilled in the art to which this invention pertains . the single figure is an exploded cross - sectional view of the work simulator embodying the device of the present invention illustrating the various component parts thereof . briefly , the above and other objects , features and advantages of the present invention are attained in one aspect thereof by providing a measuring device which permits the measurement of the rotational force applied to the shaft . in accordance with the present invention , a rotatable magnetizable disc is mounted on the rotatable shaft adjacent an electric friction brake which is adapted to engage and restrain rotation of the disc and the shaft when an electric current is applied to the brake to produce a magnetic force . the brake is disposed so as to allow the shaft to rotate freely in the absence of an electric current . the brake and its associated mounting plate are mounted perpendicular to and concentric with the axis of the rotatable shaft and mounted in a manner which allows them to rotate freely as a unit about the shaft axis . a strain gauge is mounted such that one end is stationary and immoveable , the other end is mounted off axis to the brake mounting plate such that the gauge prevents rotation of the brake mounting plate . thus when a rotational force is applied to the brake mounting plate the plate is restrained from moving by transmitting the force to the strain gauge thus stressing the gauge and causing an electrical signal to be present at the output of the strain gauge proportional to the stress inflicted on the gauge which is in turn proportional to the rotational force . referring to the drawing 17 is a cylindrical tube of sufficient inside diameter to house the entire assembly . this tube is itself held stationary by means described in pending u . s . patent application ser . no . 06 / 099 , 838 now u . s . pat . no . 4 , 337 , 050 incorporated by reference herein . to the tube as illustrated is securely attached 23 the strain gauge mounting block and to it is mounted 27 the gauge itself thus keeping one end of the gauge stationary . further , the gauge is positioned parallel with the axis of the tube between the i . d . of the tube and the axis of the tube . within the tube is mounted 34 a bearing with sufficient o . d . so as to be held in position by the i . d . of the tube . the bearing is mounted with its axis of rotation parallel with that of the tube and both the bearing axis and the tube axis coincident . within bearing 34 is mounted 14 the brake mounting plate . the action of this assembly is such that the plate is held with its axis coincident with that of the tube and is free via the bearing 34 to rotate about this axis within the tube . on one side of the brake mounting plate is attached 22 the strain gauge actuator mounted off axis precisely the same distance as the gauge and designed so as to entrap the unmounted end of the gauge , the action of this assembly is to prevent the aforementioned rotation of the brake mounted plate while any force tending to rotate the bmp will tend to deflect the gauge thus setting up stress within the gauge and causing an electrical output which registers on meter 36 . to the plate is mounted 33 the electric friction brake . this brake is mounted in a plane parallel with that of the plate with its axis coincident with the axis of the plate . central to 14 , the brake mounting plate , is mounted a bearing 31 . the o . d . of the bearing is retained within a counter bore in the plate thus retaining the bearing in the plane of the brake mounting plate with coincident axis . a shaft 12 is modified by , from left to right , a snap ring groove , two keyways 180 degrees apart about the shaft , a second snap ring groove , and a third snap ring groove . to the shaft are assembled a snap ring 32 and two square keys . the armature 13 is a ferrous disc one face of which is smooth with an o . d . matching that of the brake magnet and a central hole with two keyways sized such that the armature will slide freely along the shaft without excessive play while the two keyways engage the keys on the shaft thus allowing axial movement of the armature along the shaft while preventing relative rotation between the two . a second snap ring on the shaft prevents the armature from moving axially along the shaft so far as to allow the keyways to become disengaged from the shaft keys . a third snap ring is placed on the shaft completing the shaft assembly . a front cover 16 is provided with an o . d . of sufficient size to pilot within the i . d . of the tube . standard fasteners connect the cover to the tube and hold it in a plane parallel to that of the brake mounting plate . central to the plate cover is provided a bearing counter bore ( not shown ) in the same manner as the brake mounting plate . thus the bearing mounted in the brake mounting plate and the bearing mounted in the cover are maintained parallel and on the same axis of rotation . the shaft assembly is mounted such that one end of the shaft is inserted in the central bearing of the brake mounting plate and the other end inserted in the bearing central to the front cover . the snap rings 1 and 3 occurring inside of their respective bearings prevent axial movement of the shaft . this positions the armature in close proximity to the brake magnet with its smooth face parallel to that of the magnet and its axis of rotation coincident with that of the brake mounting plate . it can be seen that when a turning force is exerted on the shaft the shaft and the armature are free to rotate within the assembly . an electric current is passed from voltage control 35 through the brake magnet and a magnetic force is produced as its face proportional to the magnitude of current flow . this magnetic force attracts the armature which is allowed to move axially along the shaft until the face of the armature contacts the face of the brake magnet . the face of the brake magnet is friction material . it can be seen that while current is flowing in the brake the armature is attracted into intimate contact with the friction material and is retarded from rotating . the amount of retardation is a function firstly of the coefficient of friction between the friction material and the armature material , secondly of the force normal , and thirdly of the radius of gyration . the force normal being variable owing to its relationship to the magnitude of current flow . relative motion between the magnet and the armature is possible while current is flowing only if sufficient rotational force is applied to the shaft to overcome the retarding effect of the brake magnet . in order for motion to continue , the rotational force must be maintained on the shaft . in this system , the only thing preventing the brake assembly from rotation while current is flowing is the strain gauge . in this manner , any rotational force applied to the shaft while current is flowing is felt by the strain gauge and an output from the gauge is seen which is directly proportional to the force exerted on the shaft . without further elaboration it is believed that one skilled in the art can using the preceding description utilize the present invention to its fullest extent . the preferred embodiment is set forth herein is therefore to be construed as illustrative and not limitative of the invention in any way whatsoever .

a torque measuring device is described which provides for measurement of the rotative force applied against a shaft by engaging the shaft and an electric friction brake attached to a load cell for registering the force , and a reduced friction device for allowing the brake mounting plate to return to a neutral or zero position when force has been removed from the shaft . an externally selective voltage control actuates the friction brake .

fig1 and 2 show the invention in embodiment 10 . frame 20 may be of pipe and in other ways similar to a typical power rack apparatus . four parallel uprights 22 , 24 , 26 , 28 are conventionally spaced in rectangular plan configuration by plates 30 , 32 joining them in pairs at the bottom and by four transverse connections 34 at the top . each upright has a uniform , vertical series of holes 36 transversely through the walls , the holes in the first pair of side uprights 22 , 24 being in coaxial alignment and the holes in the second pair of side uprights 26 , 28 corresponding and similarly being in coaxial alignment . a respective support rod 38 , 40 is provided for detachable mounting on each side and it is a solid steel rod sized to slip horizontally through the holes 36 , joining the uprights in pairs at any chosen level provided for by the hole spacing , which may be three inches ( 7 . 5 cm ) on centers . support rod diameter may be 3 / 4 inch ( 10 mm ) to one inch ( 2 . 5 cm ). co - acting in the provision that the support rods can be used at any chosen level is a combined guided leg press or guided bench - press or guided standing - press provision . for this co - acting provision , first and second vertical guide shafts 42 , 44 , which may be either steel pipe or solid steel shafting , are respectively fixed in proximate parallel - spaced relation on the inner side of each of the rear uprights 22 and 26 , that is , between the uprights 22 and 26 by the weld - attached plates 30 , 32 at the bottom and by a weld - attached cross tube 46 at the top extending between uprights 22 and 26 , and fixing the upper ends of the guide shafts 42 , 44 . each of the guide shafts 42 , 44 may have a respective hole 48 , 50 through it in a fore - and - aft direction about one foot ( 30 cm ) to eighteen inches ( 45 cm ) from the bottom . the guide shafts 42 , 44 are at the rearward aspect of the invention 10 . a slider system 52 which is held by and disposed for sliding up and down the guide shafts , includes a respective slider sleeve 54 , 56 on each guide shaft , a cross member 58 welded to and joining the tops of the slider sleeves and a respective transversely apertured flange 60 , 62 extending forwardly along the length of each slider sleeve ; the apertured flanges are parallel to each other and to the slider sleeves . as means for adjustably securing a barbell which is an assembly of weight plates on a weight lifting bar , each of the apertured flanges 60 , 62 may have an identical , uniformly spaced series of apertures or holes 64 , 66 vertically along it , in a direction through it that is transverse to the flange and to the direction of the holes 36 in the uprights . vertical spacing for the series of apertures or holes 64 and 66 may be the same as for holes 36 . all apertures or holes in the apertured flanges 60 , 62 should be of a size to receive through them in a free - sliding relation the weight lifting bar , 68 shown , of a standard barbell , perhaps one inch ( 2 . 5 cm ) to 11 / 8 inches ( 2 . 8 cm ) in diameter . the width of the invention 10 between uprights 22 and 26 may be about 40 inches ( one meter ) for example . the distance between uprights 22 and 24 may be in the range of 3 inches ( 75 mm ) to 30 inches ( 0 . 75 m ) for example . height may be such as to permit a nominal size man to do a standing military press inside the frame 20 , using the slider system . the user &# 34 ; u &# 34 ; selects a starting height at which he or she would feel most comfortable to begin a leg press of the barbell , by the following procedure . for this , he ( or she ) places a removable rest pin 70 in each of the holes 48 , 50 in the respective lower portions of the guide shafts 42 , 44 . next , he lowers the slider system 52 until the lower ends of the slider sleeves 54 , 56 rest on the rest pins 70 . then , having chosen his starting height , he runs a weight lifting bar 68 through the appropriate - height aperture or hole in one flange 60 , through the free - swivels 72 , 74 of the foot - plate 76 , and through the co - aligned apertures or holes in the other flange 62 . at this point , the weight plates 78 can be put on the ends of the weight lifting bar 68 . next , the user decides at what height he would like to have the weight lifting bar 68 arrested should he slip or fail to maintain control of the barbell while leg pressing . to underpin this height , he inserts a support rod 38 , 40 through the selected holes 36 in the first pair 22 , 24 of uprights and similarly through the holes in the second pair 26 , 28 uprights . the user is now ready to lie on pad 80 and leg press the barbell and slider system upward , knowing that he is lying beneath a safety system that is virtually failsafe when properly used with the recommended barbell weight - load capacities . once the support rods 38 , 40 are in place , the safety system is operational . consequently , no further safety measures , such as having to replace a safety pin or turn a safety catch , need be taken by the user during the leg press , thereby eliminating danger from human error and eliminating or reducing fear of being caught under the barbell . as fig2 shows , this new safety system for guided weight lifting apparatus is comprised of three distinct structural parts . the parts of the safety system are the two pairs 22 , 24 and 26 , 28 of uprights , the support rods 38 , 40 and the holes 36 in the uprights which provide for height adjustment of the support rods . with the support rods inserted into the recommended holes ( the holes that are at a level optimally suited for the user &# 39 ; s body size and leg length ) in the upright pairs 22 , 24 and 26 , 28 , the integrity of the safety system is established prior to the start of the leg press movement , thereby making the safety system very nearly failsafe . to verify that the safety system is virtually failsafe , one has only to evaluate the consequences of some of the worst - case problems that could be imagined to develop while using the guided leg press . obviously , muscular fatigue and muscular injury would be two serious problems that the user might experience while positioned under the barbell assembly 68 , 78 . the safety system easily handles these problems because the user needs only to lower the barbell down onto the support rods 38 , 40 which the user had already positioned in the holes 36 of the upright pairs in preparation for leg pressing the barbell . even if the user were to lose consciousness while lying beneath the barbell , he would , in most instances , be shielded from serious trauma to the head , neck , spine , chest and abdomen because the barbell would once again drop onto the support rods 38 , 40 which are properly positioned above the unconscious user ( this assumes that the user had positioned the support rods at a level that would be high enough to keep the descending barbell from crushing his legs down into his chest and abdomen ). one of the worst structural problems that could be imagined , as a final example , is the breaking loose or breaking apart of the guided leg press ( the slider system 52 and / or guide shafts 42 , 44 ). this would create a situation where the barbell assembly 68 , 78 no longer has structural support in the horizontal plane . however , even with the barbell free to move in both the horizontal and vertical planes , the user is still afforded superior bodily protection because the weight lifting bar 68 is housed within a &# 34 ; safety channel &# 34 ; formed by the pairs 22 , 24 and 26 , 28 of uprights , and the support rods 38 , 40 . consequently , the falling barbell should be held within the &# 34 ; safety channel &# 34 ; in the fore - and - aft directions by the vertical uprights , thereby allowing the barbell to drop down onto the horizontal support rods . as can be seen , the safety system handles even the most serious problems with almost failsafe reliability . note also that the invention was designed with one additional safety feature , that being the placement of the weight plates 78 on the outside of the uprights 22 , 24 , 26 and 28 . because of this added feature , even if the weight plates should slide off of the ends of the weight lifting bar 68 , or even if the weight lifting bar should be sheared in half upon impact at both support rods 38 and 40 , the weight plates should in both cases drop to the floor on the outside of the four uprights . fig3 is a fragmentary detail , enlarged , taken from fig1 which focuses on the interaction between slider system 52 with weight lifting bar 68 and the safety system that was described above . this drawing clearly shows that the horizontal weight lifting bar 68 extends perpendicularly through the two imaginary vertical planes that are formed by the pairs 22 , 24 ( shown ) and 26 , 28 of uprights , and that the weight lifting bar is transverse to and above ( in spatial relationship ) the support rods 38 ( shown ), 40 , which are horizontally positioned within the aforementioned imaginary vertical planes . as can be recognized , the weight lifting bar is housed within a &# 34 ; safety channel &# 34 ; that is formed by the front uprights 24 ( shown ), 28 , the rear uprights 22 ( shown ), 26 , and the support rods 38 ( shown ), 40 . consequently , forward and rearward displacement of the barbell assembly 68 , 78 should be blocked by the respective front and rear pairs of uprights , while downward movement of the barbell is arrested by the support rods , assuming that the recommended weight - load capacity of the safety system is not exceeded . fig4 is a detail taken at 4 -- 4 , fig3 to emphasize the safety feature of massive support and back - stopping by the support rods , 38 shown , positioned under the weight lifting bar 68 of the barbell in assembly 52 . further , support rods 38 , 40 can act as rest stops when the user &# 39 ; s hands are incorporated in the exercises , as in bench - pressing . there is good access all around for the insertion and use of a bench . fig5 shows , for example , the use of the invention 10 in performing a standing - press , with the foot - plate removed . the beginning user can set - up the system with the support rods 38 , 40 at a desired starting height ( example : shoulder level ) and with the barbell , which is secured in the slider system 52 , resting on the support rods . the user can then push the barbell overhead without fear of toppling forward or backward , or of getting crushed by the weight of the barbell assembly 68 , 78 , since the barbell can only descend as low as the support rods 38 , 40 . a further feature evident is that the cross tube 46 , connecting the first and second guide shafts 42 , 44 at the top to uprights 22 and 26 , can be used for chin - up exercises . it will be apparent that the uprights are also available for all ordinary uses as a power rack apparatus , as for free - weight exercises using bar - holders 90 . fig6 shows another feature which the invention makes possible . more than one barbell at a time can be employed by securing weight lifting bars 68 , 68 &# 39 ; in separate levels of the apertures or holes ( 66 shown ) in the apertured flanges ( 62 shown ). because the apertured flanges will accommodate a two weight lifting bar set - up , the weight - load capacity ( total ) for the invention is increased . not only is total weight - load capacity increased , but single barbell weight - loads ( in the 850 to 1 , 000 lbs . range ) that might bind - up the slider system 52 on the guide shafts ( 44 shown ) because of excessive deflection of a single weight lifting bar within the flange / slider sleeve unit ( 62 , 56 shown ) can now be handled because these heavy poundages can be distributed with the two weight lifting bar set - up so that excessive deflection of either weight lifting bar is avoided . fig7 and 9 show successive positions in a view adapted from fig1 at 7 -- 7 of an alternative foot - plate detail . according to this invention , the foot - plate 176 swivels on the weight lifting bar 68 , providing added foot - press safety and comfort during the leg press movement . the significance of the swivel motion of the foot - plate can be understood by first reviewing the movement patterns that the foot and ankle undergo with a stationary type foot - plate . when the foot - plate is fixed in a horizontal position , as is usually the case with current - style leg press machines , the heel of the foot will usually lift off of the foot - plate as the barbell is lowered toward the floor . as the heel comes off of the foot - plate , barbell weight ( i . e ., force ) is placed predominantly on the distal heads of the metatarsal bones , concentrating these forces on a very limited portion of the plantar surface of the foot . because the weight is no longer optimally distributed over the entire plantar surface of the foot , there is greater probability of injury occuring to the metatarsal bones , to the ligaments of the foot arch , and to the ankle joint since this joint is usually forced into extreme dorsiflexion when a fixed , horizontal foot - plate is used . on the other hand , a rotating or swivelling foot - plate ( as introduced in this invention ) allows the entire plantar surface of the foot to maintain contact with the foot - plate during the leg press . consequently , the forces are more evenly distributed on the metatarsal bones , thereby reducing the chances for foot injury . additionally , because the ankle joint can maintain a more neutral position throughout the leg press movement ( as opposed to being forced into extreme dorsiflexion with the fixed - style foot - plate ), there is reduced risk of injury to the ankle joint also . as shown in fig7 and 9 , detachable screws and nuts 188 and &# 34 ; c &# 34 ; shaped clamps 174 loosely and adjustably fasten foot - plate 176 to the weight lifting bar 68 so that the swivelling action can take place . each aperture or hole 66 in the flange 62 may have below it at an angle a lug 190 protruding in position for limiting rotation of the foot - plate for safety to about 45 degrees from the horizontal . fig1 and 11 show the invention using support rod assemblies 38 &# 39 ; and 40 &# 39 ;, which represent a modification of the basic support rods 38 , 40 used in fig1 . support rods 38 &# 39 ; and 40 &# 39 ; are designed to use with only the two uprights 22 , 26 which are respectively fixed in proximate parallel spaced relation on the outside of each of the vertical guide shafts 42 , 44 of the guided leg press . these support rod assemblies 38 &# 39 ;, 40 &# 39 ; provide the user of the invention with the same kind of safety system , namely the adjustable &# 34 ; safety channel &# 34 ;, as described earlier . when the support rod assemblies 38 &# 39 ;, 40 &# 39 ; are used instead of the standard support rods 38 , 40 ( fig1 ), the &# 34 ; safety channel &# 34 ; is formed by the two vertical uprights 22 , 26 , the upright members 38 &# 39 ; a , 40 &# 39 ; a of the support rod assemblies , and the support rods 38 &# 39 ; b , 40 &# 39 ; b of the support rod assemblies . notice also that the use of the support rod assemblies 38 &# 39 ;, 40 &# 39 ; allows the user of the invention to position the apertured flanges 60 , 62 of the slider system in either the forward ( fig1 ) or rearward ( fig1 ) facing direction for the invention . slots 35 in transverse connections 34 &# 39 ; will accept the upright members of the support rod assemblies , 38 &# 39 ; a for example , so that the support rod assemblies , 38 &# 39 ; for example , can be raised to any height necessary in performing overhead weight lifting exercises . fig1 is a fragmentary detail , enlarged , adapted from fig1 which shows that the weight lifting bar 68 is captured within the &# 34 ; safety channel &# 34 ; that is formed by the uprights ( 22 shown ), the upright members ( 38 &# 39 ; a shown ) of the support rod assemblies , and the support rods ( 38 &# 39 ; b shown ) of the support rod assemblies . fig1 details a support rod assembly ( 38 &# 39 ; shown ) that has been detached from the upright ( 22 shown ). the support rod assembly is made up of the following portions . the first portion is a support rod ( 38 &# 39 ; b shown ), perhaps a steel rod that is 10 inches long and 3 / 4 inch to one inch in diameter . the second portion is an upright member ( 38 &# 39 ; a shown ), perhaps a steel rod that is 40 inches in length and 3 / 4 inch to one inch in diameter . the upright member is welded at one end to one of the ends of the support rod ( 38 &# 39 ; b shown ), and the length of the upright member of the support rod assembly should be such as to accommodate the use of two weight lifting bars within each apertured flange as shown at 62 , fig6 . the third portion is a steel brace plate ( 38 &# 39 ; c shown ), perhaps four inches square by 1 / 2 inch in thickness , that is welded along one of its narrow edges to the support rod ( 38 &# 39 ; b shown ) on the side opposite the upright member ( 38 &# 39 ; a shown ). after the brace plate is welded to the support rod , the free end of the support rod ( 38 &# 39 ; b shown ) must be proportioned for passing through a hole 36 of the upright . the next portion is a threaded member ( 38 &# 39 ; d shown ), perhaps a threaded steel rod that is 6 inches in length and 3 / 4 inch in diameter , which is welded at one end to the narrow edge of the brace plate that is parallel to but farthest from the upright member ( 38 &# 39 ; a shown ). the threaded member is affixed in parallel spaced relation to the support rod ( 38 &# 39 ; b shown ) in all planes , and the distance between the support rod and the threaded member , center to center , is the same as the distance , center to center , between any two successive holes 36 in an upright ( 22 shown ). also , the threaded member should be proportioned for passing through a hole 36 of the upright . the final portion of the support rod assembly is a nut ( 38 &# 39 ; e shown ) which detachably fastens the threaded member to the upright ( 22 shown ). as can be seen , the free ends of both the support rod ( 38 &# 39 ; b shown ) and the threaded member ( 38 &# 39 ; d shown ) can be inserted simultaneously through any two successive holes 36 in the upright ( 22 shown ). the nut ( 38 &# 39 ; e shown ) can then be threaded onto the threaded member ( 38 &# 39 ; d shown ), thereby mounting the support rod ( 38 &# 39 ; b shown ) to the upright . fig1 and 15 show successive positions of assembly for an apertured flange 60 &# 39 ; which will permit the use of olympic weight lifting bars in the invention . because the olympic weight lifting bar 69 has end portions 69a that are over two inches in diameter , this weight lifting bar will not slide through the one inch to 11 / 2 inch holes ( see fig1 ) that might be drilled in the apertured flange . fig1 shows the two - piece apertured flange 60 &# 39 ; disassembled , with the olympic weight lifting bar outside the flange . as can be seen , flange piece 60 &# 39 ; a is welded along the length of the slider sleeve 54 &# 39 ;. however , instead of having holes drilled through this flange piece to secure a weight lifting bar , flange piece 60 &# 39 ; a has a vertical series of identical , uniformly spaced apertures or notches 65 , extending diagonally downward in it from one edge . these nothches 65 may be 21 / 8 inches in length , one inch to 11 / 2 inches in width , and angled downward at 10 degrees from the horizontal . these notches are transverse to the flange piece and they accept the hand - held portion 69b of the olympic weight lifting bar . additionally , two screw studs 197 project perpendicularly from flange piece 60 &# 39 ; a . the second piece of the apertured flange 60 &# 39 ; is a screw and nut attached , flat steel keeper - plate 60 &# 39 ; b with a vertical series of identical , uniformly spaced horizontal notches 67 , perhaps 11 / 8 inches in length , and one inch to 11 / 2 inches in width . these notches 67 are transverse to keeper - plate 60 &# 39 ; b , and vertically spaced to match with the notch spacing in flange piece 60 &# 39 ; a at the lowest portions of the notches 65 . also , keeper - plate 60 &# 39 ; b has two holes 198 that match - up with , and that accept the screw studs 197 which project from flangel piece 60 &# 39 ; a . fig1 shows keeper - plate 60 &# 39 ; b attached to flange piece 60 &# 39 ; a by the nuts 199 which have been threaded onto the screw studs 197 . with apertured flange 60 &# 39 ; assembled , the hand - held portion 69b of the olympic weight lifting bar is secured in place within the apertured flange by the opposing notches of flange piece 60 &# 39 ; a and keeper - plate 60 &# 39 ; b . apertured flange 60 &# 39 ; will accept the hand - held portion of most weight lifting bars currently in use . this invention is not to be construed as limited to the particular forms disclosed herein , since these are to be regarded as illustrative rather than restrictive . it is , therefore , to be understood that the invention may be practiced within the scope of the claims otherwise than as specifically described .

a system for weight lifting exercises provides the user with a guided leg press / multi - press that has a safety mechanism which is adjustably limitable to prevent a barbell , an assembly of weight plates on a weight lifting bar , from falling below a chosen height . a series of holes in uprights provide a range of adjustment for barbell support rods during guided bench - press and standing - press use on a slide assembly permit a plurality of barbells to be received at one time , thereby increasing the weight - load capacity of the slider system . a part of the system serves as a chin - up bar . numerous exercises using the system may be performed . a supported barbell includes a pivotal foot - plate with angle limiting provision . a slider assembly may include a two - piece apertured flange for locking a barbell in place during an exercise .

fig1 shows an embodiment in which a ventilator mask 1 is coupled with a forehead support 3 by a spacing element 2 . a ventilator hose 4 opens into the ventilator mask 1 . the ventilator mask 1 consists of a mask body 5 made of a strong material and a sealing element 6 , which rests against the face of a patient 7 and is connected by a profile 8 with a mating profile 9 of the body 5 of the mask . the spacing element 2 has an outer wall 10 that bounds a cavity 11 , which opens into an interior space 12 of the ventilator mask 1 . in the embodiment shown in fig1 , the cavity 11 opens into an interior space 13 of the forehead support in its expanded area facing away from the ventilator mask 1 . the forehead support 3 consists essentially of a body 14 and a cushion 15 . the ventilator hose 4 is preferably rotatably supported in the body 5 of the mask . in the embodiment of fig1 , the body 5 of the mask is equipped with an inner shell 16 , which provides a double - walled construction . a flow channel 17 extends between the inner shell 16 and the mask body 5 and is connected with the interior space 12 of the ventilator mask 1 by at least one opening 18 in the inner shell 16 . the opening 18 is preferably located near the nostrils 19 of the patient 7 . furthermore , the flow channel 17 is arranged in such a way that it ends in the vicinity of the opening of the cavity 11 into the interior space 12 of the ventilator mask 1 . in this way , the respiratory gas exhaled by the patient is carried through the opening 18 and the flow channel 17 and into the area of the cavity 11 . this design largely prevents any mixing of fresh respiratory gas from the ventilator hose 4 and exhaled respiratory gas . ventilation effectiveness can be increased in this way . the spacing element 2 has an angled design in the embodiment according to fig1 . a base segment 20 extends essentially vertically , and an end segment 21 extends more or less perpendicularly to the base segment 20 in the direction of the forehead 22 of the patient 7 . the body 14 of the forehead support 3 has a mounting device 23 that fits into the end segment 21 and allows transverse positioning of the forehead support 3 relative to the spacing element 2 . the principal flow directions of the respiratory gas are indicated in fig1 by flow arrows . in particular , the drawing shows that a large portion of the exhaled respiratory gas is discharged from the forehead support 3 in a direction away from the patient 7 . optimum discharge of the respiratory gas can be achieved by suitable predetermination of the discharge openings in the area of the forehead support 3 . fig2 shows an embodiment in which discharge openings 24 are placed in the area of the spacing element 2 . the discharge openings 24 can be at least partially covered by a baffle 25 , which is installed in such a way that it can be positioned by an adjusting element 26 . by adjusting the baffle 25 , a suitable discharge resistance can be preset to prevent gas from flowing directly from the ventilator hose 4 to the discharge openings 24 . the baffle 25 thus ensures that the required ventilation pressure can develop in the ventilator mask 1 . the adjusting element 26 can be designed , for example , as a slide that can be positioned along a groove 27 . adequate positioning reliability can be provided by catches 28 . the embodiment in fig2 also provides for the placement of discharge openings 29 in the area of the cushion 15 of the forehead support 3 . in the embodiment according to fig2 , discharge openings 30 are also provided in the area of the body 14 of the forehead support 13 . in the embodiment according to fig2 , additional discharge openings 32 of the forehead support 3 are located in an upper region of the body 14 , and the size of the discharge openings 32 can be preset by closure elements 31 that can be turned . fig3 shows a cross section through the spacing element 2 . it is apparent that the displaceable baffle 25 is located in a region of transition from the cavity 11 into the discharge openings 24 . fig4 is a side view that again shows the location of the discharge openings 30 , 32 in the area of the forehead support 3 and the positioning of the closure elements 31 . it is apparent that the corresponding discharge openings 32 can be placed at both the top and the bottom of the forehead support 3 . fig5 shows an embodiment in which membrane elements 33 are arranged in the area of the discharge openings 24 of the spacing element 2 to produce a suitable discharge resistance . the membranes can also be provided with moisture - retaining properties to prevent increased drying out of the patient by the ventilation . similar membrane elements 33 can also be placed in the area of the discharge openings 29 , 30 , 32 of the forehead support 3 . in the embodiment in fig6 , slotted silicone inserts 34 are placed in the area of the cushion 15 to provide discharge openings 29 . the silicone inserts 34 can be placed both at the top and the bottom of the forehead support 3 . in the embodiment in fig7 , at least one discharge opening 30 that can be closed to a predeterminable extent by a baffle 35 is located in the area of the forehead support 3 . the baffle 35 can be rotated by means of an operating element 36 and provides an adjustable state of opening of the discharge opening 30 . the baffle 35 can be provided , for example , with holes , slots , or adjustable expiratory flaps . fig8 shows an embodiment that can be used for optimum discharge of exhaled respiratory gas without the use of a forehead support 3 . to this end , in its operating state , the ventilator mask 1 has a discharge opening 38 above a coupling part 37 for the ventilator hose , which is not shown in fig8 . the discharge opening 38 conducts the exhaled respiratory gas in a direction away from the patient . fig9 illustrates that the discharge opening 38 is preferably located in a flattened region of the ventilator mask 1 . respiratory gas is supplied exclusively through the coupling part 37 and is discharged through the discharge opening 38 . this has been found to provide optimum elimination of carbon dioxide . the embodiment according to fig1 and fig1 is functionally similar to the embodiment in fig8 and 9 . however , instead of a simple discharge opening 38 , this embodiment has a discharge connector 39 , to which an expiratory hose 40 is connected . the use of the expiratory hose 40 makes it possible for the exhaled respiratory air to be discharged at almost any desired predetermined point , so that patient comfort can be optimized in this respect . fig1 shows an embodiment in which at least one group of discharge openings 41 , 42 , which consists of at least two individual discharge openings 41 , 42 , is located in the area of the forehead support 3 . the discharge openings 41 , 42 can be closed by at least one closure element 43 , which automatically assumes a certain position , depending on the given spatial position of the patient 7 . depending on the given position of the patient 7 , it is thus predetermined that one or more of the discharge openings 41 , 42 are closed or open . this makes it possible to open or close different discharge openings 41 , 42 when the patient 7 is lying , for example , on his left side , than when he is lying on his right side . it is also possible , depending on whether the patient 7 is in an upright or reclining position , to discharge the respiratory gas through the discharge openings 41 , 42 that are the optimum discharge openings under the given current conditions . fig1 shows a partially cutaway side view of the embodiment according to fig1 . the exhaled respiratory gas is again fed in the direction of the discharge openings 41 , 42 through the cavity 11 of the spacing element 2 . fig1 shows an embodiment for realizing the closure element 43 with the use of a movable baffle . depending on the given spatial position of the forehead support 3 , the baffle is open or closed . fig1 shows an embodiment in which the closure element 43 is a movable ball that is arranged in such a way that , depending on the given position of the forehead support 3 , one or the other of the discharge openings 41 , 42 is closed or neither of the discharge openings 41 , 42 is closed . fig1 shows an embodiment in which a throttle element 44 is installed in the spacing element 2 . the throttle element 44 produces a well - defined discharge resistance for the exhaled respiratory gas and guarantees that a sufficient ventilation pressure can develop in the ventilator mask 1 . in the embodiment illustrated in fig1 , the throttle element 44 consists of a plurality of lips arranged one behind the other , which separate individual chambers 45 from each other . the chambers 45 are connected with each other only by individual overflow openings 46 . in addition to helping produce the necessary ventilation pressure , this arrangement can also improve the level of sound damping . the partially cutaway side view in fig1 shows that , in the embodiment according to fig1 , it is also possible to use a double - walled construction with an inner shell 10 . in principle , it is possible to use this double - walled construction , which helps achieve optimum elimination of carbon dioxide , in all of the design variants explained here . fig1 shows an embodiment in which movable discharge nozzles 47 are used . the discharge nozzles 47 are installed in the forehead support 3 in a way that allows them to swivel or slide . a desired direction of discharge of the respiratory gas can be preset by moving the discharge nozzles 47 into the corresponding position . for example , when the patient is in the supine position , it is possible to set the discharge nozzles 47 to discharge the respiratory gas directly upward . when the patient is lying on his right side , the discharge nozzles 47 and their openings are turned to the left , and when he is lying on his left side , the discharge nozzles 47 and their openings are turned to the right . fig1 shows a side view of the embodiment according to fig1 . it is also apparent here that exhaled respiratory gas is fed to the discharge nozzles 47 through the cavity 11 of the spacing element 2 . in the embodiment in fig2 , the throttle element 44 according to fig1 is installed in the spacing element 2 as a removable throttle module 48 . this makes it possible to supply a variety of different throttle modules 48 , which are inserted in the spacing element 2 according to the individual practical requirements of each case . fig2 shows a side view of the ventilator mask 1 with forehead support 3 , in which a replaceable throttle module 48 is positioned in the spacing element 2 . fig2 shows a design of the throttle module 48 , in which a flow path 49 is bounded in such a way by shaped sidewalls that a cross - sectional area that varies in the direction of flow 50 is realized . fig2 shows an embodiment in which the flow in the throttle module 48 follows a winding path 49 with a variable cross - sectional area . in the embodiment in fig2 , the throttle module 48 has an insert that consists of a porous material with an internal porosity of up to 4 , 500 m 2 / g . fig2 shows an embodiment in which the throttle module 48 is designed as a replaceable insert , which , for example , is adapted to specific pressure stages . for example , it is possible to use one insert for a pressure stage of 4 - 6 mbars , another insert for a pressure range of 6 - 8 mbars , and other inserts for other pressure stages . the design of the individual throttle modules 48 can be adapted within wide limits to a given practical requirement . fig2 shows an embodiment in which the throttle module 48 has a smaller number of flow paths 49 than the throttle module 48 shown in fig2 , although the flow paths 49 have larger cross - sectional areas than those in the embodiment of fig2 . in the embodiment shown in fig2 , several flow paths 49 with a curved path similar to a serpentine curve extend through the throttle module 48 . in the embodiment shown in fig2 , the throttle module 48 has a flow path 49 shaped like a nozzle module , with the nozzle cross section first constricting and then expanding in the direction of flow . in the embodiment shown in fig2 , the flow path 49 follows a course with abrupt changes in cross - sectional area , in which a contour pattern is provided that is similar in shape to the outline of a christmas tree . the embodiment according to fig3 shows another realization of the throttle module 48 with the use of a porous material , for example , a sintered material . fig3 is a schematic illustration of a throttle module 48 removed from the spacing element 2 . in the embodiment shown in fig3 , the throttle module 48 was partially inserted in the spacing element 2 . the drawing in fig3 shows the throttle module 48 in its final position in the spacing element 2 . in particular , it is proposed that the proper insertion of the throttle module 48 in the spacing element 42 be indicated by the generation of an acoustic signal . for example , it is possible , to use locking elements , which produce a clicking sound when the throttle module 48 is fully inserted . the throttle module 48 can be fixed in the spacing element 2 by spring elements , which can be released , for example , by manually squeezing the spring elements . in the embodiment in fig3 , which is a modification of the embodiment in fig1 , no passage to the interior space 12 of the ventilator mask 1 is provided vertically below the cavity 11 , but rather the entire amount of air exhaled by the patient 7 flows through the opening 18 and into the flow channel 17 between the body 5 of the mask and the inner shell 16 . this design further improves the separation of the flow paths for the respiratory gas introduced through the ventilator hose 4 and the respiratory gas exhaled by the patient and prevents thorough mixing of the fresh respiratory gas and the used respiratory gas . this can enhance the effectiveness of the ventilation and reduce the amount of fresh respiratory gas that needs to be supplied . fig3 shows a further modified embodiment . in this case , the cavity 11 is not connected with discharge openings in the vicinity of the body 14 of the forehead support 3 , but rather the cavity 11 opens into a discharge element 52 that is located basically at a height level above the forehead support 3 . the discharge element 52 can be designed , for example , in the form of a connector or a hose . additional discharge openings 53 can be placed in the spacing element 2 . fig3 shows an embodiment that is further modified relative to the embodiment in fig3 , in which respiratory gas is discharged not only through the chimney - like discharge element 52 but also through the body 14 of the forehead support 3 or the cushion 15 of the forehead support 3 . this further increases the discharge area and thus reduces discharge velocities and discharge sounds . in most of the illustrated embodiments , respiratory gas is discharged from the area of the ventilator mask 1 via a cavity 11 inside the spacing element 2 . in principle , it is also possible to place the cavity 11 outside the spacing element 2 but immediately adjacent to the spacing element 2 . for example , a hose or other suitable hollow component for conveying the exhaled respiratory gas to the vicinity of the discharge opening provided for this purpose can be arranged parallel to the spacing element 2 .

a device for artificial respiration , including a front support which is connected to a respiratory mask that includes a connection for the respiratory tube , a front support is coupled to the respiratory mask by a distancing element and at least one cavity is arranged in the region of the distancing element , the cavity leading into an inner chamber .

as used herein , by “ refreshing and disinfecting ” is meant making the air have a natural fragrant scent and inhibiting and / or killing the bacteria and / or viruses commonly found in the air . as used herein , “ comprised of eucalyptus oil , clove oil , patchouli oil , forsythia oil and schizonepeta oil ” is also referred to as compounded volatile oils , compounded traditional chinese medicinal volatile oils or the like . in the hereunder description of the preparation of the samples , the raw materials for the individual components of the compounded volatile oils are as follows : eucalyptus oil : general eucalyptus oil can be used . a specific example is the volatile oil extracted from bluegum — eucalyptus globulus labill of the myrtaceae family or camphor tree — cinnamomum camphora ( l .) presl of the lauraceae family or other plants of the same genera to which the above two plants belong in the above two families . ( the commercial product used in the examples herein was purchased from ganxu perfume oil factory , jishui county , jiangxi province , lot no . 20060825 .) forsythia oil : general forsythia oil can be used . a specific example is the volatile oil extracted from the dried fruits of weeping forsythia — forsythia suspensa ( thunb .) vahl of the oleaceae family . ( the commercial product used in the examples herein was purchased from ganxu perfume oil factory , jishui county , jiangxi province , lot no . 20060825 .) clove oil : general clove oil can be used . a specific example is the volatile oil extracted from the dried flower buds of clove — eugenia caryophyllata thunb . of the myrtaceae family . ( the commercial product used in the examples herein was purchased from ganxu perfume oil factory , jishui county , jiangxi province , lot no . 20060825 .) patchouli oil : general patchouli oil can be used . a specific example is the volatile oil extracted from the dried stems and leaves of patchouli — pogostemon cablin ( blanco ) benth of the lamiaceae family . ( the commercial product used in the examples herein was purchased from guangzhou baihua perfume co ., ltd , guangzhou , guangdong province , lot no . 20060901 .) schizonepeta oil : general schizonepeta oil can be used . a specific example is the volatile oil extracted from the whole herb of fineleaf schizonepeta herb — schizonepeta tenuifolia brig of the lamiaceae family . ( the commercial product schizonepeta oil used in the examples herein was purchased from ganxu perfume oil factory , jishui county , jiangxi province , lot no . 20060825 .) in addition to the commercially purchased products , the above - said volatile oils can be conventionally extracted from traditional chinese medicinal materials using water steam distillation or supercritical fluid extraction or using other existing and known extraction methods . the above - said eucalyptus oil , forsythia oil , clove oil , patchouli oil , and schizonepeta oil can also be respectively extracted from plants of other genera and other families . eucalyptus oil and patchouli oil were subjected to quality check as described under the relevant entries beginning at pages 280 and 272 , respectively , in part i of chinese pharmacopoeia , 2005 edition , clove oil was subjected to quality check as described in the entry beginning at page 7 in part i of chinese pharmacopoeia , 1953 edition , and forsythia oil and schizonepeta oil were subjected to quality check using in - house developed standards . hereinunder described are the non - limiting examples of the present invention , wherein the composition of the formulations below is expressed in terms of volume , unless otherwise stated . the bacteriostatic effects of individual and compounded traditional chinese medicinal volatile oils ( bacteriostatic ring method , kirby - bauer antibiotic testing , or disk dissusion antibiotic sensitivity testing ). sample 5 : kirby - bauer antibiotic testing , or disk dissusion antibiotic sensitivity testing ) oil sample 6 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 10 : 3 : 1 : 1 : 1 . method of preparation : 625 . 0 ml of eucalyptus oil , 187 . 5 ml of forsythia oil , 62 . 5 ml of clove oil , 62 . 5 ml of patchouli oil and 62 . 5 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . staphylococcus aureus ( 26112 ), e . coli ( 44113 ) and staphylococcus albus ( 26069 ) were all provided by the national institute for the control of pharmaceutical and biological products , beijing , china . the 16 - to 18 - hour liquid cultures of the above three strains were respectively spread on the surface of common culture plates evenly using sterile cotton swabs and the plates were allowed to dry briefly . pieces of susceptibility paper with predetermined amount of respective sample solution absorbed in each piece were nipped with a sterile nipper and laid flat on the surface of the above plates which have been inoculated , with three pieces of susceptibility paper on each plate . then the plates were incubated at 37 ° c . and observed the next day to obtain experimental results , as shown in table 1 . results showed that eucalyptus oil , forsythia oil , patchouli oil , clove oil and schizonepeta oil had various degrees of inhibitory effect on the growth of staphylococcus aureus , staphylococcus albus and e . coli . clove oil had the strongest effect on staphylococcus aureus , while schizonepeta oil had the strongest effect on e . coli . since three kinds of bacterial strains were used and the samples had various degrees of effect on different strains , it would be hard to evaluate the overall bacteriostatic effect of each of the samples simply by comparing the inhibitory effects of different samples on the three strains . therefore , comprehensive evaluation was needed . in the present invention , the evaluation was made using the comprehensive index method . the comprehensive index method is a commonly used comprehensive analysis method . using this method , different weights were assigned to the bacteriostatic effects of each sample on the three strains , and the weighted bacteriostatic effects were simply added together to obtain a comprehensive bacteriostatic index for the sample ( see the footnote of table 1 for the formula of calculation ). the assignment of weight was based on the importance of various factors and / or their contribution to the results . here , coccus and bacillus represent two different categories of bacteria respectively and therefore both coccus and bacillus were assigned a weight of 0 . 5 . among the two coccal strains of used , staphylococcus aureus was more pathogenic than staphylococcus albus , therefore the two coccal strains were respectively assigned a weight of 0 . 3 and 0 . 2 . results showed that sample 6 ( compounded traditional chinese medicinal volatile oils ) had the highest comprehensive bacteriostatic index , indicating that the bacteriostatic effect of compounded traditional chinese medicinal volatile oils was superior to that of the individual volatile oils . this suggested the reasonableness and superiority of the compounded formulation and reflected its novelty and inventiveness . in order to further ascertain if the individual volatile oils had synergistic reinforcing effects after they were compounded , theoretic comprehensive bacteriostatic index was calculated based on the respective bacteriostatic effect of the individual volatile oils and the ratio of each of the individual volatile oils in sample 6 . the result obtained was 10 . 1 , which was obviously lower than the actual comprehensive bacteriostatic index of 15 . 0 of sample 6 , suggesting that the individual volatile oils produced synergistic effect among themselves after they were compounded to form sample 6 and thus enhanced the bacteriostatic effect . this confirmed the conclusion obtained from direct comparison of the determined comprehensive bacteriostatic indexes of the compounded formulation and the individual volatile oils , as described in the above paragraph , indicating the novelty and inventiveness of the compounded formulation . the bacteriostatic effects of compounded traditional chinese medicinal volatile oils having different ratios of individual volatile oils ( bacteriostatic ring method , kirby - bauer antibiotic testing , or disk dissusion antibiotic sensitivity testing ). sample 7 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 5 : 1 . 5 : 2 . 5 : 2 : 3 . method of preparation : 357 . 1 ml of eucalyptus oil , 107 . 1 ml of forsythia oil , 178 . 6 ml of clove oil , 142 . 9 ml of patchouli oil and 214 . 3 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 8 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 5 : 3 : 5 : 3 : 5 . method of preparation : 238 . 1 ml of eucalyptus oil , 142 . 9 ml of forsythia oil , 238 . 1 ml of clove oil , 142 . 9 ml of patchouli oil and 238 . 1 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 9 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 5 : 4 . 5 : 7 . 5 : 4 : 7 . method of preparation : 178 . 6 ml of eucalyptus oil , 160 . 7 ml of forsythia oil , 267 . 9 ml of clove oil , 142 . 9 ml of patchouli oil and 250 . 0 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 10 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 10 : 1 . 5 : 2 . 5 : 3 : 7 . method of preparation : 416 . 7 ml of eucalyptus oil , 62 . 5 ml of forsythia oil , 104 . 2 ml of clove oil , 125 . 0 ml of patchouli oil and 291 . 7 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 11 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 10 : 3 : 5 : 4 : 3 . method of preparation : 400 . 0 ml of eucalyptus oil , 120 . 0 ml of forsythia oil , 200 . 0 ml of clove oil , 160 . 0 ml of patchouli oil and 120 . 0 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 12 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 10 : 4 . 5 : 7 . 5 : 2 : 5 . method of preparation : 344 . 8 ml of eucalyptus oil , 155 . 2 ml of forsythia oil , 258 . 6 ml of clove oil , 69 . 0 ml of patchouli oil and 172 . 4 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 13 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 1 . 5 : 2 . 5 : 4 : 5 . method of preparation : 535 . 7 ml of eucalyptus oil , 53 . 6 ml of forsythia oil , 89 . 3 ml of clove oil , 142 . 9 ml of patchouli oil and 178 . 6 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 14 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 3 : 5 : 2 : 7 . method of preparation : 468 . 8 ml of eucalyptus oil , 93 . 8 ml of forsythia oil , 156 . 3 ml of clove oil , 62 . 5 ml of patchouli oil and 218 . 8 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 15 : a mixture comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 4 . 5 : 7 . 5 : 3 : 3 . method of preparation : 454 . 5 ml of eucalyptus oil , 136 . 4 ml of forsythia oil , 227 . 3 ml of clove oil , 90 . 9 ml of patchouli oil and 90 . 9 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . the bacteriostatic effects of the above samples were determined by the method of example 1 . the experimental results are shown in table 2 . ( the ratios of each individual volatile oil in samples 7 to 15 of this example covered the following ranges : eucalyptus oil , 17 . 9 to 53 . 6 %; forsythia oil , 5 . 4 to 16 . 1 %; clove oil , 8 . 9 to 26 . 8 %; patchouli oil , 6 . 3 to 16 . 0 %; and schizonepeta oil , 9 . 1 to 29 . 2 %.) results showed that the products of all the above nine formulations had bacteriostatic effect . the theoretic comprehensive bacteriostatic indexes for each of these formulations were calculated to be 11 . 4 , 11 . 7 , 11 . 8 , 11 . 5 , 10 . 9 , 11 . 6 , 10 . 9 , 11 . 5 and 11 . 1 respectively , all lower than the corresponding determined comprehensive bacteriostatic indexes ( column d , table 2 ), which indicated that these nine formulations , through compounding , all produced synergistic effect in bacteriostatic action . therefore the formulations of these nine samples also possessed novelty and inventiveness . among the nine formulations , samples 7 , 11 , 12 , 13 and 14 showed bacteriostatic effect , samples 8 , 9 and 10 showed good bacteriostatic effect , while sample 15 showed the best bacteriostatic effect . sample 15 comprised the individual volatile oils in the following ratios : eucalyptus oil , 45 . 5 %; forsythia oil , 13 . 6 %; clove oil , 22 . 7 %; patchouli oil , 9 . 1 %; and schizonepeta oil , 9 . 1 %. the above results were obtained from the experiments based on the orthogonal design l 9 ( 3 4 ) for different ratios of the individual volatile oils . further analysis of the results according to the orthogonal design revealed that the change in the ratio of eucalyptus oil in the formulations did not affect the bacteriostatic effect very much ; and the change in the ratios of forsythia oil , clove oil and schizonepeta oil affected the bacteriostatic effect considerably , with the bacteriostatic effect increasing with the increase in their ratios ; while the ratio of patchouli oil affected the bacteriostatic effect the most , with the bacteriostatic effect first increasing and then decreasing at the ratio of patchouli oil from 6 . 3 % to 16 . 0 %. based on the information acquired in this example , the theoretical ratio of individual volatile oils resulting in the best bacteriostatic effect was 15 : 4 . 5 : 7 . 5 : 3 : 7 , that is , eucalyptus oil , 40 . 5 %; forsythia oil , 12 . 2 %; clove oil , 20 . 3 %; patchouli oil , 8 . 1 %; and schizonepeta oil , 18 . 9 %. from this optimal ratio and the finding above that “ the change in the ratio of eucalyptus oil in the formulations did not affect the bacteriostatic effect very much ; and the change in the ratios of forsythia oil , clove oil and schizonepeta oil affected the bacteriostatic effect considerably , the bacteriostatic effect increasing with the increase in their ratios ”, it could be deduced that the ratios of individual volatile oils may vary in the following ranges : eucalyptus oil , 43 to 52 %; forsythia oil , 13 to 20 %; clove oil , 21 to 30 %; patchouli oil , 7 to 15 %; and schizonepeta oil , 7 to 15 %; or alternatively , eucalyptus oil , 18 to 63 %; forsythia oil , 5 to 19 %; clove oil , 6 to 27 %; patchouli oil , 6 to 16 %; and schizonepeta oil , 6 to 29 %; or alternatively , eucalyptus oil , 21 to 71 %; forsythia oil , 8 to 48 %; clove oil , 15 to 60 %; patchouli oil , 3 to 47 %; and schizonepeta oil , 3 to 53 %; or alternatively , eucalyptus oil , 6 to 90 %; forsythia oil , 3 to 70 %; clove oil , 5 to 80 %; patchouli oil , 1 to 70 %; and schizonepeta oil , 1 to 85 %. as the change in the ratio of eucalyptus oil in the formulations did not affect the bacteriostatic effect very much , the upper and lower limits of eucalyptus oil can vary widely . as to the change in the ratios of forsythia oil , clove oil and schizonepeta oil , besides the reasonable deduction made from the vicinity of their amounts in this example , their upper limits may actually be higher than those in this example , taking into consideration the fact that their bacteriostatic effects increased with the increase in their ratios . moreover , since the change in the viable amounts of the individual components in the formulations was continuous within a range , any combinations of the points disclosed in this example and the endpoints as described above representing ranges are also viable , that is , they fall within the scope of the present invention as explicitly disclosed . likewise , any matching of any range of amount of a component with any range of amount of any other component is also viable and is deemed to be part of the present invention as explicitly disclosed . the bacteriostatic effects of compounded traditional chinese medicinal volatile oils having different ratios of individual volatile oils ( bacteriostatic ring method , kirby - bauer antibiotic testing , or disk diffusion antibiotic sensitivity testing ). method of preparation : 625 . 0 ml of eucalyptus oil , 187 . 5 ml of forsythia oil , 62 . 5 ml of clove oil , 62 . 5 ml of patchouli oil and 62 . 5 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . sample 15 : eucalyptus oil : forsythia oil : clove oil : patchouli oil : schizonepeta oil ( 15 : 4 . 5 : 7 . 5 : 3 : 3 ) method of preparation : 454 . 5 ml of eucalyptus oil , 136 . 4 ml of forsythia oil , 227 . 3 ml of clove oil , 90 . 9 ml of patchouli oil and 90 . 9 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . method of preparation : 405 . 4 ml of eucalyptus oil , 121 . 6 ml of forsythia oil , 202 . 7 ml of clove oil , 81 . 1 ml of patchouli oil and 189 . 2 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . the bacteriostatic effects of the above samples were determined by the method of example 1 . the experimental results are shown in table 3 . results showed that the products of all the above three formulations had bacteriostatic effect . sample 16 was the optimized formulation obtained by calculation based on the results of example 2 . the results in table 3 showed that sample 16 had good bacteriostatic effect . its theoretic comprehensive bacteriostatic index was calculated to be 11 . 5 , lower than its determined comprehensive bacteriostatic index of 14 . 3 , which further demonstrated that the compounding produced synergistic effect that resulted in enhanced efficacy . the formulation of sample 16 possessed novelty and inventiveness . the bacteriostatic effects of compounded traditional chinese medicinal volatile oils having different ratios of individual volatile oils ( test tube dilution method ) method of preparation : 625 . 0 ml of eucalyptus oil , 187 . 5 ml of forsythia oil , 62 . 5 ml of clove oil , 62 . 5 ml of patchouli oil and 62 . 5 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . method of preparation : 454 . 5 ml of eucalyptus oil , 136 . 4 ml of forsythia oil , 227 . 3 ml of clove oil , 90 . 9 ml of patchouli oil and 90 . 9 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . method of preparation : 405 . 4 ml of eucalyptus oil , 121 . 6 ml of forsythia oil , 202 . 7 ml of clove oil , 81 . 1 ml of patchouli oil and 189 . 2 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . one ml of tween 80 was added into 3 ml of each of samples 6 , 15 and 16 and allowed to dissolve . then nutrient broth was added to obtain diluted samples of nine concentrations , i . e . 0 . 30 ml , 0 . 15 ml , 0 . 075 ml , 0 . 0375 ml , 0 . 01875 ml , 0 . 009375 ml , 0 . 004688 ml , 0 . 002344 ml or 0 . 001172 ml of crude drug per ml of the diluted sample , each tube having a total volume of 1 ml . thermal sterilization was conducted . control tubes : strain control tube , having medium containing no drugs plus experimental strains ; and drug control tube , having drug solution without experimental strains added . for each row of drug solution , into each of the tubes having different concentrations and the strain control tube was added 0 . 1 ml of 10 6 cfu · ml − 1 experimental strain solution ( 8 - hour culture ), and the tubes were incubated at 37 ° c . for 24 hours . from each of the tubes having different concentrations , a loop of sample was obtained using an inoculating loop and streak inoculated onto a solid nutrient agar plate . the plates were incubated at 37 ° c . for 24 hours , at which time the results were observed . each tube was visually inspected for the growth of the strains with turbidity as the index , and each plate was visually inspected to see if there was growth of colonies . the minimal inhibitory concentration ( mic ) was determined , which refers to the lowest drug concentration required to completely inhibit the growth of the experimental strains . the minimal bacteriocidal concentration ( mbc ) was determined , which refers to the lowest drug concentration required to completely kill the growth of the experimental strains . mic and mbc are two important indexes representing the bacteriostatic and bacteriocidal effects of a drug . the lower the value , the better the effect of the drug against the bacteria . using these two indexes , the bacteriostatic effects of samples 6 , 15 and 16 as a function of their concentrations were evaluated . results showed that , the above three samples had various degrees of bacteriostatic and bacteriocidal effect on the experimental strains . the mic for the strains was in the range of 2 . 34 μl · ml − 1 to 75 . 0 μl · − 1 , and the mbc for the strains was in the range of 4 . 69 μl · ml − 1 to 75 . 0 μl · ml − 1 . the comprehensive bacteriostatic and bacteriocidal indexes of mic and mbc of sample 16 were both the least , and the mic of sample 16 was close to that of sample 15 , indicating that sample 16 had the best comprehensive bacteriostatic and bacteriocidal effects and also a good comprehensive bacteriostatic effect . the antiviral effects of compounded traditional chinese medicinal volatile oils having different ratios of individual volatile oils method of preparation : 625 . 0 ml of eucalyptus oil , 187 . 5 ml of forsythia oil , 62 . 5 ml of clove oil , 62 . 5 ml of patchouli oil and 62 . 5 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . method of preparation : 454 . 5 ml of eucalyptus oil , 136 . 4 ml of forsythia oil , 227 . 3 ml of clove oil , 90 . 9 ml of patchouli oil and 90 . 9 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . method of preparation : 405 . 4 ml of eucalyptus oil , 121 . 6 ml of forsythia oil , 202 . 7 ml of clove oil , 81 . 1 ml of patchouli oil and 189 . 2 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain the mixture . ribavirin ( provided by hubei institute of pharmaceutical industry , hubei , china ; lot no . 0301006 ) was used as the positive drug control . influenza a virus fm 1 strain , provided by institute of medicinal biotechnology , chinese academy of medical sciences , was passaged in mdck cells ( madin - darby canine kidney cells ) which were incubated at 37 ° c . in a 5 % co 2 incubator . the viral titer was determined by cytopathic method and chicken erythrocyte agglutination method . viral experiment was performed in a 96 - well microtiter plate ( 0 . 1 ml per well ) according to guidelines for research of new drugs of traditional chinese medicine ( promulgated by the bureau of drug administration of the ministry of public health of the people &# 39 ; s republic of china , 1994 edition ). the cells were seeded in the wells at 1 × 10 5 / ml and allowed to grow to monolayer . the drugs were diluted with maintenance solution into four different concentrations . samples of the drugs at different concentrations were added to the wells at 0 . 1 ml / well after removing the original culturing solution from the wells . the minimal dilution at which the cells did not show pathological changes was taken as the limit of non - toxicity to the cells . at the same time , the tcid 50 ( 50 % tissue culture infective dose ) of the challenging virus was assayed on the mdck cells . in the assay , virus control , cell control , drug toxicity control and positive drug control ( ribavirin ) were included . the cells were incubated at 37 ° c . in a 5 % co 2 incubator and observed for pathological changes under an inverted microscope every day , with the observations being recorded . when the cells in the virus control well showed +++ pathological changes , observation was continued for 7 days and then stopped . the degrees of cell pathological changes were recorded in the following 6 - stage scale .—: cells grew normally , no pathological changes occurred ; “±”: cells with pathological changes were less than 10 % of the whole cell monolayer ; “+”: cells with pathological changes were less than 25 % of the whole cell monolayer ; “++”: cells with pathological changes were less than 50 % of the whole cell monolayer ; “+++”: cells with pathological changes were less than 75 % of the whole cell monolayer ; and “++++”. cells with pathological changes were more than 75 % of the whole cell monolayer . the experimental results are shown in table 5 . results showed that , at an infection dose of the virus of tcid 50 = 100 , 100 μg · ml − 1 of ribavirin had markedly inhibitory effect on fm1 , and 160 μg · ml − 1 of sample 15 , which was at sublethal concentration , was also inhibitory . this indicated that sample 15 also could inhibit the common virus in the air , therefore it had the effect of disinfecting the air . ( in the examples that follow , the formulation of sample 15 was chosen as subject of further research ). traditional chinese medicinal air - refreshing disinfectant 1 : prepared from compounded traditional chinese medicinal volatile oils and a vehicle at a ratio of 1 : 9 , wherein the compounded traditional chinese medicinal volatile oils were comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 4 . 5 : 7 . 5 : 3 : 3 , and the vehicle was comprised of kerosene and absolute ethanol at a ratio of 2 . 5 : 1 . method of preparation : 45 . 5 ml of eucalyptus oil , 13 . 6 ml of forsythia oil , 22 . 7 ml of clove oil , 9 . 1 ml of patchouli oil and 9 . 1 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain compounded traditional chinese medicinal volatile oils for immediate use . 642 . 9 ml of kerosene and 257 . 1 ml of absolute ethanol were separately measured , mixed and stirred to homogeneity , and then added to the above mixture of volatile oils . the resulting mixture was mixed and stirred to homogeneity to obtain the disinfectant 1 . materials and equipments : experimental strain : staphylococcus albus 8032 , provided by academy of military medical sciences , china . the strain was at the sixth to the eighth passages and was formulated into cell suspension using common broth . aerosol generator : more than 90 % of the particles having φ ≦ 5 μm . guidance for test : item 2 . 1 . 3 in technical standard for disinfection , 2002 edition , the ministry of public health of china . the flow rate of sprayer for bacterial contamination : 21 . 7 l / min ; spraying time : 5 min ; stirring time : 5 min ; standing time : 5 min . method of disinfection : when testing , the experimental chamber was sprayed using qpq - 2300 model electric aerosol sprayer at a dose of 2 ml / m 3 and samples were taken 60 minutes after disinfection . in the control group , deionized water was used in place of the disinfectant , and the other procedures were the same as the test group . the test was done in triplicate . samples were taken using fa - 1 model impact type airborne microorganism sampler at a sampling flow rate of 28 . 3 l / min . the sampling point was located 1 . 0 meter above the ground in the middle of the chamber . samples were taken at 0 min and at 60 min after disinfection . the sampling interval for the sampler of the control group was 5 second and 5 second respectively , and the sampling interval for the sampler of the test group was 5 second and 1 minute respectively . after sampling , the numbers of viable bacteria at different time points were determined and the killing rate was calculated according to the following formula : n t : natural death rate of the bacteria in the air ; v 0 and v t : the numbers of bacteria contained in the air before the test and during the test respectively for the control group ; k t : the killing rate of the bacteria in the air by disinfection ; v 0 ′ and v t ′: the numbers of bacteria contained in the air before disinfection and during disinfection respectively for the test group . results showed that 60 minutes of disinfection by traditional chinese medicinal air - refreshing disinfectant 1 resulted in the killing of staphylococcus albus at a killing rate of more than 96 . 30 % in all three tests . this showed that traditional chinese medicinal air - refreshing disinfectant 1 could kill the common bacteria in the air , therefore it had the bacteriocidal effect on the air . traditional chinese medicinal air - refreshing disinfectant 2 : prepared from compounded traditional chinese medicinal volatile oils and a vehicle at a ratio of 1 : 39 , wherein the compounded traditional chinese medicinal volatile oils were comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 4 . 5 : 7 . 5 : 3 : 3 , and the vehicle was comprised of kerosene and isopropanol at a ratio of 2 . 5 : 1 . method of preparation : 11 . 4 ml of eucalyptus oil , 3 . 4 ml of forsythia oil , 5 . 7 ml of clove oil , 2 . 3 ml of patchouli oil and 2 . 3 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain compounded traditional chinese medicinal volatile oils for immediate use . 642 . 9 ml of kerosene and 257 . 1 ml of isopropanol were separately measured , mixed and stirred to homogeneity , and then added to the above mixture of volatile oils . the resulting mixture was mixed and stirred to homogeneity to obtain the disinfectant 2 . traditional chinese medicinal air - refreshing disinfectant 3 : prepared from compounded traditional chinese medicinal volatile oils and a vehicle at a ratio of 1 : 9 , wherein the compounded traditional chinese medicinal volatile oils were comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 4 . 5 : 7 . 5 : 3 : 3 , and the vehicle was comprised of kerosene and isopranol at a ratio of 2 . 5 : 1 . method of preparation : 45 . 5 ml of eucalyptus oil , 13 . 6 ml of forsythia oil , 22 . 7 ml of clove oil , 9 . 1 ml of patchouli oil and 9 . 1 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain compounded traditional chinese medicinal volatile oils for immediate use . 642 . 9 ml of kerosene and 257 . 1 ml of isopropanol were separately measured , mixed and stirred to homogeneity , and then added to the above mixture of volatile oils . the resulting mixture was mixed and stirred to homogeneity to obtain the disinfectant 3 . temperature and humidity : room temperature : 31 ° c ., room relative humidity : 85 %. spraying equipment : electric aerosol sprayer , model dqp - 600 , available from beijing songyuan huaxing science and technology development co ., ltd , beijing , china . the sampling points are as shown in fig1 . a total of two samplings were made at 0 h and 2 h respectively . method of sampling : at each of the five sampling points as shown in fig1 , two plates having a diameter of 9 cm were placed at a sampling height of 1 . 0 m . the lids of the plates were removed and the plates were exposed to the air for 10 minutes . then the plates were covered with the lids and incubated at 37 ° c . for 24 hours . the number of colonies was counted and the killing rate was calculated according to the following formula . disinfection operation : the disinfectant was sprayed evenly in the room using the electric aerosol sprayer at a dose of 1 ml / m 3 and the room was allowed to be disinfected for 2 hours after spraying . results showed that , disinfection of the air in a closed room using traditional chinese medicinal air - refreshing disinfectants 2 and 3 resulted in a reduction in the number of bacteria in the air by about 71 % and 76 % respectively , which were statistically significant . this indicated that traditional chinese medicinal air - refreshing disinfectants 2 and 3 could kill the bacteria in the air , therefore they had the bacteriocidal effect on the air . in view of the data of “ 1 : 9 ” and “ 1 : 39 ” in this example and the resulting effect , the ratio of the compounded volatile oils to the vehicle can vary in a wide range without appreciable influence on the effect . the present invention can be carried out in the following ranges : compounded volatile oils : & gt ; 0 to ≦ 100 %; vehicle : 0 to 99 %; wherein “& gt ; 0 ” means greater than 0 . there is no limitation on the selection of the vehicle that can be used , so long it serves to achieve the objective of the present invention . such selection can be readily made by one skilled in the art through simple measurement . examples of the vehicle include but not limited to kerosene , isopropanol , and absolute ethanol etc , or mixtures in any combination thereof . to observe the toxicity response generated after administering the traditional chinese medicinal air - refreshing disinfectant once to animals and to evaluate the safety of the air - refreshing disinfectant in human body during actual application in humans . traditional chinese medicinal air - refreshing disinfectant 2 : prepared from compounded traditional chinese medicinal volatile oils and a vehicle at a ratio of 1 : 39 , wherein the compounded traditional chinese medicinal volatile oils were comprised of eucalyptus oil , forsythia oil , clove oil , patchouli oil and schizonepeta oil at a ratio of 15 : 4 . 5 : 7 . 5 : 3 : 3 , and the vehicle was comprised of kerosene and isopropanol at a ratio of 2 . 5 : 1 . method of preparation : 11 . 4 ml of eucalyptus oil , 3 . 4 ml of forsythia oil , 5 . 7 ml of clove oil , 2 . 3 ml of patchouli oil and 2 . 3 ml of schizonepeta oil were separately measured , mixed and stirred to homogeneity to obtain compounded traditional chinese medicinal volatile oils for immediate use . 696 . 4 ml of kerosene and 278 . 6 ml of isopropanol were separately measured , mixed and stirred to homogeneity , and then added to the above mixture of volatile oils . the resulting mixture was mixed and stirred to homogeneity to obtain the disinfectant 2 . the disinfectant 2 was diluted using arawana ® peanut oil ( production date : jan . 30 , 2007 ) ( other brands of peanut oil can be used of course ) when the test was performed . nih ( national institute of health ) mice ( certificate no . : 0027327 ), male : female = 1 : 1 , weight 18 to 22 g , provided by the center for experimental animals of guangdong province , china . twenty nih mice , male : female = 1 : 1 , weight 18 to 22 g , were subjected to adaptive feeding for 2 days . prior to administration , the animals were fasted overnight , but with free access to water . for the test , 5 . 0287 g of traditional chinese medicinal air - refreshing disinfectant 2 was diluted with a suitable amount of peanut oil to 20 ml . the animals were subjected to gastric perfusion once at a dose of 20 ml / kg of body weight , i . e ., 5000 mg / kg of body weight , and immediately observed for their response . the animals were observed continually for two weeks , and the toxicity response and death distribution of the animals were recorded . the deceased animals were subjected to postmortem examination and the pathological changes recorded to determine if ld 50 was greater than 5000 mg / kg of body weight . the results of the test showed that the animals receiving gastric perfusion with traditional chinese medicinal air - refreshing disinfectant 2 once at a dose of 5000 mg / kg of body weight did not show appreciable toxicity response . the manifestations of the animals after administration were mainly decreased activities , with some animals being excited and jumping . two hours after administration , the animals &# 39 ; activities basically returned to normal , with no occurrence of animal death . therefore , the ld 50 for the animals was determined to be greater than 5000 mg / kg of body weight . according to the following toxicity evaluation standards in technical standard for disinfection ( 2002 edition ) issued by the ministry of public health of china : ld 50 greater than 5000 mg / kg of body weight represents in fact no toxicity . ld 50 in the range of 501 mg / kg to 5000 mg / kg of body weight represents low toxicity ; ld50 in the range of 51 mg / kg to 500 mg / kg of body weight represents medium toxicity ; ld50 in the range of 1 mg / kg to 50 mg / kg of body weight represents high toxicity ; and ld50 less than 1 mg / kg of body weight represents extreme toxicity . since the traditional chinese medicinal air - refreshing disinfectant 2 had an ld 50 of greater than 5000 mg / kg of body weight , it could be regarded as a non - toxic product . the traditional chinese medicinal air - refreshing disinfectant according to the present invention has marked bacteriostatic , bacteriocidal and even antiviral activity . its formulation is novel and can significantly inhibit the growth of common pathogenic bacteria in the air . oral administration of the disinfectant at a dose of 5000 mg / kg of body weight did not result in obvious toxicity response and occurrence of animal death , suggesting its safety and effectiveness . its formulation , with a refreshing odor , can be used for disinfecting and refreshing the air . all examples herein are all non - limiting examples . all numerical values cited can also be approximate values unless particularly specified . any combinations of the points disclosed in the examples and the endpoints representing ranges also fall within the scope of the present invention . any matching of any range of amount of a component with any range of amount of any other component is also deemed to be part of the present invention . modifications made according to the present invention are also deemed to be part of the present invention .

the air - refreshing disinfectants currently sold in the market mostly contain artificially synthesized chemical disinfectants . frequent exposure to the air containing such chemicals may be somewhat harmful to the human body . therefore the present invention provides an air - refreshing disinfectant , and in particular an air - refreshing disinfectant which is not chemically synthesized and takes natural materials as raw materials and traditional chinese medicinal volatile oils as main effective ingredients . it is characterized by bacteriostatic and antiviral effects , long - lasting fragrance and cost - effectiveness , and is beneficial to human health . to achieve this objective , the present invention , by taking advantage of the bacteriostatic , antiviral and fragrant characteristics of traditional chinese medicinal volatile oils , employs specific combinations of eucalyptus oil , clove oil , patchouli oil , forsythia oil and schizonepeta oil as the active ingredients of the air - refreshing disinfectant .

overview of articulating shaft . turning to the drawings , wherein like numerals denote like components throughout the several views , fig1 depicts a surgical instrument , which in the illustrative versions is more particularly a surgical stapling and severing instrument 10 , that is capable of practicing the unique benefits of the present invention . in particular , the surgical stapling and severing instrument 10 is sized for insertion , in a nonarticulated state as depicted in fig1 , through a trocar cannula passageway to a surgical site in a patient ( not shown ) for performing a surgical procedure . once an implement portion 12 is inserted through a cannula passageway , an articulation mechanism 14 incorporated into a distal portion of an elongate shaft 16 of the implement portion 12 may be remotely articulated , as depicted in fig1 , by an articulation control 18 . an end effector , depicted in the illustrative version as a staple applying assembly 20 , is distally attached to the articulation mechanism 14 . thus , remotely articulating the articulation mechanism 14 thereby articulates the staple applying assembly 20 from a longitudinal axis of the elongate shaft 16 . such an angled position may have advantages in approaching tissue from a desired angle for severing and stapling , approaching tissue otherwise obstructed by other organs and tissue , and / or allowing an endoscope to be positioned behind and aligned with the staple applying assembly 20 for confirming placement . handle . the surgical and stapling and severing instrument 10 includes a handle portion 22 proximally connected to the implement portion 12 for providing positioning , articulation , closure and firing motions thereto . the handle portion 22 includes a pistol grip 24 toward which a closure trigger 26 is pivotally and proximally drawn by the clinician to cause clamping , or closing , of the staple applying assembly 20 . a firing trigger 28 is farther outboard of the closure trigger 26 and is pivotally drawn by the clinician to cause the stapling and severing of clamped tissue clamped in the staple applying assembly 20 . thereafter , a closure release button 30 is depressed to release the clamped closure trigger 26 , and thus the severed and stapled ends of the clamped tissue . the handle portion 22 also includes a rotation knob 32 coupled for movement with the elongate shaft 16 to rotate the shaft 16 and the articulated staple applying assembly 20 about the longitudinal axis of the shaft 16 . the handle portion 22 also includes a firing refraction handle 34 to assist in retracting a firing mechanism ( not depicted in fig1 ) should binding occur , so that opening of the staple applying assembly 20 may occur thereafter . it will be appreciated that the terms “ proximal ” and “ distal ” are used herein with reference to a clinician gripping a handle of an instrument . thus , the surgical stapling assembly 20 is distal with respect to the more proximal handle portion 22 . it will be further appreciated that , for convenience and clarity , spatial terms such as “ vertical ” and “ horizontal ” are used herein with respect to the drawings . however , surgical instruments are used in many orientations and positions , and these terms are not intended to be limiting and absolute . an illustrative multi - stroke handle portion 22 for the surgical stapling and severing instrument 10 of fig1 is described in greater detail in the co - pending and commonly - owned u . s . patent application entitled “ surgical stapling instrument incorporating a multistroke firing position indicator and retraction mechanism ” to swayze and shelton iv , ser . no . 10 / 374 , 026 , the disclosure of which is hereby incorporated by reference in its entirety , with additional features and variation as described herein . while a multi - stroke handle portion 22 advantageously supports applications with high firing forces over a long distance , applications consistent with the present invention may incorporate a single firing stroke , such as described in co - pending and commonly owned u . s . patent application “ surgical stapling instrument having separate distinct closing and firing systems ” to frederick e . shelton iv , michael e . setser , and brian j . hemmelgarn , ser . no . 10 / 441 , 632 , the disclosure of which is hereby incorporated by reference in its entirety . implement portion ( articulating elongate shaft and staple applying assembly ). in fig1 - 3 , the implement portion 12 advantageously incorporates the multiple actuation motions of longitudinal rotation , articulation , closure and firing within a small diameter suitable for endoscopic and laparoscopic procedures . the staple applying assembly 20 (“ end effector ”) has a pair of pivotally opposed jaws , depicted as an elongate channel 40 with a pivotally attached anvil 42 ( fig1 ). closure and clamping of the anvil 42 to the elongate channel 40 is achieved by longitudinally supporting the elongate channel 40 with a frame assembly 44 ( fig3 ) rotatingly attached to the handle portion 22 over which a double pivot closure sleeve assembly 46 longitudinally moves to impart a closing and opening respectively to a distal and proximal motion to the anvil 42 , even with the staple applying assembly 20 articulated as in fig2 . the staple applying assembly 20 is described in greater detail in co - pending and commonly - owned u . s . patent application ser . no . 10 / 955 , 042 , “ articulating surgical stapling instrument incorporating a two - piece e - beam firing mechanism ” to frederick e . shelton iv , et al ., filed 30 sep . 2004 , the disclosure of which is hereby incorporated by reference in its entirety . with particular reference to fig3 , the frame assembly 44 includes a single pivot frame ground 48 whose proximal end is engaged to the rotation knob 32 , with a right half shell 50 thereon shown in fig3 . it should be appreciated that a proximal end of the closure sleeve assembly 46 , specifically of a closure straight tube 52 , encompasses the proximal end of the frame ground 48 , passing further internally to the handle portion 22 to engage closure components ( not shown ) that longitudinally translate the closure sleeve assembly 46 . a circular lip 54 at the proximal end of the closure straight tube 52 provides a rotating engagement to such components . engaging components of the rotation knob 32 pass through a longitudinal slot 56 on a proximal portion of the straight closure tube 52 to engage an aperture 58 proximally positioned on the frame ground 48 . the longitudinal slot 56 is of sufficient length to allow the closure longitudinal translation of the closure sleeve assembly 46 at various rotational angles set by the rotation knob 32 to the closure sleeve assembly 46 and the frame ground 48 . the elongate shaft 16 supports the firing motion by receiving a firing rod 60 that rotatingly engages firing components of the handle portion 22 ( not shown ). the firing rod 60 enters a proximal opening 62 along the longitudinal centerline of the frame ground 48 . the distal portion of the frame ground 48 includes a firing bar slot 64 along its bottom that communicates with the proximal opening 62 . a firing bar 66 longitudinally translates in the firing bar slot 64 and includes an upwardly projecting proximal pin 68 that engages a distal end 70 of the firing rod 60 to form a firing member . the handle portion 22 supports articulation by incorporating a rectangular reservoir cavity 72 , one lateral portion depicted in a distal portion of the rotation knob 32 . a bottom compartment 74 that resides within the rectangular reservoir cavity 72 has laterally spaced apart left and right baffles 76 , 78 . an articulation actuator 80 slides laterally overtop of the bottom compartment 74 , its downward laterally spaced left and right flanges 82 , 84 , which are outboard of the baffles 76 , 78 , each communicating laterally to left and right push buttons 86 , 88 that extend outwardly from the respective shell halves of the rotation knob 32 . the lateral movement of the articulation actuator 80 draws left and right flanges 82 , 84 nearer and farther respectively to the left and right baffles 76 , 78 , operating against left and right reservoir bladders 90 , 92 of a fluidic articulation system 94 , each bladder 90 , 92 communicating respectively and distally to left and right fluid conduits or passageways 96 , 98 that in turn communicate respectively with left and right actuating bladders 100 , 102 . the latter oppose and laterally pivot a t - bar 104 of the articulation mechanism 14 . the frame assembly 44 constrains these fluidic actuations by including a top and distal recessed table 106 of the frame ground 48 upon which resides the fluid passages 96 , 98 and actuating bladders 100 , 102 . the t - bar 104 also slidingly resides upon the recessed table 106 between the actuating bladders 100 , 102 . proximal to the t - bar 104 , a raised barrier rib 108 is aligned thereto , serving to prevent inward expansion of the fluid passages 96 , 98 . the frame assembly 44 has a rounded top frame cover ( spacer ) 110 that slides overtop of the frame ground 48 , preventing vertical expansion of the fluid passages 96 , 98 and actuating bladders 100 , 102 , as well as constraining any vertical movement of the t - bar 104 . in particular , the frame cover 110 includes features that enable it to also provide an articulation locking member 111 . a distal end (“ rack ”) 112 of the t - bar 104 engages to pivot a proximally directed gear segment 115 of an articulated distal frame member 114 of the articulation mechanism 14 . an articulating closure ring 116 encompasses the distal frame member 114 and includes a horseshoe aperture 118 that engages the anvil 42 . a double pivoting attachment is formed between the closure straight tube 52 and articulating closure ring 116 over the articulating mechanism 14 , allowing longitudinal closure motion even when the articulation mechanism 14 is articulated . in particular , top and bottom distally projecting pivot tabs 119 , 120 on the closure straight tube 52 having pin holes 122 , 124 respectively are longitudinally spaced away from corresponding top and bottom proximally projecting pivot tabs 126 , 128 on the articulating closure ring 116 having pin holes 130 , 132 respectively . an upper double pivot link 134 has longitudinally spaced upwardly directed distal and aft pins 136 , 138 that engage pin holes 130 , 122 respectively and a lower double pivot link 140 has longitudinally spaced downwardly projecting distal and aft pins 142 , 144 that engage pin holes 132 , 124 respectively in fig2 - 3 , an articulation lock mechanism 200 is advantageously incorporated to maintain the staple applying assembly 20 at a desired articulation angle . the articulation lock mechanism 200 reduces loads on the left and right actuating bladders 100 , 102 . in particular , a compression spring 202 is proximally positioned between a proximal end 204 of the articulation locking member 111 and the handle portion 22 , biasing the articulation locking member 111 distally . selective abutting engagement of a distal frictional surface distally projecting from the articulation locking member 111 engages a corresponding locking gear segment in a brake plate ( not shown ) received into a top proximal recess 220 of the articulating frame member 114 . the articulation lock mechanism 200 is described in greater detail in the commonly - owned u . s . patent application ser . no . 11 / 194 , 437 , “ surgical instrument with an articulation shaft locking mechanism ” to wales et al ., filed 1 aug . 2005 , the disclosure of which is hereby incorporated by reference in its entirety . the elongate shaft 16 is depicted in an articulated position with the closure sleeve assembly 46 removed from around the frame assembly 44 and without the elongate channel 40 and anvil 42 . articulation actuator 80 is shown moved laterally to the left to compress right proximal reservoir bladder 90 and expanded distal right actuation bladder 100 moving t - bar 104 to the position shown . thus , lateral movement of the articulation actuator 80 articulates the distal frame 114 clockwise about the single pivot frame ground 48 as shown . the articulation actuator 80 advantageously also automatically engages and disengages the articulation lock mechanism 200 . in particular , a toothed detent surface 225 along a proximal top surface of the articulation actuator 80 receives an upwardly projecting locking pin 226 from the proximal end 204 of the articulation locking member 111 . the engagement of the locking pin 226 within the root of the toothed detent surface 225 provides sufficient distal movement of the articulation locking member 111 for locking engagement . lateral movement by an operator of the articulation actuator 80 proximally urges the locking pin 226 proximally , and thus disengages the articulation locking member 111 from the distal frame member 114 . when the operator releases the articulation actuator 80 , the locking pin 226 is urged by the compression spring 202 into the adjacent detent in detent surface 225 to lock the locking mechanism 111 , and thereby the staple applying assembly 20 , and to constrain the articulation mechanism 14 at a desired articulation position by constraining and expanding the inflated shape of the proximal left and right reservoir bladders 90 , 92 . in use , a laterally moving articulation mechanism 230 is shown schematically in fig4 - 7 and includes a fluid control system 235 having fluid filled parallel left and right fluid bladders 236 , 238 extending longitudinally therein that move a lateral member or t - bar 240 laterally by the movement of fluids 242 . all directions are in reference to the longitudinal axis . referring to the unarticulated view of fig4 and 5 , the distally located end effector 232 pivots about pin 244 and has a gear segment 246 at a proximal end . pivot pin 244 is attached to a frame ( not shown ). a rack 248 at a distal end of the t - bar 240 operably engages gear segment 246 . t - bar 240 and rack 248 are laterally moveable along axis a - a . a distal portion of the long left and right fluid bladders 236 , 238 lies laterally to the laterally moveable t - bar 240 and are laterally constrained within a closure sleeve 250 and vertically constrained by a frame 252 below and a spacer 254 above . left actuating fluid bladder 236 is filled with fluid 242 and has left distal actuating bladder 256 , left fluid passageway 258 , and a left proximal reservoir bladder 260 . right fluid bladder 238 contains fluid 242 and has a right distal actuating bladder 262 , right fluid passageway 264 , and right proximal reservoir bladder 266 . a fixed divider 270 extends from the frame 252 and separates the bladders 260 , 266 and the fluid passageways 258 , 264 . the fixed divider 270 and the closure sleeve 250 constrain the fluid passageways 258 , 264 and prevent expansion in the fluid passage sections 258 , 264 of the bladders 236 , 238 . a laterally moveable “ c ”- shaped compression member 272 is included in articulation control mechanism 230 for the compression of one of the proximal reservoir bladders 260 , 266 and the articulation of the end effector 232 . in addition , other components such as a firing bar 274 passing through a firing bar slot 276 in the frame 252 may be incorporated ( fig5 , 7 ). rather than a rounded rectangular shape , the cross sectional shape of a bladder may be modified to be any shape . for example it could be advantageous to construct the distal and / or proximal bladders as a pleated bellows . in fig8 , a tubular shaft 278 for the surgical instrument 10 is as described above for fig4 - 7 with the exception that a left actuating bladder 256 a and a right actuating bladder 262 a are both of a rectangular pleated design with the former shown in a compressed state and the latter shown in an expanded state in a lateral cavity 280 . pleated right actuating bellows 262 a collapse easily into the confined area of the right portion of the lateral cavity 280 as depicted . similarly , pleated left actuating bellows 256 a expand easily to fill the area of left portion of the lateral cavity 280 . while not shown , pleated bladders may also be used for the proximal reservoir bladders . it should be appreciated that actuating bladders and distal bladders may be formed into other cross sectional shapes such as rounds , squares , triangles , hexagons , octagons , or any other shape that meets the needs of the mechanism . fluid bladders . it should be appreciated with the benefit of the present disclosure that such bladders may be constructed in various ways from various combinations of materials . while shown as a unified part above , these bladders may be assembled from multiple parts or constructed as a single unitary fluid bladder . for multiple part construction , at least one of the bladders may be attached to any of the other elements . many leak proof attachment methods are available for assembly such as welding , glue , press fit , heat staking , crimp fittings , clamps fittings , joints and the like . two basic types of fluid bladders may be constructed . one is a high pressure , non - elastic rigid bladder from either rigid or elastomeric materials , and the other is a lower pressure elastomeric balloon . rigid balloon materials are known in the medical arts and are used for dilation or angioplasty or the expansion of stents within blood vessel walls . rigid balloons are made from non - compliant or low compliant materials that retain their designed size and shape under high - pressure loading . typically , these balloons are thin walled and are formed from high tensile materials with low elongation . typical materials for these balloons are polyvinyl chloride ( pvc ), cross linked polyethylene , and polyester ( pet ) polyethylene terrapthalate , nylon and others . for angioplasty balloons , thin walled sections of pet tubing may be blow molded into a balloon shape . each of the left and right fluid bladders may be formed from a continuous piece of thin walled tubing with both the proximal and distal bladders formed by expanding local sections of the thin walled tubing . expansion of the proximal and distal bladder areas may be accomplished by locally heating the tubing and blow molding the bladder shapes therein . one of the open ends of the formed fluid bladders may then be sealed , and the other open end of the bladders may act as a fill port for fluids . after filling , the open fill port is sealed . alternately , the fluid bladders may be assembled from multiple pieces rather than a single piece . non - bladder portions of the fluid bladders , such as fluid passageways , may be formed from rigid or semi - rigid tubing or other materials . alternately , elastomeric balloons may also be used to construct fluid bladders . these elastomeric materials are formed into a first shape and , with the application of pressure , may expand to a larger shape . elastomeric materials may expand and return to the original shape a number of times without degradation of the elastomeric properties . while not able to handle pressures as high as rigid materials , elastomeric bladders may be used to articulate . confining or constraining the elastomeric fluid bladders between walls or constraints prevents bulging of bladder material into unwanted areas and increases the forces that may be applied . elastomeric bladders may be constructed by various processes including dip molding or , like iv bags , formed from two sheets that are welded or glued together . elastomeric bladders may be formed from latex , rubber , silicone , polyurethane , polyethelene , polypropelene , teflon , or any one of a number of elastic or semi - elastic engineering materials . additionally , conventional blow molding techniques may be used to form bladders . unlike the thin walled pet shrink tubing used in angioplasty balloons , conventional blow molding techniques use a hollow tube or molded hollow preform that is heated and moved to an injection station where low pressure air is typically used to initially inflate the rod or preform . a burst of high - pressure gas is then applied to force the expanded hot tube or preform into contact with the walls of the mold to cool the blown material in the net shape . while producing thin walls , the preform blow molding process produces thin walls that are much thicker than the less than 4 mil angioplasty balloons . this process forms many current products such as soda bottles , disposable pipettes with a rigid tube and expanded bladder , and containers . for the formation of bladders , a preform shape is first injection molded with the appropriate material thickness at the expandable bladder areas to provide the desired wall thickness when the bladders are expanded in the blow molding process . once the bladders are blow molded into net shape , they may be filled with fluid and sealed . appropriate blow molding materials include nylon , polyester ( pet ), polyethelene , polyprolelene , high density polyethelene ( hdpe ) and any one of a number of known blow molding materials . in addition to rigid and elastomeric bladders , bladder construction may be springy or flaccid . that is , at least one of the proximal bladders or at least one of the distal bladders may be constructed from a spring material that wants to resume its original shape after compression and release . alternately , at least one of the proximal bladders or at least one of the distal bladders may be constructed from a generally flaccid material . such materials have a weak spring rate , if any , and do not tend to expand back to the original pre - deformed shape . flaccid bladders or springy bladders may advantageously include the internal compression spring that forces the walls of the bladder outward . the internal compression spring may be formed from a variety of materials including metallic springs , plastic springs , foams , squeezable elastomerics and the like . a sealed assembly of a full flaccid bladder with a partially filled spring bladder ( on a passageway ) results in the spring bladder expanding and drawing fluid from the flaccid bladder . assembly of a pair of partially compressed spring bladders ( of equal spring rate walls and size ) results in both spring bladders being in the partial compressed position . compression of one of the partially filled spring bladders results in full expansion of the uncompressed spring bladder and reduction of the compressed spring bladder . release of the compressed spring bladder enables the compressed spring bladder to expand and draw fluid back into the compressed spring bladder . this process is spring rate controlled and if both bladders have the same spring rate , the fluid will be drawn back into the released compressed spring bladder until both spring bladders are equally filled . if desired , mismatched spring rates for the spring bladders may be used to draw and store fluids into one of the bladders as desired . in fig9 , as an example of an added resilient structure , a bladder 800 is depicted to include an actuating bladder 802 in fluid communication through a fluid passage or conduit 804 to a reservoir bladder 806 . in this illustrative version , a compression spring 808 laterally biases the actuating bladder 802 to an expanded state . advantageous features of the compression spring 808 includes providing a restoring force to expand bladder 802 or to center an end effector ( not shown ), as well as other advantages . if desired , springs may be placed in either one of both bladders 802 , 806 or in both bladders 802 , 806 . in fig1 , an alternate resilient structure , depicted as an open cell foam 810 , fills the actuating bladder 802 rather than using a compression spring . thus , fluid may be forced into and out of the open cell foam 810 as desired for expansion with the open cell foam 810 providing a degree of resilience . in fig1 , a metal - walled bladder 900 may be formed from metal tubing 902 that is heated and pressure blown with a plugged end 904 either closed by a plug 906 before or after forming of an enlarged portion 908 . the dimensions of the enlarged portion 908 may be controlled by selecting the temperature of heating , the amount of the metal tubing 902 that is heated , and / or surrounding the metal tubing 902 with a fixture ( not shown ) that constrains expansion to desired outer diameters for a neck portion 910 , the enlarged portion 908 , and the plugged end 904 . resulting thinner walls 912 of the enlarged portion 908 provides a desired degree of flexibility as a trade - off with burst strength deemed suitable for a fluid reservoir or actuator . in fig1 , a fluid control assembly 1000 may be assembled from a flaccid bladder 1002 that communicates via a rigid conduit 1004 to a deformable bladder 1006 . the deformable bladder 1006 may be advantageously formed of a shape memory alloy ( sma ) which are metals , such as niti ( nickel - titanium ), cuznal , and cualni . smas exhibit two very unique properties : shape memory effect and pseudo - elasticity , made possible through a solid state phase change , that is a molecular rearrangement , which occurs in the shape memory alloy . in most smas , a temperature change of only about 10 ° c . is necessary to initiate a phase change between martensite and austenite . martensite , the relatively soft and easily deformed phase of smas , exists at lower temperatures . austenite , the stronger phase of shape memory alloys , occurs at higher temperatures . the shape of the austenite structure is cubic . the un - deformed martensite phase is the same size and shape as the cubic austenite phase on a macroscopic scale , so that no change in size or shape is visible in shape memory alloys until the martensite is deformed . the temperatures at which each of these phases begin and finish forming are represented by the following variables : m s , for the temperature at which marsenite starts to form ; m f , for the temperature at which marsenite finishes forming ; and a f , for the temperature at which arsenite finishes forming . the shape memory effect is observed when the temperature of a piece of shape memory alloy is cooled to below the temperature m f . at this stage , the alloy is completely composed of martensite which can be easily deformed . after distorting the sma , the original shape can be recovered simply by heating the wire above the temperature a f . the heat transferred to the wire is the power driving the molecular rearrangement of the sma , similar to heat melting ice into water , but the sma remains solid . the deformed martensite is now transformed to the cubic austenite phase , which is configured in the original shape of the wire . pseudo - elasticity occurs in smas when the sma is completely composed of austenite ( temperature is greater than a f ). unlike the shape memory effect , pseudo - elasticity occurs without a change in temperature . the load on the sma is increased until the austenite becomes transformed into martensite simply due to the loading . the loading is absorbed by the softer martensite , but as soon as the loading is decreased , the martensite begins to transform back to austenite since the temperature of the wire is still above a f , and the wire springs back to its original shape . thus , the deformable bladder 1006 may be deformed by fluid pressure and / or mechanical pressure with the shape memory effect or pseudo - elasticity relied upon to restore the deformable bladder 1006 to a desired shape ( e . g ., compressed or expanded ). the flaccid bladder 1002 transfers a corresponding amount of fluid through the rigid conduit 1004 in proportion to the change in volume of the deformable bladder 1006 . either the flaccid bladder 1002 or the deformable bladder 1006 may serve as an actuating bladder with the other serving as a reservoir bladder having a controlled volume . for example , a deformable bladder 1006 ( i . e ., actuating bladder ) may be formed to have a pleated , compressed state that is then heat treated to remember that shape . alternatively , the deformable bladder 1006 may formed to have an expanded shape and then be deformed to a compressed state . in fig1 , an alternative flaccid or resilient bladder 1100 is formed from longitudinally continuous tubing material 1102 by heat sealing or internally gluing an inner diameter 1104 of one end 1106 that is held closed and flattened until cooled and / or set to form a non - communicating seal . an expanded portion 1108 of the tubing material 1102 communicates through a neck portion 1110 . in fig1 , a further alternative laminate bladder 1200 that may be advantageously used in the surgical instrument of fig1 is formed from a blow molded inner plastic layer 1202 with sufficient strength to define an expanded shape of the bladder 1200 . a resilient layer 1204 , such as latex rubber , encompasses the inner plastic layer 1202 to provide additional strength and perhaps a compression force to bias the bladder 1200 toward a smaller volume . an outer lubricant layer 1206 ( e . g ., silicone , teflon ) assists in assembling the bladder 1200 into a surgical instrument ( not shown ) and is used to avoid binding / adhesion to walls of a bladder cavity that could cause improper expansion or contraction . alternately , whereas a three - layer laminated bladder is described above with the layers in a selected order , laminated bladders can be made from any two or more layers and the order of the layers and layer materials can be varied to suit the needs of the surgical instrument . for example , it can be advantageous to add an additional lubricated layer as the innermost layer to the three layers 1202 , 1204 , and 1206 listed above for a dry fluid such as microparticles ( described below ), or to use an inner protective layer on an outer metal layer to act as a barrier between the metal and fluid . while the present invention has been illustrated by description of several embodiments and while the illustrative embodiments have been described in considerable detail , it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail . additional advantages and modifications may readily appear to those skilled in the art . for example , a single reservoir bladder may serve as both a left and right actuating bladder as described in the aforementioned and incorporated u . s . patent application ser . no . 11 / 061 , 908 entitled “ surgical instrument incorporating a fluid transfer controlled articulation mechanism ” to kenneth wales and chad boudreaux filed on 18 feb . 2005 . for another example , reservoir and / or actuating bladders may be incorporated into a surgical instrument for purposes other than articulation , such as for opening and / or closing an anvil of a stapling and severing end effector as described in commonly owned and co - pending u . s . patent application ser . no . 11 / 165 , 094 , entitled “ surgical instrument having fluid actuated opposing jaws ” to wales et al ., filed 23 jun . 2005 , the disclosure of which is hereby incorporated by reference in its entirety . as yet another example , a single fluid transfer approach may be incorporated wherein a single fluid actuator expands and compresses to effect articulation , perhaps assisted by a resilient opposing member that is not in fluid or pneumatic communication with the handle . an application consistent with such a design , for instance , could include just one bladder attached to a t - bar so that when compressed by the withdrawal of fluid , it pulls the t - bar with it . as yet a further example , fluids used in a laterally moving device may be either compressible or incompressible . as used herein , the term “ fluid ” comprises liquids , gases , gels , microparticles , and any other material which may be made to flow between a pressure gradient . while any fluid may be used , sterilized solutions such as saline , mineral oil or silicone are illustrative flowable materials .

a surgical instrument particularly suited to endoscopic use articulates an end effector by including a fluid transfer articulation mechanism that is proximally controlled . a fluid control , which is attached to a proximal portion , transfers fluid through the elongate shaft through a first fluid passage to a first fluid actuator that responds by articulating an articulation joint . two opposing fluid actuators may respond to differential fluid transfer to effect articulation . thereby , design flexibility is achieved by avoiding the design constraints of transferring a mechanical motion through the tight confines of the elongate shaft sufficient to effect articulation .

in fig1 medication delivery vehicle 10 is depicted in its preferred embodiment comprising a substantially truncated conical shaped member 11 . member 11 comprises a wall portion 13 in which the desired medication is retained for subsequent dispensing directly to the desired site . conical shaped wall 13 terminates at one end with a first , substantially circular - shaped edge 15 , and at the opposed and in a second , substantially concentrically aligned circular - shaped portal - defining edge 17 . member 11 and its truncated conical shaped wall portion 13 incorporates a quantity of therapeutic medication contained directly within wall portion 13 . medication may be contained in either a single compartment reservoir within wall portion 13 or can be distributed in a finely divided manner in porous material defining multiple interconnected reservoirs . one material which is employed to form wall portion 13 is an imperforate polymeric material such as described in u . s . pat . no . 3 , 618 , 604 or a microporous polymeric material in which the pores are filled with a liquid or gel medium for controlling the release rate of medication as described in u . s . pat . no . 3 , 828 , 777 . for more detailed description of such materials and their structures , reference should be made to the cited patents . in the preferred embodiment , medication delivery vehicle 10 comprises an overall size and shape dimensioned to fit the particular channel - like conduit , opening , vessel , or orifice which is directly adjacent the desired organ or site at which the medication is desired . in general , the diameter of edges 15 and 16 are constructed to comprise the precise size for the area in which delivery vehicle 10 is to be securely implanted . although specific dimensions are detailed below , the particular configurations are provided merely for exemplary purposes , and not in any way to limit the scope of this invention . regardless of the particular diameter of concentrically aligned portal - defining edges 15 and 17 , as well as the resulting angular slope at which sidewalls 13 is provided , the preferred configuration for medication delivery vehicle 10 is a substantially truncated conical shape member 11 . this configuration is preferred in order to allow direct surgical implantation or manual insertion of medication delivery vehicle 10 at the desired location , while also assuring that the medication delivery vehicle in no way impedes the normal bodily function or fluid flow through the conduit , opening , channel or orifice in which medication delivery vehicle 10 is positioned . furthermore , it has been found that truncated conical shape member 11 also provides an inherently stable member which is quickly and easily retainingly embedded in the desired receiving channel - like zone , in a secure , fixed orientation , free from unwanted rolling , twisting , or dislodgement . in fig2 medication delivery vehicle 10 is depicted in an elongated , channel - like conduit 21 . conduit 21 is depicted as a general representation or any substantially cylindrical , elongated tubular - shaped fluid carrying member or vessel found throughout the body . such fluid carrying member includes arteries , veins , the digestive tract , the colon , rectum , the ear canal and the trachea or windpipe . as shown in fig2 medication delivery vehicle 10 is securely embedded in tubular conduit 21 , with the substantially truncated conical shaped wall portion 13 in direct abutting embedded engagement with conduit 21 . furthermore , the normal fluid passing through conduit 21 is not affected by delivery vehicle 10 , since the fluid is free to flow through the portal defined by edges 17 and 15 . in the preferred embodiment , the larger diameter portal - defining edge 15 is positioned to receive the fluid flowing through conduit 21 , while portal - defining edge 17 represents the exit portal as the fluid passes through medication delivery vehicle 10 . although medication delivery vehicle 10 can be arranged in the directly opposite manner , it has been found that by having the fluid flow through the larger diameter portal first , delivery vehicle 10 operates more efficiently , while providing further assurance that vehicle 10 is not in any way dislodged or moved from its embedded position . if desired , medication delivery vehicle 10 may be constructed from a biodegradable or bioerodable material . one such bioerodable material is defined in u . s . pat . no . 3 , 867 , 519 . in this way , the removal of medication delivery vehicle 10 from its implanted position , such as a surgically implanted position , is not necessary , since medication delivery vehicle 10 will be degraded and carried away through normal bodily functions after the desired medication has been fully and completely dispensed . in addition , medication delivery vehicle 10 may also comprise a composite structure with a drug impregnated matrix and an insoluble polymeric membrane as the outer skin thereof , in a general manner as defined in u . s . pat . no . 3 , 854 , 480 . in fig3 - 6 , medication delivery vehicle 10 of the present invention is depicted in its ophthalmic embodiment . in this embodiment , delivery vehicle 10 is inserted in the eye to dispense medication at a controlled rate for an extended period of time . for example , this delivery vehicle 10 may be used to treat chronic disorders such as glaucoma by continuously dispensing a drug such as pilocarpine at a controlled rate for a period up to a week without replacement . in this embodiment , delivery vehicle 10 comprises a body 12 formed from a nonallergenic material which is insoluble in lacrimal or tear fluids . a quantity of therapeutic medication is confined within the body so that it may be diffused through the surface of the body into the lacrimal fluids when the body is placed on the surface of the eyeball . as shown in fig3 the body 12 has a generally annular shape . the walls of the body have a slight spherical curvature so that the body resembles the frustum of a sphere defined between two parallel planes perpendicular to the polar axis 14 of the sphere . such a frustospherical , annular shape has a polar marginal edge 16 at the front or anterior portion of the body and an equatorial marginal edge 18 at the rear or posterior edge of the body . the diameter of the annular body is smallest at the polar marginal edge 16 and is largest at the equatorial marginal edge 18 . the diameters and curvature of the body are selected to allow the body to be placed in the eye as shown in fig4 - 6 . to more clearly understand this embodiment of the present invention , a brief description of the anatomy of the eye is provided in connection with fig4 - 6 . the eye fits in a cavity of the skull known as the orbit and is exposed at the anterior portion by a palpebral opening or fissure defined by the upper eyelid 20 and lower eyelid 22 . the globe 24 or eyeball connects at the posterior with the optic nerve 26 and is comprised of two merged , generally spherical sections , the anterior section being defined as the cornea 28 which is transparent and the posterior section being defined as the sclera 30 which is white and more commonly referred to as the white of the eye . the eye muscles 32 and 34 are attached to the sclera for moving the eye in its orbital socket . the pupil 36 of the eye is an opening on the optical axis and is defined by the iris 38 or colored portion of the eye situated posteriorly of and visible through the transparent cornea 28 . as shown in fig5 and 6 , the cornea 28 has a much smaller radius of curvature than the sclera 30 . in actuality , neither the cornea nor the sclera are truly spherical but tend to flatten slightly as the distance from the optical axis increases . the curvature of the cornea differs from person to person , and hence is difficult to utilize as an interface with delivery vehicles such as soft contact lenses which ar placed directly on the cornea . the junction of the sclera 30 and cornea 28 is identified as the limbus 40 and can be seen in the eye at the point where the white sclera joins the transparent cornea . the limbus , accordingly , defines the outer limit of the cornea which contains a high concentration of nerve endings serving to protect the cornea from dryness and injury from foreign objects . it is this corneal - scleral junction that identifies the region in which ophthalmic delivery vehicles should not intrude ; otherwise the natural protective systems of the eye attempt to work the delivery vehicle out of the eye . the conjunctiva 42 is a thin mucous membrane that connects the inner side of the eyelids to the eyeball in the vicinity of the corneal - scleral junction or limbus 40 . as seen in fig4 the conjunctiva is a folded membrane having a palpebral portion 44 that connects with the margins of the eyelids and extends in the posterior direction to a fold or fornix 46 and a bulbar portion 48 which extends from the fornix in the anterior direction over the eyeball where it merges with the sclera and the cornea at the limbus 40 . the conjunctiva 42 thus forms a circular cul - de - sac known as the conjunctival sac which surrounds the eyeball and prevents foreign objects from migrating rearwardly under the eyelids to areas within the orbit behind the eyeball . the conjunctiva also serves as a small reservoir for lacrimal fluids which are wiped across the cornea by blinking the eyelids as needed to prevent corneal dryness . in the presence of irritations in the eye and the secretion of excess lacrimal fluids , the conjunctival sac fills with fluids and overflows to form tears , initially at the nasal corner of the eyelids . in this embodiment of the present invention , the delivery vehicle 10 is positioned on the globe of the eye coaxially of the optical axis and is sized so that it circumscribes the corneal - scleral junction 40 without intruding upon the junction . thus , as illustrated in fig4 and 6 , the polar marginal edge 16 of the body 12 has a diameter slightly larger than the diameter of the cornea 28 . it is also common for the corneal - scleral junction to be flattened at the top and bottom edges so that it has a slightly elliptical shape with , for example , a horizontal dimension 12 mm and a vertical dimension of 11 mm . preferably , body 12 of delivery vehicle 10 also has a slightly elliptical shape conforming to that of the junction . as a minimum , the inside diameter of the polar marginal edge should not be less than 11 mm to prevent intrusion onto the cornea 28 . the annular body 12 extends from the polar marginal edge 16 over the eyeball in the posterior direction with the upper and lower portions projecting into the conjunctival sacs behind the upper and lower eyelids 20 and 22 . the curvature on the inner surface of the body between the marginal edges 16 and 18 is preferably matched with the curvature of the sclera in the region adjacent the limbus 40 so that the body lies flat on the bulbar portion 48 of the conjunctiva and remains in place due to the curvature and the capillary action developed by the film of lacrimal fluid on the eye and in the conjunctival sacs . the eyelids 20 and 22 overlie the exterior surface of the body 12 as shown most clearly in fig5 and 6 and develop additional forces for holding the body in place coaxially of the cornea 28 . the degree to which the body 12 extends posteriorly behind the eyelids 20 and 22 depends partly upon the amount of semipermeable surface area needed to dispense medication in the eye . if the polar marginal edge 16 is spaced , for example , 1 mm from the cornea 28 , then the diameter of the equatorial marginal edge 18 may be smaller than the corresponding diameter of a body which has the polar marginal edge 16 2 mm from the cornea , assuming the same dose rate is desired . it is contemplated , that the width of the annular body measured from the polar marginal edge to the equatorial marginal edge will in most cases be not more than 4 mm and will lie generally in the range of 2 - 4 mm . the thickness of the body from the interior surface contacting the bulbar portion 48 of the conjunctiva to the exterior surface contacting the palpebral portion 44 may also vary between 0 . 1 mm and 1 mm with a nominal dimension being 0 . 2 mm . by employing this embodiment of delivery vehicle 10 in the eye , the lacrimal fluid and the blinking action of the eyelids carry medication diffused through the surface of the body over the eyeball and allow the medication to operate in the eye and surrounding regions . the body 12 is held firmly in position by capillary forces and the curvatures of the sclera in the region of the limbus 40 . thus , movement of the eyeball does not have a tendency to dislodge the body . the body is sized to remain outside of the highly sensitive corneal region to prevent irritation and also fully exposes the cornea in a natural manner to the eyelids and lacrimal fluids . accordingly , the foreign - body awareness problem and the retention problems of the prior art devices are minimized , and with the cornea fully exposed , drying or oxygen depletion which occurs after prolonged wearing of a soft contact lens is avoided entirely . in fig7 medication delivery vehicle 10 of the present invention is shown in an alternate implanted position . in this embodiment , medication delivery vehicle 10 is inserted directly into the auditory meatus or ear canal 50 , in order to deliver medication directly to the inner ear . in this embodiment , medication delivery vehicle 10 is preferably constructed with a substantially truncated conical shape and securely embedded in ear canal 50 , directly adjacent the membrane tempani 51 , found near the end of the auditory meatus . since the auditory meatus comprises a substantially oval shaped , cylindrical canal composed of very flexible , fibrocartilage for the first one - third of an inch , delivery vehicle 10 may comprise one substantially uniform size for adults and another substantially uniform size for children . however , if desired , delivery vehicle 10 may be constructed with a specific , individualized size . once implanted , gravity would cause the medication contained within delivery vehicle 10 to be slowly dispensed to the desired site , without any change or degradation in hearing being experienced by the user . in fig8 another alternate embodiment of medication delivery vehicle 10 is shown . in this embodiment , medication delivery vehicle 10 is inserted directly in the trachea 54 for delivering medication to bronchial tubes 55 and the lungs ( not shown ). typically , such diseases as asthma could be efficiently and effectively treated by having medication delivered directly to these affected areas . as shown in fig8 medication delivery vehicle 10 is embedded directly in trachea 54 , with wall portion 13 of medication delivery vehicle 10 in direct , abutting , secure engagement with the walls of trachea 54 . in this way , the medication contained in the wall portion 13 of delivery vehicle 10 is dispensed at a controlled rate over an extended period of time , directly to bronchial tubes 55 and the lungs . in this embodiment , the medication is dispensed both by gravity as well as by the air flow through delivery vehicle 10 during normal breathing . in this embodiment , medication delivery vehicle 10 is constructed in an overall configuration to assure secure , retained embedded engagement along the walls of trachea 54 . the trachea , or windpipe , is a substantially cylindrical tube composed of cartilage and membrane . in general , the trachea is about four and one - half inches long , with an average diameter of about 7 / 8 inches . as a result , this embodiment of medication delivery vehicle 10 would incorporate the preferred , generally truncated conical shape , with larger diameter , portal defining edge 15 having a diameter of about 5 / 8 inches and with smaller diameter portal defining edge 17 having a diametcr of about 9 / 16 inches . in addition , the vertical distance between edges 15 and 17 would preferably be between about one - quarter inches to about one inch . in fig9 delivery vehicle 10 is depicted inserted in a nasal passageway 58 , in order to dispense medication directly to the mucous membranes surrounding the nasal passageway . wall portion 13 of delivery vehicle 10 is positioned in direct , abutting , secure engaged contact with the walls of nasal passageway 58 , with the medication contained in wall portion 13 of delivery vehicle 10 ready to be dispensed at a controlled rate over an extended period of time directly to the desired site . in this embodiment , medication is dispensed by the air flowing through delivery vehicle 10 during normal breathing . in addition , medication delivery vehicle 10 is preferably constructed with a particular size dimensioned for the nasal passageways of the individual requiring the medication delivery . also shown in fig9 is the pharynx , which is a musculo - membraneous tube located behind the nose , mouth and larynx . the pharynx is about four and one - half inches in length and represents another site in which medication delivery vehicle 10 of the present invention could be implanted . as is readily apparent from the foregoing detailed disclosure and the examples of uses for the delivery vehicle of the present invention , medication delivery vehicle 10 of the present invention is capable of delivering any desired medication directly to any particular organ or site without causing potentially adverse effects from the medication circulating throughout the body , or in any way adversely affecting normal bodily functions . by providing a medication delivery vehicle having a generally truncated conical shape , the vehicle can be quickly and easily embedded or surgically implanted in any particular channel - like conduit , vessel , or cavity to deliver the desired medication to the precise location , without in any way adversely affecting the fluid flowing through the channel - like vessel or conduit . furthermore , secure retained embedment in the desired position is provided while the desired medication is delivered at a controlled rate , over an extended period of time . in an alternate embodiment , the medication delivery vehicle of the present invention may comprise an elongated , continuous , flexible , tape - like structure which can be wrapped around particular sites to which medication must be dispensed at a desired , controlled rate . in this embodiment , bones , muscles , tendons and subcutaneous sacs and joints for diseases such as arthritis are efficiently an effectively treated . in this embodiment , the substantially continuous elongated length of membrane is constructed with the desired medication contained therein , and the membrane is wrapped about the bone , muscle or other affecred area for allowing medication to be dispensed directly to the particular site where an injury or disease has been found . in this way , the advantages obtained by the medication delivery vehicle of the present invention are efficiently attained and the treatment of specific localized diseases are treated without adversely affecting the entire body . it will thus be seen that the objects set forth above , among those made apparent from the preceding description , are efficiently attained , and since certain changes may be made in carrying out the above method or in the constructions set forth without departing from the scope of the invention , it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense . it is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described , and all statements of the scope of the invention which , as a matter of language , might be said to fall therebetween .

by providing an implantable insert incorporating a reservoir in which a therapeutic medication is stored , with said insert having a construction through which the medication is dispensed , a medication delivery vehicle is obtained which is capable of being inserted directly adjacent various organs in order to provide requisite medications directly to the organ . in the preferred embodiment , the medication delivery vehicle of this invention comprises a truncated conical shape , thereby allowing the delivery vehicle to be inserted into channel - like orifices , conduits , or vessels leading to the particular organ to which medication delivery is sought , without interfering with the normal bodily functions or the passage of fluids through the channel - like areas and without further movement from the site of implantation . in another embodiment , the delivery vehicle comprises a frusto - spherical annular shape for being inserted on the eye in circumscribing relationship with the corneal - scleral junction , without intruding upon that junction . in this way , medication is delivered directly to the cornea of the eye .

the biologically active film of the present invention is prepared by the alternate adsorption film method , or layer - by - layer self - assembly method . with this method , alternating positively and negatively charged layers are deposited onto a base material or substrate by soaking or dipping the base material in a cationic solution and in an anionic solution until a multilayer film of the desired thickness is formed . each individual layer has a thickness within the nanometer range . specifically , the thickness of each deposited polymeric layer is generally less than about 200 nanometers . in one embodiment , the thickness is less than about 100 nanometers . in one embodiment , the thickness is of each layer is within the range of about 5 nanometers to about 60 nanometers . in another embodiment , the thickness of each layer is within the range of about 15 nanometers to about 50 nanometers . fig1 ( not to scale ) illustrates the biologically active film of the present invention , in which biologically active coating 10 is deposited onto substrate 12 . biologically active coating 10 is made up of alternating layers of cationic polyelectrolyte 16 and anionic polyelectrolyte 18 . in one embodiment , the coating comprises 2 to 100 bilayers of cationic and anionic polyelectrolytes . in another embodiment , the coating comprises 4 to 50 bilayers , and in yet another embodiment , 4 to 35 bilayers . biologically active agent 14 is complexed with either the cationic or anionic layer , depending on the charge of the agent . as used herein , the term “ complexed ” means the biological agent is interconnected with , intermingled with , deposited with , dispersed within , and / or bonded to the polyelectrolyte . for example , if the biologically active agent were positively charged , such as silver ions , ag + , the agent would be complexed with the cationic polyelectrolyte . the silver ions can be deposited simultaneously with the cationic polyelectrolyte . the cationic and anionic layers are deposited onto the substrate from dilute solutions , typically aqueous , of polyelectrolytes . polyelectrolytes , in general , are polymers with groups that are capable of ionic dissociation and may be a constituent or substituent of the polymer chain . the number of these groups capable of ionic dissociation in polyelectrolytes is normally so large that the polymers are water - soluble in the dissociated form ( also called polyions ). the term polyelectrolyte also means ionomers with which the concentrations of ionic groups are insufficient for water solubility , but which have significant charges to enter into self - assembly . in one embodiment , the concentration of the polyelectrolyte in solution is about 0 . 05 % to about 1 % by weight . depending on the nature of the groups capable of dissociation , polyelectrolytes are divided into polyacids and polybases . on dissociation of polyacids , there is formation of polyanions , with elimination of protons , that can be both inorganic and organic polymers . polybases contain groups capable to take up protons , for example , by reaction with acids to form salts . useful polycations include polydiallyldimethyl ammonium chloride ( pdda ), polyallylamine hydrochloride , and copolymers containing quaternary ammonium acrylic monomers . examples of quaternary ammonium acrylic monomers include methacryloxyethyltrimethyl ammonium chloride , acryloxyethyl dimethylbenzyl ammonium chloride , methacryloxyethyl dimethylbenzyl ammonium chloride and acryloxyethyltrimethyl ammonium chloride . polymers capable of hydrogen bonding , or hydrogen donors include polyethyleneimine ( pei ), polyvinylimidazole , polylysine , poly - n - methyl - n - vinylacetamide , polyvinyl - pyrrolidone , polyvinyl alcohol , polyacrylamide and copolymers of aminoacrylates . the polymers can also become cationic at low ph due to protonation . copolymers of acrylamide and acryloxytrimethylammonium chloride are particularly useful . substituted acrylamides and methacrylamides may be included into the copolymer in relatively small amounts . in large amounts , substituted acrylamides and methacrylamides adversely affect the solubility of the polycation . in one embodiment , the cationic copolymer comprises a copolymer of acrylamide monomer and acryloxyethyltrimethyl ammonium chloride . in another embodiment , the cationic copolymer comprises a cationic acrylamide commercially available from cytec under the trade name superfloc c - 491 . in yet another embodiment , the cationic copolymer comprises a cation - modified polyvinyl alcohol commercially available from kuraray under the designation cm - 318 . the anionic layer is deposited onto the substrate from a dilute solution , typically aqueous , of polyanions . polyanions are formed from the dissociation of polyacids . examples of polyacids include polyphosphoric acid , polyvinylsulfuric acid , polyvinylsulfonic acid , polyvinylphosphonic acid , polyvinylphenylsulphuric acid , polyamino acid , polyglutamic acid , polymethacrylic acid , polyethylene sulphonic acid , poly ( 2 - acrylamide - 2 - methyl - 1 - propanesulfonic acid ) and poly ( acrylic acid ) ( paa ). examples of the corresponding salts include polyphosphate , polysulfate , polysulfonate , polyphosphonate , polyacrylate , polystyrene - sulfonic acid sodium salt , polyvinyl - sulfonic acid potassium salt , poly ( sodium 4 - styrenesulfonate ) ( pss ), and a polyamic acid salt ( paatea ). polyelectrolytes suitable for use in the present invention include biopolymers such as , for example , alginic acid , gum arabic , nucleic acids , pectins , proteins and others , and chemically modified biopolymers such as , for example , ionic or ionizable polysaccharides , for example carboxymethylcellulose , chitosan and chitosan sulfate , and ligninsulfonates . it is possible to crosslink polyelectrolyte molecules within and / or between the individual layers , for example , by crosslinking amino groups with aldehydes . a further possibility is to use amphiphilic polyelectrolytes , for example amphiphilic block or random copolymers with partial polyelectrolyte characteristics . such amphiphilic copolymers consist of units differing in functionality , for example acidic or basic units on the one hand , and hydrophobic units on the other hand , such as styrenes , dienes or siloxanes etc ., which can be arranged as blocks or randomly distributed over the polymer . it is possible by using copolymers that change their structure as a function of the external conditions to control the permeability or other properties of the coating in a defined manner . the release of the biologically active agent ( s ) can be controlled via the dissolution of the coating layers by using polyelectrolytes that are degradable under particular conditions , for example photo -, acid -, base - or salt - labile polyelectrolytes . the biologically active agent of the present invention may be an antibacterial agent , an antifungal agent , an analgesic agent , a tissue healant agent , a local anesthetic agent , an antibleeding agent , an enzyme or a vasoconstrictor , or any other biologically active agent . one or more biologically active agent may be combined in the coating of the present invention . where the biologically active agent is deposited onto the substrate in the negatively charged layer , the agent is an anionic agent . examples of such anionic agents include those selected from antibacterials including fusidic acid , pseudomonic acid , ceftriaxone ( rocephin ); antifungals including nafcillin , nystatin , and undecylenic acid ; analgesics including salicylic acid , salicylsulfonic acid and nicotinic acid ; and antibleeding agents including adenosine diphosphate . such biologically active agents may be used in the form of their salts . ( 1 ) fusidic acid is also known as ( z )- 16 -( acetyloxy )- 3 ; α , 11α - dihydroxy - 29 - nor - 8α , 9 , 13α , 14 - dammara - 17 ( 20 ), 24 - dien - 21 - oic acid ; 3α , 11α , 16γ - trihydroxy - 29 - nor - 8α , 9 , 13α , 14 - dammara - 17 ( 20 ), 24 - dien - 21 - oic acid 16 - acetate ; 3α , 11α , 16 - trihydroxy - 4α , 8 , 14 - trimethyl - 18 - nor - 5α , 8α , 9 , 13α , 14γ - cholesta -( 20 ), 24 - dien - 21 - oic acid 16 - acetate ; 3α , 11 , 16 - trihydroxy - 4 , 8 , 10 , 14 - tetramethyl - 17 -( 1 ′- carboxyisohept - 4 ′- enylidene ) cyclo - pentanoperhydrophenanthrene 16 - acetate ; and ramycin . its sodium salt , sodium fusidate , is also known as zn 6 , fucidine , fucidina , fucidine and fucidin intertulle . ( 2 ) pseudomonic acids . a group of antibacterial antibiotics produced by pseudomonas fluorescens ncib 10586 that have unusual structural features . four members of the group are known : pseudomonic acid a , the major component , pseudomonic acid b , the 3 , 4 , 5 - trihydroxy analog of a ( also referred to as pseudomonic acid 1 ), pseudomonic acid d , the 4 - nonenoic acid analog of a ; and pseudomonic acid c , in which the epoxide oxygen is replaced by a double bond . pseudomonic acid a . mupirocin . [ 2s - 2α ( e ), 3β , 4β , 5α [ 2r *, 3r *-(( 1r *,- 2r *)]]]- 9 -[[ 3 - methyl - 1 - oxo - 4 -[ tetrahydro - 3 , 4 - dihydroxy - 5 -[[ 3 -( 2 - hydroxy - 1 - methylpropyl ) oxiranyl ] methyl ]- 2h - pyran - 2 - yl ]- 2 - butenyl ] oxy ] nonanoic acid ; pseudomonic acid a ; trans - pseudomonic acid ; brl - 4910a ; bactoderm ; bactroban ; eismycin . c 26 h 44 o 9 ; mol wt 500 . 63 . c 62 . 38 %, h 8 . 86 %, o 28 . 76 %. major component of the pseudomonic acids , q . v ., an antibiotic complex produced by pseudomonas fluorescens ncib 10586 . pseudomonic acid c , c 26 h 44 o 8 , [ 2s -[ 2α ( e ), 3 β , 4β , 5α ( 2e , 4s *, 5r *)]]- 9 [[ 3 - methyl - 1 - oxo - 4 - tetrahydro - 3 , 4 - dihydroxy - 5 -( 5 - hydroxy - 4 - methyl - 2 - hexenyl )- 2h - pyran - 2 - yl ]- 2 - butenyloxy ) nonanoic acid . pseudomonic acid d , c 26 h 42 o 9 , [ 2s -[ 2α [ e ( e )], 3β , 4β , 5α -[ 2r *, 3r *( 1 r *, 2r *)]]- 9 -[[ 3 - methyl - 1 - oxo - 4 - tetrahydro - 3 , 4 - dihydroxy - 5 -[[ 3 -( 2 - hydroxy - 1 - methylpropyl ) oxiranyl ]- methyl ]- 2h - pyran - 2 - yl )- 2 - butenyl ] oxy )- 4 - nonenoic acid . ( 3 ) nafcillin is also known as 6 -( 2 - ethoxy - 1 - naphthamido )- 3 , 3 - dimethyl - 7 - oxo - 4 - thia - 1 - azabicyclo [ 3 . 2 . 0 ] he ptane - 2 - carboxylic acid ; 6 -( 2 - ethoxy - 1 - naphthamido ) penicillanate ; and 6 -( 2 - ethoxy - 1 - naphthamido ) penicillin . the sodium salt is also known as naftopen and unipen . ( 4 ) nystatin is also known as fungicidin ; diastatin ; candiohermal ; mycostatin ; moronal ; nystan ; nystavescent ; and o - v statin . ( 5 ) undecylenic acid , also known as 10 - undecenoic acid ; 10 - hendecenoic acid ; 9 - undecylenic acid ; declid ; renselin ; and sevinon . ( 7 ) salicylsulfuric acid is also known as 2 -( sulfooxy ) benzoic acid ; salicylic acid , acid sulfate ; and salicylic acid sulfuric acid ester . ( 8 ) nicotinic acid is also known as 3 - pyridinecarboxylic acid ; pyridine - γ - carboxylic acid ; p . p . factor ; pellagra preventive factor ; antipellagra vitamin ; niacin ; nicacid ; nicagin ; niconacid ; nicotinipca ; nicyl ; akotin ; daskil ; tinic ; nicolar ; and wampocap . ( 9 ) adenosine diphosphate is also known as adenosine 5 ′-( trihydrogen diphosphate ); adp ; adenosine 5 ′- pyrophosphoric acid ; 5 ′- adenylphosphoric acid ; and adenosinediphosphoric acid . where the biologically active agent is deposited in the positively charged layer , the agent is a cationic agent . examples of such cationic agents include those selected from anti - bacterials including chlorhexidine , bacitracin , chlortetracycline , gentamycin , kanamycin , neomycin b , polymyxin b , streptomycin , and tetracycline ; antifungals including amphotericin b , clotrimazole , and miconazole ; tissue healants including cysteine , glycine and threonine ; local anesthetics , e . g ., lidocaine ; enzymes including trypsin , streptokinase , plasmin ( fibrinolysin ) and streptodornase ; deoxyribonuclease ; and cationic vasoconstrictors including epinephrine and serotonin . such biologically active agents may be used in the form of their salts . ( 1 ) chlorhexidine , also known as n , n ″- bis ( 4 - chlorophenyl )- 3 , 12 - diimino - 2 , 4 , 11 , 13 - tetraazatetradecanediimidamide ; 1 , 1 ′- hexamethylenlenebis [ 5 -( p - chlorophenyl ) biguanide ]; 1 , 6 - bis [ n ′-( p - chlorophenyl )- n 5 - biguanido ] hexane ; 1 , 6 - bis ( n 5 - p - chlorophenyl - n ′- diguanido ) hexane ; 1 , 6 - di ( 4 ′- chlorophenyldiguanido ) hexane ; 10 , 040 ; hibitane ; nolvasan ; rotersept ; and sterilon . its gluconate is known as hibiscrob . ( 3 ) chlortetracycline , also known as 7 - chloro - 4 - dimethylamino - 1 , 4 , 4a , 5 , 5a , 6 , 11 , 12a - octahydro - 3 , 6 , 10 , 12 , 12a - pentahydroxy - 6 - methyl - 1 , 11 ,- dioxo - 2 - naphthacene carboxamide ; 7 - chlorotetracycline ; acronize ; aureocina ; aureomycin ; biomitsin ; biomycin ; and chrysomykine . ( 4 ) gentamycin includes gentamicin c 18 , which is also known as 0 - 3 - deoxy - 4 - c - methyl - 3 -( methylamino )- γ - l - arabinopyranosyl ( 1 → 6 )- 0 [ 2 , 6 - dramino - 2 , 3 , 4 , 6 - tetradeoxy - α - d - erythro - hexo pyranosy 1 -( 1 → 4 )]- 2 - deoxy - d - streptamine and as gentamicin d . the c complex sulfate is also known as cidomycin , garamycin , garasol , gentalyn , genticin , gentocin , refobacin , and sulmycin . ( 5 ) kanamycin includes : kanamycin a sulfate , also known as cantrex , cristalomicina , kamycin , kamynex , kanacedin , kanamytrex , kanasig , kanicin , kannasyn , kantrex , kantrox , otokalixin , resistomycin ( bayer ), opthalmokalixan , kantrexil , kano , kanescin , and kanaqua ; kanamycin b , is also known as nk 1006 , bekanamycin , and aminodeoxykanamycin ; and kanamycin b sulfate , also known as kanendomycin , and kanamycin . ( 6 ) neomycin is also known as mycifradin ; myacyne ; fradiomycin ; neomin ; neolate ; neomas ; nivemycin ; and vonamycin powder v . it also includes neamine , which includes : neomycin a , and neomycin b , which is also known as framycetin , enterfram , framygen , soframycin , actilin , and antibiotique e . f . 185 . neomycin b sulfate is also known as fraquinol , myacine , neosulf , neomix , neobrettin , and tuttomycin . ( 7 ) polymyxin includes : polymyxin b , which is a mixture of polymyxins b . and b 2 ; polymyxin b sulfate , which is also known as aerosporin ; polymyxin b 1 ; polymyxin b 1 hydrochloride ; polymyxin b 2 ; polymyxin d 1 ; polymyxin d 2 ; and polymyxin e , which is also known as colistin ; colimycin ; coly - mycin ; totazina ; and colisticina . ( 8 ) streptomycin is also known as 0 - 2 - deoxy - 2 -( methylamino )- α - l - glucopyranoxy ]-( 1 → 2 )- o - 5 - deoxy - 3 - c - formyl - α - l - lyxofurano - syl ( 1 → 4 )- n , n ′- bis ( aminoiminomethyl )- d - streptamine ; and streptomycin a . its sesquisulfate is also known as streptomycin sulfate , agristrep , streptobrettin , streptorex , and vetstrep . streptomycin b is also known as mannosidostreptomycin ; and mannosylstreptomycin . ( 9 ) tetracycline is also known as 4 -( dimethylamino )- 1 , 4 - 4a , 5 , 5a , 6 ,- 11 , 12a - octahydro - 3 , 6 , 10 , 12 , 12a - pentahydroxy - 6 - methyl - 1 ,- 11 - dioxo - 2 - naphthacene carboxamide ; deschlorobiomycin ; tsiklomitsin ; abricycline ; achromycin ; agromicina ; ambramicina ; ambramycin ; bio - tetra ; bristaciclina ; cefracycline suspension ; criseo - ciclina ; cyclomycin ; democracin ; hostacyclin ; omegamycin ; panmycin ; polycycline ; purocyclina ; sanclomycine ; steclin ; tetrabon ; tetracyn ; tetradecin . its hydrochloride is also known as achro , achromycin v , ala tet , ambracyn , artomycin , cefracycline tablets , cyclopar , diacycline , dumocyclin , fermentmycin , mephacyclin , partrex , quadracycline , quatrex , ricycline , rocyc - line , stilciclina , subamycin , sustamycin , teline , telotrex , tetra - bid , tetrachel , tetracompren , tetra - d , tetrakap , tetralution , tetramavan , tetramycin , tetrosol , totomycin , triphacyclin , unicin , and unimycin . its phosphate complex is also known as panmycin phosphate , sumycin , tetradecin novum , tetrex , and upcyclin . its lauryl sulfate is known as lauracycline . ( 10 ) amphotericin b is also known as fungizone ; fungilin ; and ampho - moronal . ( 11 ) clotrimazole is also known as 1 -( 2 - chlorophenyl ) diphenyl - methyl ]- 1h - imidazole ; 1 -( o - chloro - α , α - diphenylbenzyl ) imidazole ; 1 -[ α -( 2 - chlorophenyl ) benzldryl ) imidazole ; 1 -[( o - chlorophenyl ( diphenylmethylimidazole ; dipheny -( 2 - chlorophenyl )- 1 - imidazolylmethane ; 1 -( o - chlorotrityl ) imidazole ; fb 5097 ; bay b 5097 ; and canesten ; lotrimin ; mycosporin . ( 12 ) miconazole is also known as 1 -[ 2 -( 2 , 4 - dichlorophenyl )- 2 -[( 2 , 4 - dichlorophenyl ) methoxyethyl ]- 1h - imidazole ; and 1 -[ 2 , 4 - dichloro - γ -[( 2 , 4 - dichlorobenzyl - oxy ] phenethyl ] imidazole . its nitrate is also known as r - 14889 , albistat , brentan , conofite , daktarin , dermonistat , epi - monistat , gyno - daktarin , gyno - monistat , micatin , and monistat . ( 13 ) cysteine , cys ( iupac abbrev .) is also known as ol - cysteine ; γ - mercaptoalanine ; 2 - amino - 3 - mercaptopropanoic acid ; 2 - amino - 3 - mercaptopropionic acid ; and α - amino - - thiolpropionic acid . ( 14 ) glycine , gly ( iupaac abbrev . ), is also known as aminoacetic acid ; aminoethanoic acid ; glycocoll ; and glycosthene . ( 15 ) threonine , thr ( iupac abbrev . ), is also known as 2 - amino - 3 - hydroxybutyric acid ; α - amino - γ - hydroxybutyric acid ; and 2 - amino - 3 - hydroxybutanoic acid . ( 16 ) lidocaine is also known as 2 -( diethylamino )- n -( 2 , 6 - dimethylphenyl ) acetamide ; 2 - diethylamino - 2 ′, 6 ′- acetoxylidide ; α - diethylamino - 2 , 6 - dimethylacetanilide ; lignocaine ; xylocalne ; xylotox ; leostesin ; rucaina ; isicaine ; duncaine ; xylestesin ; anestacon ; gravocain ; lidothesin ; and xylocitin . ( 17 ) fibronolysin is also known as plasmin ; serum tryptase ; actase ; and thrombolysin . ( 18 ) epinephrine is also known as 4 -[ 1 - hydroxy - 2 -( methylamino )- ethyl ]- 1 , 2 - benzenediol ; 3 , 4 - dihydroxy - α -[( methylamino ) methyl ]- benzyl alcohol ; 1 -( 3 , 4 - dihydroxyphenyl )- 2 -( methylamino ) ethanol ; 3 , 4 - dihydroxy - 1 -[ 1 - hydroxy - 2 -( methylamino )- ethylbenzene ; methyl - aminoethanolcatechol ; and adrenalin . ( 19 ) serotonin is also known as 3 -( 2 - aminoethyl )- 1h - indol - 5 - ol ; 5 - hydroxytryptamine ; 3 -( γ - aminoethyl )- 5 - hydroxyindole ; 5 - hydroxy - 3 -( γ - aminoethyl ) indole ; enteramine ; thrombocytin ; thrombotonin ; and 5 - ht . ( 20 ) metal salts , or like compounds with antibacterial metal ions , e . g ., copper , silver , gold , platinum , zinc , tin , antimony and bismuth , and optionally with nonmetallic ions of antibacterial properties . ( 21 ) quaternary ammonium compounds , e . g ., cetrimide , domiphen bromide , and polymeric quaternaries . a particularly useful antimicrobial agent is ag + . the silver ion is derived from a suitable silver salt , including silver bromide , silver fluoride , silver chloride , silver nitrate , silver sulfate , silver alkylcarboxylate , silver sulphadiazine or silver arylsulfonate . other biologically active agents include those disclosed in “ biochemistry of antimicrobial action ” by t . j . franklin and g . a . snow , 4 th edition , chapman and hall , 1981 , incorporated herein by reference . the biologically active coating may contain two or more active agents . in one embodiment , for example , the coating contains silver ions and cetrimide . both the silver ions and the cetrimide can be deposited simultaneously in the cationic layers . alternatively , silver ions can be deposited in one or more of the cationic layers , and cetrimide can be separately deposited in one or more other cationic layers of the biologically active coating . in one embodiment , the multilayer coating is substantially transparent . the multilayer coating can be deposited onto a substantially transparent substrate , for example , a thin film dressing . the underlying wound can then be monitored without removing the dressing . in one embodiment of the invention , the biologically active coating contains inactive barrier layers within the coating structure . for example , the coating can comprise blocks of biologically active bilayers and blocks of inactive bilayers . fig2 illustrates a biologically active film on a substrate in which the film includes biologically active bilayer blocks 10 a and 10 b and inactive bilayer blocks 20 a and 20 b . the blocks of biologically active bilayers are made up of alternating positively charged and negatively charged layers having a biologically active agent or agents in at least one of the positively charged and negatively charged layers . the blocks of inactive bilayers are made up of alternating positively charged and negatively charged layers having no biologically active agents in either the positively charged or negatively charged layers . the inactive bilayers can facilitate sustained release of the biologically active agent ( s ) by impeding the rapid diffusion of the active agent through the coating . the inactive bilayers may comprise the cationic polyelectrolytes and anionic polyelectrolytes described above . alternatively , the positively charged layer may comprise cationic polyelectrolytes and the negatively charged layer may comprise an inorganic material . examples of inorganic materials include negatively charged platelets having a thickness of less than about 10 nanometers . useful inorganic material includes platelet clays that are easily exfoliated in aqueous or polar solvent environments . the clays may be naturally occurring or synthetic . platelet clays are layered crystalline aluminosilicates . each layer is approximately 1 nanometer thick and is made up of an octahedral sheet of alumina fused to 2 tetrahedral sheets of silica . these layers are essentially polygonal two - dimensional structures , having a thickness of 1 nanometer and an average diameter ranging from 30 to 2000 nanometers . isomorphic substitutions in the sheets lead to a net negative charge , necessitating the presence of cationic counter ions ( na +, li +, ca ++, mg ++, etc .) in the inter - sheet region . the sheets are stacked in a face - to - face configuration with inter - layer cations mediating the spacing . the high affinity for hydration of these ions allows for the solvation of the sheet in an aqueous environment . at sufficiently low concentrations of platelets , for example less than 1 % by weight , the platelets are individually suspended or dispersed in solution . this is referred to as “ exfoliation ”. useful clays are those belonging to the smectite family of clay , including montmorillonite , saponite , beidellite , nontronite , hectorite , laponite fluorohectorite and mixtures of these . a particularly useful clay is montmorillonite . this clay is usually present in a sodium ion exchange form . montmorillonite clay is commercially available from southern clay products , inc . under the trade name cloisite . in one embodiment , the clay comprises sodium montmorillonite . other useful inorganic materials in platelet form include layered titanates , including those within the chemical formula ti 1 − δ o 2 4δ − ; layered perovskites , including hca 2 nb 3 o 10 , hsrnb 3 o 10 , hlanb 2 o 7 and hcalanb 2 tio 10 ; and mica . the substrate onto which the antimicrobial coating is deposited may be any substrate that the cationic material can be adsorbed directly , or indirectly with the aid of an adhesion promoter or tie layer . the substrate may be a polymeric material , metal , glass , fabric , a ceramic material , a crystalline material , or a multilayer substrate of one or more of these materials . in one embodiment , the substrate is optically transparent . the substrate may be rigid , or may be flexible . when the coating is to be used in a wound dressing , the substrate must be sufficiently conformable to conform to the contours of skin to which it will be applied . the film may be porous , non - porous , woven or nonwoven or a foam film . the substrate may be chosen from , for example , non - woven meshes ; woven meshes of fiberglass or acetate ; gauze ; polyurethane foams ; polymeric films including polyolefins ( linear and branched ), halogenated polyolefins , polyamides , polystyrenes , nylon , polyesters , polyester copolymers , polyurethanes polysulfones , styrene - maleic anhydride copolymers , styrene - acrylonitrile copolymers , ionomers based on sodium or zinc salts of ethylene methacrylic acid , polymethyl methacrylates , cellulosics , acrylic polymers and copolymers , polycarbonates , polyacrylonitriles , and ethylene - vinyl acetate copolymers ; composite wound dressings , and adhesive - coated , thin - film dressings . the substrate may be an untreated film that is amenable to adsorption . alternatively , the film may be treated by first exposing the film to an electron discharge treatment at the surface , e . g ., corona treatment . other surface treatments to enhance the adsorption of the cationic organic material are well known . for example , the surface of the substrate may be plasma treated , chemically treated or solvent washed . additionally , polymeric films that have been pretreated to promote adhesion are commercially available . examples of such pretreated films include the pet films available from dupont teijin films under the designation st504 ( one side treated ) and st505 ( both sides treated ). in one embodiment , the surface of the substrate is roughened to improve adhesion and to increase the surface area of the substrate surface . with increased surface area , such as with roughened surfaces and foamed substrates , the activity of the antimicrobial agent is increased . the substrate can be a single - layered film or it can be a multi - layered construction . the multi - layered construction can be , for example , coextruded films and laminated films . the multi - layered constructions have two or more layers , and in one embodiment , two to about seven layers , and in one embodiment , about three to about five layers . the layers of such multi - layered constructions and polymer films can have the same composition and / or size or they can be different . the substrate can have any thickness that is suitable for the intended use of the antimicrobial article . in one embodiment the thickness of the substrate may be in the range of about 0 . 3 to about 20 mils , and in another embodiment , about 0 . 3 to about 10 mils , and in yet another embodiment about 0 . 5 to about 7 mils , and in a further embodiment about 1 to about 5 mils . the substrate can also be a foam sheet having a thickness of up to 2 inches , or 1 . 5 inches , or 1 . 25 inches or 1 inch . in one embodiment of the present invention , the substrate onto which biologically active coating is deposited is a thin film dressing . examples of thin film dressings are those described in u . s . pat . nos . 6 , 346 , 653 ; 6 , 066 , 773 ; 6 , 043 , 406 ; 5 , 762 , 620 ; 5 , 520 , 629 ; 5 , 501 , 661 ; 5 , 489 , 262 and 5 , 437 , 622 , all of which are incorporated by reference herein . generally , thin film wound dressings comprise a multilayer configuration having an upper cover sheet , an adhesive layer and a bottom carrier or liner . the liner is removed for application of the dressing to the patient . the thin film dressing is flexible in order to conform to the contour of the patient . the thin film dressing may be transparent for improved monitoring of the wound site . an absorbent material may be positioned on the adhesive layer . the absorbent material can be an absorbent pad placed in the middle of the dressing so that the pad is surrounded by adhesive for sufficient adhesion to the patient . alternatively , the absorbent material is a hydrogel that is positioned on the adhesive layer or positioned directly on the upper cover sheet . absorbent hydrogels and hydrogel adhesives are known in the art . the absorbent material itself may contain medication , for example , an antibiotic , a healing promoting agent , an anti - inflammatory agent , a transdermal diffusable pharmaceutical , a coagulant or an anti - coagulant . in one embodiment of the present invention , a hydrogel layer is applied to the biologically active film . this configuration is particularly useful as a wound dressing . fig4 shows biologically active film 10 applied to substrate 12 . hydrogel layer 24 is applied over the biologically active film 10 , so that the hydrogel is in direct contact with the patient &# 39 ; s skin . substrate 12 can be any flexible film . in one embodiment , substrate 12 is the cover sheet of the thin film dressing . in another embodiment , illustrated in fig5 , an adhesive layer 26 is pattern - coated over the biologically active film 10 that is deposited onto substrate 12 . useful adhesives are any known medical grade adhesives . the medical adhesives include suitable acrylic based pressure sensitive adhesives ( psas ), suitable rubber based pressure sensitive adhesives and suitable silicone pressure sensitive adhesives . in one embodiment , illustrated in fig6 , a wound dressing 60 comprises an antimicrobial coating 61 on a polymeric foam substrate 62 . the substrate 62 may comprise a polyurethane foam . the coating 61 comprises about 4 to about 32 bilayers of pei with ag + layers alternating with paa layers . the concentration of ag + in each cationic layer is about 1 mm to about 100 mm , or about 2 mm to about 20 mm . the overall thickness of the antimicrobial coating 61 is less than 1 micron . the ag + coating of the dressing is effective against the activity of s . aureus , e . coli , mrsa , vre , p . aeruginosa , c . albicans , e . faecalis , s . pyogenes , c . perfringens , klebsiella pneumoniae and e . faecium . in one embodiment similar to that described with reference to fig6 , a wound dressing comprises a coating of alternating layers of pei with cetrimide as the cationic layers and paa as the anionic layers on a foam substrate . the number of bilayers is about 4 to about 32 . the concentration of the cetrimide in the cationic layer is about 1 mm to about 100 mm , or about 2 mm to about 20 mm . in one embodiment , the coating on the wound dressing comprises alternating bilayers of ( a ) pei / ag + and paa layers and ( b ) pei / cetrimide and paa layers . the total number of bilayers is about 4 to about 32 . in another embodiment , illustrated in fig7 , a wound dressing 70 comprises a first antimicrobial coating 71 on foam substrate 73 and a second antimicrobial coating 72 overlying the first coating 71 . the first coating 71 comprises about 8 bilayers of pei with ag + layers alternating with paa layers . the concentration of ag + in the cationic layers is the same as that of the ag + layer of the coating 61 described above . the second coating 72 comprises about 8 bilayers of cetrimide layers alternating with paa layers . in one embodiment , illustrated in fig8 , a controlled release wound dressing 80 comprises a first antimicrobial coating 81 of alternating layers of pei / ag + and paa on substrate 84 , an intermediate coating 82 of alternating layers of pei and paa overlying coating 81 , and a second antimicrobial coating 83 of alternating layers of cetrimide and paa overlying coating 82 . the total number of bilayers is about 4 to about 35 . in one embodiment , the number of bilayers in coating 81 is about 8 . the number of bilayers in coating 82 is about 4 and the number of bilayers of coating 83 is about 4 . in one embodiment , illustrated in fig9 , a controlled release wound dressing 90 comprises a first antimicrobial coating 91 of alternating layers of pei / cetrimide and paa on substrate 95 , an antibiotic layer 92 of alternating layers of pei and paa / antibiotic component overlying coating 91 , an intermediate layer 93 of alternating layers of pei and paa overlying coating 92 , and a second antimicrobial layer 94 of alternating layers of pei / ag + and paa overlying coating 93 . in another embodiment , a biocompatible coating is formed on a substrate . the biocompatible coating comprises alternating layers of chitosan and pss on a substrate . the concentration of chitosan in the cationic layer and pss in the anionic layer is about 0 . 1 % to about 0 . 3 % by weight . the number of bilayers is about 2 to about 20 , or about 2 to about 8 . in one embodiment , illustrated in fig1 , a multifunctional , multi - layer dressing 100 comprises a biocompatible component and a controlled release antimicrobial component on a substrate 104 . an antimicrobial coating 101 comprising alternating layers of pei / ag + and paa are formed on substrate 104 . an intermediate coating 102 comprising alternating layers of pei and paa overlies coating 101 . a biocompatibility layer 103 comprising alternating layers of chitosan and pss overlies coating 102 . the total number of bilayers is about 3 to about 35 . in one embodiment , coating 101 comprises about 8 bilayers , coating 102 comprises about 4 bilayers and coating 103 comprises about 4 bilayers . additional bilayers of pei / ag + and paa may be coated onto the biocompatibility layer 103 . in one embodiment , illustrated in fig1 , a hydrogel dressing 110 comprises an antibacterial component 111 and a hydrogel contact component 112 . the antibacterial component 111 comprises a substrate coated with alternating layers of pei / ag + and paa . the hydrogel contact component 112 comprises a hydrogel such as those known in the art as being particularly useful in wound dressings . in another embodiment , illustrated in fig1 , a hydrocolloid dressing 120 comprises an antibacterial component 121 and a hydrocolloid contact component 122 . the antibacterial component 121 comprises a substrate coated with alternating layers of pei / ag + and paa . the hydrocolloid contact component 122 comprises a hydrocolloid such as those known in the art as being particularly useful in wound dressings . the process for making the biologically active coating of the present invention comprises the steps of ( 1 ) dipping the substrate into an aqueous cationic polyelectrolyte solution , ( 2 ) rinsing the substrate with water , ( 3 ) drying the layer of cationic polymer ( 4 ) dipping the substrate into an aqueous anionic polyelectrolyte solution , ( 5 ) rinsing the substrate with water , ( 6 ) drying the deposited anionic polymer , ( 7 ) repeating the steps 1 - 6 to produce a multilayer biologically active film on the substrate . in one embodiment , a polar solvent other than water is used to deposit the organic material and to rinse the deposited layer . prior to dipping the substrate into the aqueous cationic polyelectrolyte solution , the substrate may be rinsed with methanol and then washed with water . optionally , the substrate may be surface treated to improve the adhesion of the cationic polymer layer . in one embodiment , the aqueous cationic polyelectrolyte solution comprises a solution of about 0 . 05 % to about 1 . 5 % by weight of cationic polymer . in one embodiment , the cationic polyelectrolyte solution comprises a solution of about 1 . 0 % by weight of cationic polymer . the thickness of each organic polymer layer is generally less than about 200 nanometers . in one embodiment , the thickness is less than about 100 nanometers . in one embodiment , the thickness is of each organic layer is within the range of about 5 nanometers to about 60 nanometers . in another embodiment , the thickness of each organic layer is within the range of about 15 nanometers to about 50 nanometers . the immersion time of the substrate in each of the coating solutions may be varied according to the particular coating solution , substrate composition , coating composition , or desired coating properties . the substrate may be held stationary in the coating solution , or the substrate may be moved within the coating solution bath , or may be continuously moved through the coating solution bath , for example , as a moving web of substrate material . the antimicrobial activity of the films of the present invention is evaluated using the kirby - bauer ( zone of inhibition ) and dow shake flask ( log reduction ) test methods . the kirby - bauer test is conducted by placing the test article in contact with agar containing 10 5 colony forming units per ml . the dow shake flask test is conducted by subjecting the test article to a flack containing test broth that is inoculated with 10 5 colony forming units per ml . the number of viable microbes following 24 hours of contact with continuous agitation are quantified . this process is repeated every 24 hours using fresh organism until the targeted number of hours have been exhausted . an antimicrobial film is produced on a 7 mil corona - treated pet substrate by depositing multiple pei - ag + / paa bilayers . the pet substrate is first immersed in pei - ag + solution ( 1 mg / ml pei ; 20 millimolar ( mm ) agno 3 ) for 5 min . and then rinsed in water . the substrate is then immersed in a 3 mg / ml paa solution for 5 min . and rinsed again in water . multilayers are obtained by repetitive deposition of pei - ag + and paa . for deposition of bilayers subsequent to the first bilayers , the immersion time is about 1 minute . antimicrobial films made up of 2 - 50 bilayers are produced . the antimicrobial activity of the films is evaluated using the kirby - bauer test , which places the film in contact with agar containing 10 5 colony forming units per ml . the zone of inhibition of the films is about 1 mm to about 3 mm s . aureus after 24 hours . an antimicrobial film is produced on a 7 mil pet substrate by depositing multiple pei - ag + / paa bilayers alternating with multiple “ inactive ” barrier pdda / clay bilayers . the pet substrate is first immersed in pei - ag + solution ( 1 mg / ml pei ; 20 mm agno 3 ) for 5 min . and then rinsed in water . the substrate is then immersed in a 3 mg / ml paa solution for 5 min . and rinsed again in water . six active bilayers are obtained by repetitive deposition of pei - ag + and paa . the coated substrate is then immersed in a cationic solution of pdda ( 3 mg / ml ), rinsed and immersed in an anionic solution of sodium montmortillonite ( 3 mg / ml ), and rinsed again in water . six inactive bilayers are obtained by repetitive deposition of pdda / clay . the antimicrobial film consists of 7 alternating blocks of 6 active and inactive bilayers ( total of 42 bilayers ). an antimicrobial film is produced on a 7 mil pet substrate by depositing multiple pei - cetrimide / paa bilayers . the pet substrate is first immersed in pei - cetrimide solution ( 1 mg / ml pei ; 20 mm cetrimide ) for 5 min . and then rinsed in water . the substrate is then immersed in a 3 mg / ml pm solution for 5 min . and rinsed again in water . multilayers are obtained by repetitive deposition of pei - cetrimide and paa . antimicrobial films made up of 16 bilayers are produced . the zone of inhibition of the antimicrobial film , evaluated using the kirby - bauer test , measures 8 mm to about 10 mm for s . aureus and 1 mm to about 4 mm for e . coli after 24 hours . an antimicrobial film is produced on a 7 mil pet substrate by depositing multiple pei - ag + / paa bilayers and multiple pei - cetrimide / paa bilayers . the pet substrate is first immersed in pei - ag + solution ( 1 mg / ml pei ; 20 mm agno 3 ) for 5 min . and then rinsed in water . the substrate is then immersed in a 3 mg / ml paa solution for 5 min . and rinsed again in water . eight bilayers are obtained by repetitive deposition of pei - ag + and paa . the coated pet substrate is then immersed in pei - cetrimide solution ( 1 mg / ml pei ; 20 mm cetrimide ) for 5 min . and rinsed in water , followed by immersion in a 3 mg / ml paa solution for 5 min . and rinsing in water . eight bilayers are obtained by repetitive deposition of pei - cetrimide and paa . antimicrobial films containing both ag + and cetrimide having a total of 16 bilayers are produced . the zone of inhibition of the antimicrobial film , evaluated using the kirby - bauer test , measures 6 mm to about 9 mm for s . aureus and 1 mm to about 3 mm for e . coli after 24 hours . an antimicrobial film is produced on a 7 mil pet substrate by depositing multiple pei - cetrimide / paa bilayers and multiple pei / cephalosporin - paa bilayers . the pet substrate is first immersed in pei - cetrimide solution ( 1 mg / ml pei ; 20 mm cetrimide ) for 5 min . and rinsed in water , followed by immersion in a 3 mg / ml paa solution for 5 min . and rinsing in water . eight bilayers are obtained by repetitive deposition of pei - cetrimide and paa . the coated substrate is then immersed in pei solution ( 1 mg / ml ), rinsed and then immersed in a cephalosporin - paa solution ( 5 mm cephalosporin ; 1 mg / ml pm ) for 5 min . and rinsed again in water . eight bilayers are obtained by repetitive deposition of pei and cephalosporin - paa . antimicrobial films containing both cetrimide and cephalosporin having a total of 16 bilayers are produced . an antimicrobial film is produced on a polyurethane foam substrate having a thickness of 0 . 625 inch ( 1 . 59 cm ) by depositing multiple pei - ag + / paa bilayers . the foam substrate is first immersed in pei - ag + solution ( 1 mg / ml pei ; 20 mm agno 3 ) for 5 min . and then rinsed in water . the foam substrate is then immersed in a 3 mg / ml paa solution for 5 min . and rinsed again in water . multilayers are obtained by repetitive deposition of pei - ag + and paa . antimicrobial films made up of 16 bilayers are produced . the 16 bilayer foam results in a 5 log reduction of microbial population within the first 2 hours of contact and is sustained for 72 hours . a controlled release antimicrobial film is produced on a polyurethane foam substrate by depositing multiple pei - cetrimide / paa bilayers onto the substrate . the foam substrate is first immersed in a pei - cetrimide solution ( 1 mg / ml pei ; 20 mm cetrimide ) for 5 minutes and then rinsed in water . the foam substrate is then immersed in a 3 mg / ml paa solution for 5 minutes and rinsed again in water . eight bilayers are obtained by repetitive deposiiton of pei - cetrimide and paa . the coated substrate is then immersed in a pei solution ( 1 mg / ml ) for 5 minutes , rinsed and then immersed in a paa solution ( 3 mg / ml ) for 5 minutes and rinsed again in water . four bilayers are obtained by repetitive deposition of pei and paa . the coated substrate is immersed in pei - ag + solution ( 1 mg / ml of pei ; 20 mm agno 3 ) for 5 minutes and rinsed in water . the substrate is then immersed in a paa solution ( 3 mg / ml pm ) for 5 minutes and rinsed again in water . eight bilayers are obtained by repetitive deposition of pei - ag + and paa . multifunctional antimicrobial films made up of 20 bilayers are produced . a controlled release antimicrobial film is produced on a polyurethane foam substrate by depositing multiple pei - ag +/ paa bilayers onto the substrate . the foam substrate is first immersed in a pei - ag + solution ( 1 mg / ml pei ; 20 mm agno 3 ) for 5 minutes and then rinsed in water . the foam substrate is then immersed in a 3 mg / ml paa solution for 5 minutes and rinsed again in water . eight bilayers are obtained by repetitive deposiiton of pei - ag + and paa . the coated substrate is then immersed in a pei solution ( 1 mg / ml ) for 5 minutes , rinsed and then immersed in a paa solution ( 3 mg / ml ) for 5 minutes and rinsed again in water . four bilayers are obtained by repetitive deposition of pei and paa . the coated substrate is immersed in pei solution ( 1 mg / ml of pei ) for 5 minutes and rinsed in water . the substrate is then immersed in a cephalosporin - paa solution ( 3 mg / ml paa ; 5 mm cephalosproin ) for 5 minutes and rinsed again in water . four bilayers are obtained by repetitive deposition of pei and cephalosporin - paa solution . the coated substrate is immersed in pei - cetrimide solution ( 1 mg / ml of pei ; 20 mm cetrimide ) for 5 minutes and rinsed in water . the substrate is then immersed in a paa solution ( 3 mg / ml pm ) for 5 minutes and rinsed again in water . eight bilayers are obtained by repetitive deposition of pei and paa . multifunctional antimicrobial films made up of 24 bilayers are produced . a controlled release antimicrobial film having a biocompatibility layer is produced by depositing multiple pei - chitosan / pss bilayers onto a polyurethane foam substrate . the foam substrate is first immersed in a pei - chitosan solution ( 1 mg / ml pei ; 20 mm chitiosan ) for 5 minutes and then rinsed in water . the foam substrate is then immersed in a 3 mg / ml pss solution for 5 minutes and rinsed again in water . four bilayers are obtained by repetitive deposition of pei - chitosan and pss layers . the coated substrate is then immersed in a pei solution ( 1 mg / ml ) for 5 minutes , rinsed and then immersed in a paa solution ( 3 mg / ml ) for 5 minutes and again in water . four bilayers are obtained by repetitive deposition of pei and paa . the coated substrate is then immersed in a paa solution ( 3 mg / ml paa ) for 5 minutes and rinsed again in water . eight bilayers are obtained by repetitive deposition of pei - ag + and paa . a 16 bilayer film having antimicrobial and biocompatible blocks are produced . a biocompatibility film is produced on a polyurethane foam substrate by depositing multiple pei - chitosan / pss bilayers onto the foam . the foam substrate is first immersed in a pei - chitosan solution ( 1 mg / ml ; 20 mm chitosan ) for 5 minutes and then rinsed in water . the foam substrate is then immersed in a 3 mh / ml pss solution for 5 minutes and rinsed again in water . four bilayers are obtained by repetitive deposition of pei - chitosan and pss . although the invention has been shown and described with respect to a certain embodiment or embodiments , it is obvious that equivalent alterations and modifications will occur to others skilled in the art upon reading and understanding of this specification . in particular regard to the various functions performed by the above described elements ( components , assemblies , compositions , etc . ), the terms used to describe such elements are intended to correspond , unless otherwise indicated , to any element that performs the specified function of the described element ( i . e ., that is functionally equivalent ), even though not structurally equivalent to the disclosed structure which performs the function in the herein illustrated exemplary embodiment or embodiments of the invention . in addition , while a particular feature of the invention may have been described above with respect to only one or more of several illustrated embodiments , such feature may be combined with one or more other features of the other embodiments , as may be desired and advantageous for any given or particular application .

a electrostatically self - assembled coating having a biologically active agent incorporated therein is provided . more particularly , a wound dressing having an antimicrobial coating within the dressing construction wherein an antimicrobial agent is released from the dressing over a period of time is produced using a layer - by - layer deposition process .

tropoelastin is the protein that is expressed and post - translationally modified from the gene encoding elastin , prior to cross - linking to form elastin . martin et al . ( 1995 ) gene , 154 , 159 - 166 , details the making of the synthetic gene and subsequent expression of synthetic human elastin ( shel ). a used herein , “ tropoelastin ” encompasses full length tropoelastin , isoforms of tropoelastin , genetically engineered tropoelastin constructs , fragments and derivatives of tropoelastin , unless otherwise specified . full length tropoelastin refers to the full protein sequence expressed from the human elastin gene . given that exon 1 encodes a signal peptide that is subsequently cleaved , this form would span from domain 2 to domain 36 ( domains 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 26a , 27 , 28 , 29 , 30 , 31 , 32 , 33 and 36 ). notably , human tropoelastin lacks domains 34 and 35 . fragments of tropoelastin include any isoforms or constructs expressed from genetically engineered nucleic acid molecules . the following are representative isoforms and fragments . fragments include tropoelastin not including one or more amino acids of a particular domain , or not including one or more domains . f / l lacking 22 and 26a ( shelδ26a ) is the most common isoform expressed by humans in vivo . it corresponds to the full length sequence above , but lacks domains 22 and 26a . f / l lacking 22 but with 26a ( shel ) is an isoform corresponding to full length tropoelastin but lacking domain 22 . shelδ26a and shel isoforms are referenced in wu et al . ( 1999 ) j . biol . chem . 274 , 21719 - 21724 . shel n - 18 is a construct spanning from domain 2 ( n - terminus ) up to and including domain 18 . shel17 - 27 is a construct spanning from domain 17 up to and including domain 27 . shel 27 - c is a construct spanning from domain 27 up to and including domain 36 ( c - terminus ). clarke et al . ( 2005 ) biochemistry . 44 ( 30 ): 10271 - 81 references these constructs . d36 domain has the following amino acid sequence : ifpgaclgkacgrkrk ( seq id no : 1 ). as used herein , reference to d36 includes portions of this sequence , and / or d36 in combination with other domain regions , and derivatives of domain 36 and its sub - fragments , covalently linked to a molecular extension containing at least one primary amine for the purpose of covalent attachment to provide a composite protoelastin material ”. the sequence of domain 36 and its importance to integrin binding is detailed in rodgers and weiss ( 2004 ) biochimie 86 , 173 - 178 . protoelastin is recombinant human tropoelastin ( and variations on this sequence ), including alternative splicing constructs , fragments , and genetically engineered constructs which may include insertions or deletions based on the human elastin sequence , either cross - linked or uncross - linked , which is engineered for use as a biomaterial by covalent binding , crosslinking , blending , laminating , or coating . thrombogenicity refers to the tendency of a material in contact with blood to produce a thrombus , or clot . all surfaces will be thrombogenic , given low enough flow rates and high enough viscosity , though some perform better than others . existing vascular materials like stainless steel , dacron and eptfe are all considered to be pro - thrombogenic . both collagen and fibronectin are also highly thrombogenic , while trials of the protoelastin described herein show it to be no more thrombogenic than saline . endothelialization refers to the attachment and proliferation of endothelial cells on the surface of the substrate material . the luminal surface of the vasculature is covered by a layer of endothelial cells , which mediate blood interactions and modulate the proliferation of other cell types like smooth muscle cells . the endothelial cell lining is easily damaged and this is known to occur during stent deployment , or bypass grafting of autologous vessels . this damage can lead to a host of negative performance consequences such as neointimal hyperplasia and clot formation . currently available commercial synthetic vascular materials have no endothelial cells when implanted and rely on host cells attaching and proliferating . the literature generally indicates that the faster a functioning endothelial cell layer can be recruited , the better the vascular material will perform . as described in u . s . pat . no . 7 , 258 , 988 , the vascular endothelium forms a “ container ” for blood . as long as this cellular layer remains intact and is functioning normally , a non - thrombogenic surface is presented to the circulating blood , allowing it to remain fluid and perform its nutritive functions unimpeded by intravascular clotting . physical disruption of the endothelial lining , even on a microscopic scale , elicits an immediate hemostatic response , involving localized activation of the coagulation cascade and the adherence and aggregation of platelets , an adaptive reaction that serves to limit blood loss at sites of injury .” mechanically stable refers to sufficient mechanical stability / strength to tolerate physiological blood flows ( measured as ultimate tensile strength at present ) and to withstand deformation and aneurysm formation . the uniqueness of the elastin - polymer constructs extends to compliance and elasticity , a characteristic lacking from commercial grafts and one attributed to their failure ( as measured by young &# 39 ; s modulus at present ). mechanical stability includes long term biological stability , such that the material is not eroded significantly over time , and the ability to withstand deformation during surgical or percutaneous delivery and implantation such as by suturing or by high - pressure balloon inflation . the materials disclosed herein include human recombinant tropoelastin in combination with other synthetic or natural biomaterials to impart the desired mechanical and biological properties . in some of the preferred embodiments , the elastin is blended with the polymer ; in other embodiments , the elastin is formed into a laminate with films or layers of polymer . in other embodiments , elastin is used as a coating for existing implantable materials . elastin is an extracellular matrix protein that is found within skin , lungs , bladder , elastic cartilage and arteries . elastin is an insoluble polymer that is assembled extracellularly and is composed of monomer tropoelastin molecules . elastin is principally synthesized during the development or growth of tissues , with tropoelastin expression occurring during mid - to late fetal or embryonic periods . tropoelastin is encoded by a single - copy gene including 36 domains , as shown in fig1 a . domain 1 is a signal peptide . domains 2 , 3 , 5 , 7 , 9 , 11 , 13 , 14 , 16 , 18 , 20 , 22 , 24 , 26 , 28 , 30 , 32 and 33 are hydrophobic domains ; domains 4 , 6 , 8 , 10 , 12 , 15 , 17 , 19 , 21 , 23 , 25 , 27 , 29 , and 31 are hydrophilic crosslinking exons ; domain 26a is a hydrophilic exon ; domain 36 is the hydrophilic c - terminus . domains 26a and 36 are not easily characterized . exons 22 , 23 , 24 , 26a , 32 and 33 are subject to alternative splicing , giving rise to multiple tropoelastin isoforms . alternative splicing of tropoelastin mrna transcripts results in various tropoelastin isoforms . representative tropoelastin splice forms and derivatives are shown in fig1 b . ( i ) is the tropoelastin including all possible domains expressed by the elastin gene ; ( ii ) is a common isoform lacking domains 22 and 26a ; ( iii ) is a common isoform lacking domain 22 , but including 26a ; ( iv ) is a construct encompassing the n - terminus ; ( v ) is a construct encompassing the center ; ( vi ) is a construct encompassing the c - terminus ; and ( vii ) is a construct encompassing domain 36 . fig1 c is a schematic of common derivatives of tropoelastin : ( i ) a frequently expressed isoform ; ( ii ) formyl methionine modification of the n - terminus ; and ( iii ) n - terminal tag such as his - tag . human tropoelastin is synthesized as an approximately 72 , 000 da protein by a variety of cells including smooth muscle cells , endothelial cells , fibroblasts and chondrocytes . secretion is followed by an orchestrated interplay of macromolecular partners that assist in delivering tropoelastin monomers to sites of elastogenesis . such interactions facilitate identification of sites for elastin assembly through associating microfibrillar proteins and encourage deposition with previously accreted tropoelastin . tropoelastin is encoded by a single gene that possesses 36 exons and gives rise to multiple isoforms . in human tropoelastin the mrna encodes a 72 , 000 da polypeptide which undergoes splicing and removal of signal peptide , leaving a mature protein with a molecular weight ranging from 60 , 000 da to 70 , 000 da ( visconti et al ., 2003 ) ( visconti et al ., ( 2003 ) matrix biol , 22 , 109 - 21 ). domains 22 , 23 , 24 , 26a , 30 , 32 and 33 undergo developmentally regulated alternative splicing ( bashir et al ., 1989 ) ( bashir et al ., ( 1989 ) j biol chem , 264 , 8887 - 91 ), resulting in these multiple isoforms ( parks and deak , 1990 ) ( parks and deak , ( 1990 ) am j respir cell mol biol , 2 , 399 - 406 ). one skilled in the art will appreciate that these isoforms behave similarly for the purposes of their use as a biomaterial . these can be modified by substituting , adding , or deleting one or more amino acids within these domains , or one or more domains . preferred tropoelastin splice variants include fragments encompassing roughly the first third of the molecule ( called n18 ), the middle third ( called 17 - 27 ) and the c - terminal third ( called 27 - c ). this also extends to individual domains and short peptides suspected to be important to cell recognition , such as domain 36 . domain 36 , the c - terminus of tropoelastin , is known to be highly conserved ( greater than 78 %) across species and contains two characteristic features which may impart some conformational preference . two cysteine residues are found in domain 36 and form a disulfide bond , while the protein terminates with the positively charged rkrk ( seq id no : 2 ) sequence . integrin binding in this region ( rodgers and weiss , 2004 ) ( rodgers and weiss , ( 2004 ) biochimie , 86 , 173 - 178 ) and evidence of interaction with glycosaminoglycans that mediate cell adhesion ( broekelmann et al ., 2005 ) ( broekelmann et al ., ( 2005 ) j biol chem . 280 ( 49 ): 40939 - 47 ) are further indications of the importance of the conserved c - terminus . elastin is an extremely durable and insoluble biopolymer and is formed through the lysine - mediated cross - linking of its soluble precursor tropoelastin . in vivo , tropoelastin is excreted into the extracellular space and is quickly cross - linked by the action of an enzyme called lysyl oxidase . complex , permanent covalent cross - links are formed . conversion to elastin occurs in vivo by the action of lysyl oxidase , which converts the epsilon amine on side chains of occasional lysines in tropoelastin to the adipic semi - aldehyde . coacervation juxtaposes modified and unmodified lysines to facilitate irreversible covalent cross - linking . tropoelastin and elastin are used interchangeably herein after crosslinking . historically , elastin and tropoelastin have been difficult to isolate . both can be harvested from a variety of animal sources including bovine , porcine and equine , preferably from elastin rich tissue such as ligament and aorta . elastin is extracted from these tissue using harsh conditions including refluxing in ethanol , autoclaving , acid and trypsin digestion and sodium hydroxide . these conditions strip away fats and other matrix proteins like collagen , but also damage the elastin . obtaining the protein monomer precursor of elastin ( tropoelastin ) in large quantities remains difficult , with the monomer cross - linked into elastin before it can be harvested . initially , isolation relied on animal hosts , usually pigs , with a copper deficient diet ( mecham and foster , ( 1979 ) biochimica et biophysica acta , 577 , 147 - 58 ), deactivating the enzymes cross - linking function and perturbing elastic fiber assembly . the time and effort involved in this procedure was certainly not reflected in the average yield of 0 . 1 % tropoelastin to aortic weight ( sandberg and wolt , ( 1982 ) methods in enzymology , 82 pt a , 657 - 65 ). the method evolved marginally to introduce an enzyme inhibitor ( rich and foster , ( 1984 ) biochem j . 217 , 581 - 4 ) and chicks ( abraham and carnes , ( 1978 ) j biol chem , 253 , 7993 - 5 ), but remained inefficient . as an alternative to tropoelastin , some researchers artificially make ‘ soluble elastin ’ by chemically treating elastin samples . both α - elastin ( cox et al ., ( 1973 ) biochim biophys acta , 317 , 209 - 13 ), an oxalic acid derivative of elastin , and κ - elastin , solubilized with potassium hydroxide have been investigated . investigations with these systems continue to the present , while it is recognized that chemically degraded elastin cannot precisely represent the in vivo monomer ( starcher et al ., ( 1973 ) biochim biophys acta , 310 , 481 - 6 ). ‘ soluble elastin ’ the soluble product of acid or base digestion of animal derived elastin is commercially available and the most commonly used variant in the literature . recombinant tropoelastin was first expressed as a fusion protein in an e . coli bacterial system some 17 years ago ( indik et al ., ( 1990 ) arch biochem biophys , 280 , 80 - 6 ). the hplc purified protein exhibited an amino acid composition and size ( 72 kda ) anticipated for the full length clone used . the high purity of the recombinant protein produced in this system was beneficial , while persistent smaller fragments and the limitation of small yields were problematic , with only 2 - 4 mg produced per liter of culture . soon after , a recombinant 60 kda mature form of tropoelastin ( martin et al ., ( 1995 ) gene , 154 , 159 - 66 ) was expressed , following significant improvements to the bacterial expression system . this system boasts significantly higher yields of protein . tropoelastin is now produced in gram quantities in a highly reproducible manner . other groups have been involved in recombinant tropoelastin production , but none can produce it in comparable high yields and high purity . this recombinant protein is recognized by cells to form elastin ( stone et al ., ( 2001 ) amer . j . respir . cell . mol . biol . 24 , 733 - 739 ), associates at 37 ° c . ( toonkool et al ., ( 2001 ) j . biol . chem . 276 , 28042 - 50 ) and can be cross - linked chemically to form an elastin - like material ( mithieux et al ., ( 2004 ) adv . in protein chemistry , 70 , 437 - 61 ). while this system can produce large quantities of high purity protein , monomer can be expressed in other recombinant systems or chemically synthesized . recombinant human elastin behaves very differently from elastin sourced from animals , the most common type discussed in the prior art . biocompatibility and elasticity are intrinsic properties of endogenous elastin as demonstrated by its crucial role in aortic function . it mediates interactions with endothelial cells and provides recoil and , in combination with collagen , strength . recombinant tropoelastin is preferably expressed in the e . coli expression system described in u . s . pat . no . 6 , 232 , 458 . u . s . pat . no . 6 , 232 , 458 is directed to a method of recombinantly producing large scale quantities of human tropoelastin in a bacterial system . the tropoelastin can be chemically modified in a variety of ways known in the art . the tropoelastin can be modified at the n - terminus , the c - terminus , and / or at one or more of the sidechains of the amino acids of tropoelastin . suitable chemical modifications include , but are not limited to , pegylation , formylation , acylation , attachment of linkers , such as peptide linkers , attachment of growth factors and / or cell attachment moieties , alkylation , and combinations thereof . exemplary chemical modifications include , but are not limited to , acylation of the n - terminus , formylation of the n - terminus , n - terminal extensions , amidation of the c - terminus , glycosylation , iodination of tyrosine , and alkylation reactions , such as methylation . protoelastin , as used herein , is a material that incorporates tropoelastin . the material is engineered to have desirable properties for a particular use . for example , the protoelastin may be engineered for human clinical vascular applications . in this embodiment , the preferred material for use as a vascular graft has an ultimate tensile strength of at least 3 mpa . typically , increased strength is obtained through the selection of the other components of the composition and chemical modification , such as cross - linking of the recombinant human tropoelastin . protoelastin , in the preferred embodiment , displays physical and structural properties similar to those of naturally occurring elastin including similar compliance and favorable cellular interactions ( mithieux and weiss , ( 2005 ) adv . protein chem . 70 , 437 - 61 ). these properties also can be manipulated by changing protein concentration , cross - linker type and polymerization conditions to engineer a material to suit a range of vascular biomaterial applications . the tropoelastin is applied to , crosslinked with , tethered to , blended with , or laminated as part of , one or more materials to form a protoelastin material . the tropoelastin can be applied to ceramic , bone , metal , or polymer substrates to provide a biocompatible elastic surface . typical metals include stainless steel and titanium . in one embodiment , the material is or includes one or more biodegradable or non - biodegradable synthetic polymers such as polylactides , polyglycolic acids , polycaprolactones , polycaprolactams , polyhexamethylene adipamide , polycarbonates , polyamides , polyanhydrides , polyamino acids , polyesters , polyacetals , polycyanoacrylates , polyvinyl alcohols , polyvinyl chlorides , polyethylenes , polyurethanes , polypropylenes , polyacrylates , polystyrenes , polyvinyl oxides , polyvinyl fluorides , poly ( vinyl imidazoles ), polyethylene oxides , polytetrafluoroethylenes , silicone polymers and copolymers and combinations thereof . in another embodiment , the material is or includes one or more natural materials such as a protein , sugar or polysaccharide , or combination thereof . representative examples include collagen , preferably type 1 and / or type 3 , fibrin , gelatin , vitronectin , fibronectin , laminin , hyaluronic acid , glycosaminoglycans , their derivatives and mixtures thereof . preferred glycosaminoglycans include chondroitin sulfate , dermatan sulfate , keratan sulfate , heparan sulfate , heparin and hyaluronan . in the preferred embodiment , the graft is formed from a synthetic non - biodegradable polymer such as polyethylene terephthalate ( dacron ®), expanded polytetrafluoroethylene ( eptfe ) and polyurethanes . examples of suitable commercially available materials include pellethane ®, chronoflex ®, estane ®, elast - eon ®, texin ®, demospan ®, corethane ®, technoflex ®, technothane ®, biorubber ® and biospam ®. as demonstrated in the examples , it is critical to tether or crosslink the tropoelastin to the substrate , thereby forming a protoelastin material . tethering is required to avoid the elastin from being removed by the shear forces associated with the passage of blood through the blood vessel and graft . as used herein , a film or coating will typically be in the range of a few microns in thickness , or less . in a preferred embodiment , the coating consists primarily of protoelastin that promotes endothelial cell growth on a surface . fig3 - 5 exemplify some of the protoelastin biomaterials . fig2 is a schematic of a tube 10 formed of protoelastin . a tube formed solely of tropoelastin , even cross - linked tropoelastin , does not have the mechanical properties necessary for use in vascular applications . in a preferred embodiment as described herein , shown in fig3 a and 3b , tube 20 is a polymeric graft 22 having a crosslinked elastin layer 24 tethered on the inside luminal surface . fig4 a and 4b are schematics of tube 30 formed of layers of tropoelastin 34 alternating with a layer of polymer 32 . fig5 a and 5b are schematics of tube 40 formed of layers of tropoelastin 44 alternating with one or more layers of polymer 42 . fig6 is a schematic of metallic substrate 50 with a graded transition 52 to an activated upper polymer layer 54 ( such as embedded acetylene , hexane or other carbon - containing chemical ) using standard technologies . this upper layer 54 is activated by piii or plasma treatment to facilitate protein attachment . protoelastin 56 is obtained by covalent attachment of protein to this upper layer by immersion in a solution of tropoelastin or tropoelastin derivatives . the material properties of the protoelastin can be modified by blending the tropoelastin with one or more other polymeric materials . the properties can be further modified through crosslinking and / or covalent coupling . in one embodiment , the material is or includes one or more biodegradable or non - biodegradable synthetic polymers such as polylactides , polyglycolic acids , polycaprolactones , polycaprolactams , polyhexamethylene adipamide , polycarbonates , polyamides , polyanhydrides , polyamino acids , polyesters , polyacetals , polycyanoacrylates , polyvinyl alcohols , polyvinyl chlorides , polyethylenes , polyurethanes , polypropylenes , polyacrylates , polystyrenes , polyvinyl oxides , polyvinyl fluorides , poly ( vinyl imidazoles ), polyethylene oxides , polytetrafluoroethylenes , silicone polymers and copolymers and combinations thereof . the protoelastin can include more than one polymer component . in another embodiment , the material is or includes one or more natural materials such as a protein , sugar or polysaccharide , or combination thereof . representative examples include collagen , preferably type 1 and / or type 3 , fibrin , gelatin , vitronectin , fibronectin , laminin , hyaluronic acid , glycosaminoglycans , their derivatives and mixtures thereof . preferred glycosaminoglycans include chondroitin sulfate , dermatan sulfate , keratan sulfate , heparan sulfate , heparin and hyaluronan . the protoelastin materials can be used for drug delivery , incorporating a therapeutic , prophylactic or diagnostic agent , or incorporate materials such as growth factors which facilitate attachment and proliferation of one or more cell types . preferred therapeutic agents which may be delivered include : growth factors : vascular endothelial growth factor , fibroblast growth factor , hepatocyte growth factor , connective tissue growth factor , placenta - derived growth factor , angiopoietin - 1 and granulocyte - macrophage colony - stimulating factor . agents modulating cellular behavior in relation to bioprosthesis : microfibrillar collagen , fibronectin , fibrin gels , synthetic arg - gly - asp ( rgd ) adhesion peptides , tenascin - c , del - 1 , ccn family ( e . g . cyr61 ) hypoxia - inducible factor - 1 , acetyl choline receptor agonists and monocyte chemoattractant proteins . gene delivery agents : viral vectors for gene delivery ( adenoviruses , retroviruses , lentiviruses , adeno - associated viruses ) and non - viral gene delivery agents / methods ( e . g . polycation polyethylene imine , functional polycations consisting of cationic polymers with cyclodextrin rings or dna within crosslinked hydrogel microparticles , etc .). agents modulating cell replication / proliferation : target of rapamycin ( tor ) inhibitors ( including sirolimus , everolimus and abt - 578 ), paclitaxel and antineoplastic agents ( including alkylating agents , e . g . cyclophosphamide , mechlorethamine , chlorambucil , melphalan , carmustine , lomustine , ifosfamide , procarbazine , dacarbazine , temozolomide , altretamine , cisplatin , carboplatin and oxaliplatin ), antitumor antibiotics ( bleomycin , actinomycin d , mithramycin , mitomycin c , etoposide , teniposide , amsacrine , topotecan , irinotecan , doxorubicin , daunorubicin , idarubicin , epirubicin , mitoxantrone and mitoxantrone ), antimetabolites ( deoxycoformycin , 6 - mercaptopurine , 6 - thioguanine , azathioprine , 2 - chlorodeoxyadenosine , hydroxyurea , methotrexate , 5 - fluorouracil , capecitabine , cytosine arabinoside , azacytidine , gemcitabine , fludarabine phosphate and aspariginase ), antimitotic agents ( vincristine , vinblastine , vinorelbine , docetaxel , estramustine ) and molecularly targeted agents ( imatinib , tretinoin , bexarotene , bevacizumab , gemtuzumab ogomicin and denileukin diftitox )) antiplatelet , antithrombotic and fibrinolytic agents agents : glycoprotein iib / iiia inhibitors , direct thrombin inhibitors , heparins , low molecular weight heparins , platelet adenosine diphosphate ( adp ) receptor inhibitors , fibrinolytic agents ( streptokinase , urokinase , recombinant tissue plasminogen activator , reteplase and tenecteplase etc ). gene targeting molecules : small interference ( si ) rna , micro rnas , dnazymes and antisense oliogonucleotides cells : progenitor cells ( endothelial progenitor cells , cd34 + or cd133 + monocytes , hemopoietic stem cells , mesenchymal stem cells , embryonic stem cells ) and differentiated cells ( endothelial cells , fibroblasts and smooth muscle cells ) pharmacologic agents of local treatment of atherosclerosis : high density lipoprotein cholesterol ( hdl ), hdl mimetics and hydroxymethylglutaryl coa ( hmg - coa ) reductase inhibitors . these materials are then applied to or formed into material which forms , in whole or in part , a material for biomedical use . the application will determine the selection and design of the mechanical properties . the material can be applied as a part of a variety of clinical vascular applications including a vascular conduit , a stent , a stent - graft , a surgically or percutaneously implantable heart valve , a vascular / septal occlusion device , a vascular closure device or as a surface coating for a vascular device / application . other useful materials are matrices for tissue engineering , bone implants and prosthetics including pins , rivets , screws and rods , as well as artificial knees and other joints , especially at the surfaces where the metal ceramic or bone interfaces with the host tissue . still other application include the use of the material for delivery of therapeutic , prophylactic or diagnostic agents , as discussed above . in still other applications , the materials are used for non - therapeutic applications , for example , in cell culture . elastin is one of the major structural components of vessels and conduits . it makes up 28 - 32 % of large arteries and imparts recoil and durability to these conduits . elastin is formed through the cross - linking of its soluble precursor tropoelastin , which is initiated through the action of the enzyme lysyl oxidase ( lox ) ( kagan and sullivan , ( 1982 ) methods in enzymology , 82 , 637 - 650 ) on exposed lysines of tropoelastin . importantly , elastin is responsible for the two vessel characteristics that are deficient in current graft materials and are implicated in their failure : compliance and favorable cellular interaction . in the artery for example , elastin is found in distinct locations performing different functions . the adventitia is characterized by elastin fibers which are interspersed with collagen , providing mechanical strength and recoil , emphasized by the decreased arterial compliance and hypertension observed in mice with a single deletion in the elastin gene (( wagenseil et al ., ( 2005 ) amer . j . physiol . — heart and circulation physiology , 289 , h1209 - 17 ). a continuous sheet of elastin also forms the internal elastic lamina , providing a surface on which endothelial cells form a monolayer and a covering for the layer of smooth muscle cells that make up the tunica media . the total absence of elastin , again in a mouse model , results in the early death of the animals from uncontrolled proliferation of smooth muscle cells causing arterial obstruction ( li et al ., 1998 ). in the preferred embodiment , the combination of tropoelastin and a copolymer that is engineered for human clinical vascular applications has an ultimate tensile strength of at least 3 mpa . each component can be either a homogenous material or a composite of two or more materials . the components may be arranged in alternating or non - alternating patterns . the protoelastin is present in an effective amount and location to promote vascular compatibility , including increased endothelialization , and / or reduced thrombogenicity , and / or reduced neointimal hyperplasia . other useful materials are matrices for tissue engineering and / or drug delivery , bone implants and prosthetics including pins , rivets , screws and rods , as well as artificial knees and other joints , especially at the surfaces where the metal , ceramic or bone interfaces with the host tissue . in the majority of these cases , the critical role of the protoelastin is to increase the biocompatibility of the implant or matrix , promoting cell attachment or diminishing the formation of scar tissue , abnormal proliferation of cells ( i . e ., restenosis or scarring ), and integration of the implant into the host . the protoelastin can be applied to the surface of a tissue culture container . the tissue culture container can be a flask , a dish , a multi - well plate , a micro plate or a slide . the coating should be effective to promote cell attachment and cell proliferation , preferably promoting the formation of a confluent cellular surface coating . for use as a biomaterial , elastin &# 39 ; s primary properties have traditionally been seen as elasticity and resilience to degradation by proteases . throughout the literature it has long been acknowledged that elastin alone lacks sufficient mechanical strength to be used as a stand alone biomaterial , especially in the vascular space . a major limitation of elastin as a vascular graft material is its low ultimate tensile strength . required mechanical stability for a predominantly elastin biomaterial will vary dependant on the application . if it is used as a coating for an eptfe graft , the tensile strength can effectively be zero and the measure of its success will be its persistence to on the surface . an elastin based conduit or graft will have the highest requirements , with a necessity to at least match in vivo examples ( human aorta having a tensile strength of 1 to 2 mpa and a stiffness of 10 to 12 mpa ). mechanical strength is achieved through 1 ) control of formulation and 2 ) control of fabrication . in terms of formulation one can manipulate the tropoelastin concentration , the type ( and duration ) of cross - linking and the intermingling of other copolymers in solution . strength is also a function of the fabrication technique . the mechanical properties of the protoelastin can be modified by changing the protein concentration ( this can mean thickness , but also includes actual percentage of protein in solution . by way of example , when electrospinning the concentration of tropoelastin in solution can be raised from 10 % w / v to 20 % w / v — or the original solution can be delivered for a longer time , giving a thicker material . currently it is common to electrospin tropoelastin solutions ranging from 1 % w / v up to 25 % w / v — depending on the type and proportion of copolymer . the listed example of a solution containing 5 % w / v tropoelastin and 5 % w / v polycaprolactone is representative of a typical blend . we would prefer not to be limited to a range , given that the amount of protein needed for coating of a surface could well be much less and the blend ratios of some polymers have not yet been elucidated ) the cross - linking type and duration , the presence and type of copolymer , and the fabrication method . in this context fabrication method refers to the method of producing the protoelastin material . specifically electrospinning is currently preferred though centrifugally cast molding is also listed in the examples . electrospinning will generally speaking result in a more robust end product than casting , which in turn gives a stronger material than one molded under gravity alone . the protoelastin can be an enzymatically or chemically cross - linked to itself , to one or more other polymers or to a substrate . enzymatic cross - linking can be achieved using any lysyl oxidase capable of converting epsilon amines to adipic semi - aldehydes or through the enzyme catalysis of transglutaminase . the chemical cross - linking can be achieved using any from the group of reagents with at least one amine reactive group , for example , using a chemical cross - linking reagent such as bis ( sulfosuccinimidyl ) suberate ( bs3 ), 1 - ethyl - 3 -[ 3 - dimethylaminopropyl ] carbodiimide hydrochloride ) ( edc ), glutaraldehyde , n - hydroxysuccinimide ) ( nhs ) and 1 , 6 - diisocyanatohexane ( hmdi ) and combinations thereof . 2 . methods of making coatings and covalent coupling to a substrate the tropoelastin can be applied to a surface by spraying , dipping , or other methods known to those skilled in the art . in one embodiment the substrate material is modified to create reactive surface groups which facilitate covalent interaction . in the case of inert polymeric materials like eptfe , the surface requires activation . both ‘ classical ’ plasma processes ( bilek et al . ( 2004 ) in smart materials iii , vol . 5648 ( ed , wilson , a . r .) spie , pp . 62 - 67 .) and higher energy plasma immersion ion implantation ( bilek et al . ( 2002 ) surface and coatings technology , 156 , 136 - 142 .) ( piii ) are applicable . in a preferred embodiment , the tropoelastin is covalently tethered to the polymer when a solution of the protein is incubated with the activated surface . piii has recently been shown to increase the functional lifetime of attached proteins and may be preferred ( nosworthy et al . ( 2007 ) acta biomater , 3 , 695 - 704 .). similarly , dacron ® surfaces can be predisposed to covalent attachment of tropoelastin using chemical means ( phaneuf et al ( 1995 ) journal of applied biomaterials , 6 , 289 - 99 .). metallic substrates can be also be functionalized by applying the piii process to the substrate while it is immersed in a carbon containing plasma or in a vapour of the monomer used to deposit the plasma polymer layer or by codeposition of a graded substrate / polymer layer which terminates in the polymer . in a preferred embodiment this technique would be used to bind tropoelastin to a range of metals including stainless steel . the protoelastin can be in the form of a laminate , wherein the tropoelastin is layered onto one or more layers of polymer , preferably stabilized by cross - linking and / or covalent tethering to the substrate , which may then be covered with one or more additional layers of polymer . for vascular applications and implants that interface with cells or tissue , the luminal side of the laminate or exterior portion of the implant is preferable covered with the protoelastin . the selection of the polymer ( s ), the number and thickness of the polymer and tropoelastin layers , and the degree of cross - linking of the tropoelastin will determine the strength and rigidity of the laminate . the tropoelastin can be blended with one or more polymers , as described above , to create materials having desired mechanical properties . the properties will depend on the polymer that is selected , the relative concentration of polymer to tropoelastin , and the method of blending and cross - linking or covalent coupling , if any . the polymeric materials can be blended with the tropoelastin dissolved in an appropriate mutual solvent . for electrospinning , materials are best dissolved in polar organic solvents . 1 , 1 , 1 , 3 , 3 , 3 - hexafluoropropanol ( hfp ) is preferred . other solvents such as tetrahydrofuran ( thf ), n , n - dimethylformamide ( dmf ), trifluoroacetic acid ( tfa ) and dichloromethane can also be used . tropoelastin blends can also be prepared in aqueous systems like phosphate buffered saline ( pbs ) for other fabrication techniques by taking advantage of its unique temperature behaviors ( e . g . increased solubility at 4 ° c .). electrospinning of fine fibers provides the greatest control over the architecture of the constructs . by way of example , electrospun recombinant human tropoelastin has a tensile strength of about 0 . 5 mpa , but when it is co - spun with collagen in a 50 : 50 ratio , strength is doubled . when tropoelastin is electrospun with a polymer such as polycaprolactone , the strength of the final material is even greater ( up to 3 mpa ), while the elasticity contribution of elastin can be retained . biostable polymers such as nylon and dacron are preferred . composite tubular materials that have favorable characteristics for grafting have been engineered using the electrospinning technique . the tubes are suturable , porous ( when viewed by scanning electron microscopy ) and can be reproducibly manufactured . in a preferred embodiment , the tubes are composites of tropoelastin and polycaprolactone , subsequently cross - linked with hmdi . non - degradable or less degradable polymers that are used with the tropoelastin will be more stable . the material can be applied as a part of a variety of clinical vascular applications including a vascular conduit , a stent , a stent - graft , a surgically or percutaneously implantable heart valve , a vascular / septal occlusion device , a vascular closure device or as a surface coating for a vascular device / application . the present invention will be further understood by reference to the following non - limiting examples . tropoelastin was dissolved in cold phosphate buffered saline ( pbs ) at a concentration of 100 mg / ml . the amine reactive cross - linker , bis ( sulfosuccinimidyl ) suberate ( bs3 ) was freshly prepared by dissolving in pbs immediately prior to use to a concentration of 100 mm . the solutions were mixed in a 1 : 10 ratio to give a final cross - linker concentration of 10 mm . the solution was poured into a mould , prior to placement at 37 ° c . to facilitate coacervation and cross - linking . the resulting protoelastin was washed repeatedly with pbs and stored in a sterile environment . 100 mg of tropoelastin was placed in a small weight boat . in 10 μl aliquots , 100 μl of pbs was added to the tropoelastin slowly over several minutes . with the addition of each aliquot , a spatula was used to fold the solution into the protein . the tropoelastin eventually took on a gum - like consistency , which could be drawn into fibers and molded into shapes . to fix , the protein was submerged in a 10 % 1 , 6 - diisocyanatohexane ( hmdi ) in propanol solution and allowed to stand overnight . elasticity was restored to the protoelastin by repeated washing in water and then in pbs . tropoelastin ( 300 mg ) was dissolved in cold pbs ( 2 . 7 ml ) over several hours . when the protein solution had fully dissolved , bs3 ( 17 . 1 mg ) was dissolved in a separate solution of pbs ( 300 μl ). the tropoelastin and bs3 solutions were briefly mixed in an iced vessel , before being transferred to a suitable mould , also on ice . the capped mould was placed in a centrifuge , preheated to 37 ° c . the mould was centrifuged at 1500 rpm for 5 min , before transfer to a 37 ° c . incubator where it was left to set overnight . after careful removal from the mold , the protoelastin tube was washed repeatedly with pbs and stored in a sterile environment . the electrospinning method was adapted from ( li et al ., ( 2005 ) small . 1 ( 1 ): 83 - 6 ). briefly , a tropoelastin solution ( 5 % w / v ) was mixed with a copolymer ( 5 % w / v ) in 1 , 1 , 1 , 3 , 3 , 3 - hexafluoropropanol . the homogenous solution was loaded into a 1 ml plastic syringe equipped with a blunt 18 gauge needle . constant flow rates ( 0 . 5 ml / h ) were achieved using a syringe pump ( sp100 iz syringe pump , protech international ) and the needle connected to the positive output of a high voltage power supply ( es30p / 20w , gamma high voltage research inc .). the metallic target for the fibers carried a negative charge , provided by a second power supply . electrospinning was carried out with the needle voltage set at 20 kv , the target voltage set at − 3 kv and with an air gap distance of approximately 15 cm . electrospun fibers were cross - linked using a 10 % hmdi solution in isopropanol and washed with water and pbs . to produce tubes by electrospinning requires the adaptation of standard procedures . a recent review details the broad variation in equipment set up design ( teo and ramakrishna ( 2006 ) nanotechnology , 17 , r89 - r106 ) specifically , protoelastin based tubes were electrospun using a modified version of method employing knife - edge electrodes ( teo , et al . ( 2005 ) nanotechnology , 16 , 918 - 924 .). briefly , protein and polymer components were mixed in 1 , 1 , 1 , 3 , 3 , 3 - hexafluoropropanol . the homogenous solution was loaded into a 1 ml plastic syringe equipped with a blunt 18 gauge needle . constant flow rates ( 0 . 5 ml / h ) were achieved using a syringe pump ( sp100 iz syringe pump , protech international ) and the needle connected to the positive output of a high voltage power supply ( es30p / 20w , gamma high voltage research inc .). fibers were drawn towards a carbon steel surgical blade ( size 20 ), positioned approximately 15 cm from the needle tip . fibers were collected on a rotating mandril which also oscillated longitudinally . multiple layers , containing varied components could be built up in this fashion . the completed tube was rinsed in isopropanol , removed from the mandril and cross - linked overnight using a 10 % hmdi solution in isopropanol . finally , the tube was washed repeatedly with pbs and stored in a sterile environment . the thrombogenicity of protoelastin was assessed in vitro , using an activated partial thromboplastin time ( aptt ) assay ( cullberg et al ., ( 2001 ) brit . j . cli . pharmacol ., 51 , 71 - 91 ). this assay determines the ability of a material to effect the activation of the contact factors of coagulation and thus change the clotting time of human plasma . normal citrated plasma was mixed with a kaolin - phospholipid suspension ( 5 g / l in pbs ) and left at 37 ° c . for 10 min , with occasional shaking . at exactly 10 min , pre - warmed cacl 2 ( 0 . 025m ) was added and a stopwatch started . the time for the mixture to clot was recorded . the protocol was repeated for plasma containing saline or ground protoelastin particles instead of kaolin , and again clotting times were recorded . results are shown in fig7 and demonstrate the non - thrombogenicity of the elastin coated material . the effect of protoelastin , fibronectin and bovine serum albumin ( bsa ), on human umbilical vein endothelial cell ( huvec ) attachment was assessed in comparison to plastic alone . a 96 well plate was divided such that there were six triplicate time points ( 0 , 0 . 5 , 1 , 2 , 4 , and 6 h ) for each treatment . protoelastin , bsa and fibronectin were added such that each well received 100 μl / 10 μg of protein . plates were stored at 4 ° c . overnight , to allow adequate coating of the plate surfaces . the next day , all protein solutions were removed from the wells . approximately 15 , 000 huvec &# 39 ; s were added to each well , except for the zero time point , which received media alone . the dmem media was supplemented with 20 % heat - inactivated human serum , glutamine , penicillin - streptomycin and pyruvate . plates were incubated at 37 ° c ., with 5 % co 2 . at each time interval , solution was removed and wells covered with fresh media until the completion of the assay . at this time , all wells were emptied and washed three times with pbs . the number of adhered cells was determined calorimetrically using one solution cell proliferation assay ( promega ). each well received 100 μl of fresh media and 20 μl of reagent , before incubation at 37 ° c ., with 5 % co 2 for 90 min . absorbance was read at 490 nm in a plate reader . results are shown in fig8 a and demonstrate that the huvecs show superior attachment to a protoelastin coated surface . the effect of protoelastin , fibronectin and bovine serum albumin ( bsa ), on human umbilical vein endothelial cell ( huvec ) growth was assessed in comparison to plastic alone . a 6 well plate was divided such that there were 3 time points ( 1 , 2 and 3 days ) for each treatment . protoelastin , bsa and fibronectin were added such that each well received 2 ml / 200 μg of protein . plates were stored at 4 ° c . overnight , to allow adequate coating of the plate surfaces . the next day , all protein solutions were removed from the wells . approximately 40 , 000 huvec &# 39 ; s were added to each well . the dmem media was supplemented with 20 % heat - inactivated human serum , glutamine , penicillin - streptomycin and pyruvate . plates were incubated at 37 ° c ., with 5 % co 2 . at each time interval , solution was removed . wells requiring further incubation were washed and supplied with fresh media . wells ready for assay were washed three times with pbs and the number of cells was determined calorimetrically using one solution cell proliferation assay ( promega ). each well received 100 μl of fresh media and 20 μl of reagent , before incubation at 37 ° c ., with 5 % co 2 for 90 min . absorbance was read at 490 nm in a plate reader . results are shown in fig8 b , with fibronectin and protoelastin providing the best surface for the proliferation of huvecs at 3 days . measurements of tensile strength and young &# 39 ; s modulus were carried out with an instron 4302 computerized universal testing machine . strips of test material measuring 20 mm wide by 60 mm long were accurately cut . after clamping , the test area was approximately 20 mm × 20 mm . samples were then stretched at a constant rate of 1 mm per minute until break , while force and elongation measurements were recorded . results were plotted in the form a stress - strain curve and young &# 39 ; s modulus recorded over the initial linear portion of the curve . the results are shown in fig9 a for tensile strength and fig9 b for young &# 39 ; s modulus ( elasticity ), showing that the tropoelastin : polycaprolactone 50 : 50 and 25 : 75 have a tensile strength comparable to aorta , and that the young &# 39 ; s modulus increases with increasing polycaprolactone content . the growth of human umbilical vein endothelial cells ( huvec ) was assessed on electrospun tropoelastin : polycaprolactone composites . a 96 well plate was divided such that the three formulations ( 100 % tropoelastin ; 50 : 50 and 25 : 75 tropoelastin : polycaprolactone ) were observed at 24 and 48 h . samples of electrospun material were cut into 8 mm circles and pressed into place . approximately 30 , 000 huvec &# 39 ; s were added to each well . the dmem media was supplemented with 20 % heat - inactivated human serum , glutamine , penicillin - streptomycin and pyruvate . plates were incubated at 37 ° c ., with 5 % co 2 . at each time interval , solution was removed . wells requiring further incubation were washed and supplied with fresh media . wells ready for assay were washed three times with pbs and the number of cells was determined calorimetrically using one solution cell proliferation assay ( promega ). each well received 100 μl of fresh media and 20 μl of reagent , before incubation at 37 ° c ., with 5 % co 2 for 90 min . absorbance was read at 490 nm in a plate reader . the results are shown in fig1 . the proliferation of the huvecs increased dramatically with increasing concentration of tropoelastin . dacron ® was predisposed to bonding with protoelastin according to the method of phaneuf et al . j . app . biomater . 6 , 289 - 99 ( 1995 ). briefly , dacron segments were washed in and aqueous tween 20 solution containing na 2 co 3 for 30 min at 60 ° c . before rinsing with water . after oven drying , samples were boiled in a 0 . 5 % sodium hydroxide for 30 min , rinsed again with water and dried . protoelastin was covalently linked to the treated dacron ® surface using 1 - ethyl - 3 -[ 3 - dimethylaminopropyl ] carbodiimide hydrochloride ( edc ) according to the method of grabarek and gergely ( 1990 ) anal biochem . 185 ( 1 ): 131 - 5 . in a two step reaction , edc ( 2 mm ) and sulfo - n - hydroxysuccinimide ( sulfo - nhs ) ( 5 mm ) was added to a 100 % ethanol solution contain dacron ® samples and reacted for 15 min . 2 - mercaptoethanol ( final concentration of 20 mm ) was added to quench the edc . protoelastin was added at an equal molar ratio to the solution and allowed to react for 2 hours at room temperature . the reaction was quenched with the addition of hydroxylamine to a final concentration of 10 mm . samples of eptfe were activated for protein attachment using a plasma modification chamber ( gan et al . ( 2006 ) nuclear instruments and methods in physics research b , 247 . 254 - 260 ). briefly , from this protocol , plasma treatments were carried out in nitrogen gas at a pressure of 2 × 10 − 3 torr . the forward power used in the chamber was 100 w with a reverse power of 12 w when matched . plasma immersion ion implantation ( piii ) with high voltage pulse bias of 20 kv and 20 μs duration at a frequency of 50 hz was used for more intense modification of the surface . samples were reacted within the chamber for a period of 800 seconds for either plasma or piii modification . treated materials were punched into 10 mm circles and incubated with a 1 mg / ml tropoelastin solution overnight at 37 ° c . no additional cross - linking agent was necessary for the formation of covalent linkages . tropoelastin coated samples were then washed three times with pbs and blocked with a 10 mg / ml bsa solution for 1 h at room temperature . at this time , a subset of samples from each treatment was boiled in 5 % sds for 10 mins . samples were then washed again with pbs before treatment with 1 ml of monoclonal anti - elastin antibody ( primary ) and incubated for 1 h at room temperature . following pbs washing , 1 ml of hrp mouse antibody ( secondary ) was added before a second incubation period . finally , 1 ml of ( 2 , 2 ′- azino - bis ( 3 - ethylbenzthiazoline - 6 - sulphonic acid ) abts solution was supplied to each sample and the absorbance at 405 nm read after 1 h at 37 ° c . absorbance is expressed relative to tropoelastin - free controls . fig1 shows the amount of tropoelastin retained on eptfe after no treatment , plasma treatment or piii treatment . in each case , a no wash case is compared to boiling in sds . on untreated eptfe , sds washing removes all of the protein , given that no permanent bonds are formed , in contrast to the plasma and piii cases , where the sds washed samples are not significantly different from their pre - wash controls . cellular responses to cross - linked tropoelastin were assessed 13 weeks after implantation in the dorsum of male guinea pigs , with collagen implants used as a control . both cross - linked tropoelastin and collagen elicited a similar reaction that was limited to a typical cell mediated response to the presence of a foreign body . “ the observed cellular infiltrates did not suggest the presence of a specific immunological reaction . the collagen control had a short - lived duration following implantation and was largely dispersed by week four . the cross - linked tropoelastin samples were uniformly surrounded by fibrous encapsulation with minimal to moderate inflammation ” modifications and variations of the present invention will be obvious to those skilled in the art from the foregoing detailed description and are intended to come within the scope of the appended claims . references cited herein are specifically incorporated by reference .

biocompatible materials suitable for use in vascular applications have been engineered , combining human recombinant tropoelastin with other synthetic or natural biomaterials to form protoelastin . the materials can be in the form of elastin films on metal , bone , ceramic or polymer substrates , laminates of alternating polymer and elastin , blends of polymer and elastin , or elastin crosslinked with or tethered to polymer . the flexibility in engineering and design makes protoelastin biomaterials suited not only to the production of conduits but any number of other vascular applications that require blood contacting surfaces . tropoelastin and the subsequently engineered biomaterial protoelastin provide the opportunity to satisfy a large unmet need for a biocompatible material adaptable enough to meet a range of diverse vascular uses . these are mechanically stable , elastic , strong and biocompatible ( i . e ., not thrombogenic and promoting adhesion of cells , especially human endothelial cells .

the balloon dilatation catheter 10 of the present invention has an inner catheter 20 , an outer catheter 30 and a balloon 40 . inner catheter 20 comprises a proximal inner tube 21 , a distal inner tube 22 and a bumper tip 23 . these three elements define a guidewire lumen extending therethrough . outer catheter 30 comprises a proximal outer tube 31 and a distal stem 32 . these two elements define a second lumen extending therethrough . inner catheter 20 is disposed inside the second lumen of outer catheter 30 so that a predetermined length of the distal portion of inner catheter 20 extends out of the distal end of outer catheter 30 . an unoccluded space still remains in the second lumen between the inner surface of outer catheter 30 and the outer surface of inner catheter 20 when inner catheter 20 is inserted into the second lumen to define an inflation lumen . balloon 40 is disposed about inner catheter 20 and has its distal neck 41 connected to bumper tip 23 and its proximal neck 42 connected to distal stem 32 . the bond between distal neck 41 and bumper tip 23 and the bond between proximal neck 42 and distal stem 32 can be achieved by the application of heat . preferably a laser bond , such as described in copending application ser . no . 07 / 800 , 201 filed nov . 29 , 1991 is used . the balloon cavity 43 is in communication with the inflation lumen . balloon 40 can be formed from a variety of materials such as polyethylene , polyethylene terephthalate or nylon . the proximal ends of proximal outer tube 31 and proximal inner tube 21 are inserted into and held securely by a branched hub 50 . a first opening 51 and a second opening 52 are formed in branched hub 50 . first opening 51 is in communication with the guidewire lumen of inner catheter 20 . this arrangement allows a guidewire ( not shown ) to extend inside inner catheter 20 from the proximal end of catheter 10 and out past the distal end of catheter 10 . second opening 52 is in communication with the inflation lumen . this arrangement allows inflation fluid to be injected in second opening 52 through the inflation lumen and into balloon cavity 43 to thereby inflate balloon 40 . the material used to form the various elements of inner catheter 20 and outer catheter 30 should be selected to give catheter 10 sufficient pushability at its proximal portion and sufficient flexibility at its distal portion . for example , a relatively stiff material should be selected for proximal outer tube 31 and proximal inner tube 21 while a relatively flexible material should be selected for distal stem 32 , distal inner tube 22 and bumper tip 23 . it has been found that enhanced performance , measured by the pushability of catheter 10 through the vascular system and the trackability of catheter 10 over a guidewire through tortuous coronary arteries , is achieved by the use of polyethylene for proximal inner tube 21 and various grades of polyester for the remaining elements of inner catheter 20 and outer catheter 30 . preferably dupont hytrel polyester is used . proximal outer tube 31 is 72 d , distal stem 32 is 55 d , distal inner tube 22 is 63 d and bumper tip 23 is 45 d . when bumper tip 23 is made from such a soft material as 45 d hytrel ® polyester , trauma to the blood vessel in which catheter 10 is inserted is minimized as catheter 10 tracks a guidewire to a treatment site . the relative dimensions of the various elements forming inner catheter 20 and outer catheter 30 are also selected to give enhanced performance . for example , the outer diameter of proximal outer tube 31 is larger than the outer diameter of distal stem 32 . this provides outer catheter 30 with a relatively stiff proximal portion having decreasing stiffness toward the distal portion . the wall thickness of distal stem 32 is at least as large as the wall thickness of proximal outer tube 31 . in addition , the outer diameter of proximal inner tube 21 is larger than the outer diameter of distal inner tube 22 . preferably the wall thickness of proximal inner tube 21 should be equal to or smaller than the wall thickness of distal inner tube 22 . preferably the outer diameter and wall thickness of bumper tip 23 are larger than the outer diameter and wall thickness of proximal inner tube 21 . this arrangement yields inner catheter 20 with increasing flexibility from the proximal portion to the distal portion . in addition , the relative wall thicknesses prevent the guidewire lumen located inside balloon cavity 43 from collapsing when balloon 40 is inflated . the various elements of inner catheter 20 and outer catheter 30 are bonded end to end by thermal bonding , laser bonding , adhesive bonding or by conventional mechanical means . the distal end of proximal inner tube 21 is bonded to the proximal end of distal inner tube 22 by heat , laser bonding , chemical adhesive or other conventional mechanical means . similarly , the distal end of distal inner tube 22 is bonded to the proximal end of bumper tip 23 by heat , laser bonding , chemical adhesive or other conventional mechanical means . the distal end of proximal outer tube 31 is bonded to the proximal end of distal stem 32 by heat , laser bonding , chemical adhesive or other conventional mechanical means . preferably distal neck 41 is bonded to bumper tip 23 at about the midpoint of bumper tip 23 so that the juncture between bumper tip 23 and distal inner tube 22 is located inside of balloon cavity 43 . distal stem 32 is preferably bonded to distal inner tube 22 adjacent to proximal neck 42 of balloon 40 . any type of bond can be used . for example , distal stem 32 can be bonded to distal inner tube 22 by a chemical adhesive , a thermal bond , laser bonding or by any conventional mechanical bonding means . preferably a thermal bond is used . in one method of thermally bonding distal stem 32 to distal inner tube 22 , a first mandrel is placed inside the lumen of distal inner tube 22 and another crescent shaped mandrel is placed inside the lumen of distal stem 32 along one portion of the outside of distal inner tube 22 . the first mandrel maintains the patency of the lumen of distal inner tube 22 during the thermal bonding procedure . the crescent shaped mandrel is used to maintain the patency of the lumen of distal stem 32 between the outer surface of distal inner tube 22 and the inner surface of distal stem 32 . in addition , this crescent shaped mandrel positions a portion of distal inner tube 22 into contact with distal stem 32 . a heat shrink tube is placed over distal stem 32 in the area where the bond 60 is to occur prior to the application of heat . a double jaw clamp is then positioned over the heat shrink tube . one jaw is heated while the other jaw is cooled . the heated jaw contacts the heat shrink tube in the area where distal inner tube 22 contacts distal stem 32 to bond them together . the cooled jaw contacts the remaining portion of the heat shrink tube . the amount of heat applied , i . e . time and temperature , depends on the material used for distal inner tube 22 and distal stem 32 and can be determined by simple , routine experimentation . since it is preferable that distal inner tube 22 and distal stem 32 are formed from different grades of the same material , a homogeneous bond occurs between distal inner tube 22 and distal stem 32 . after sufficient heat is applied to weld a portion of distal inner tube 22 to a portion of distal stem 32 , the heat shrink tube is removed leaving distal stem 32 bonded to distal inner tube 22 at bond 60 . bond 60 should extend along distal inner tube 22 and distal stem 32 a distance sufficient to ensure a secure bond . bond 60 extends from the most distal end of distal stem 32 proximally for at least 0 . 030 inches . preferably bond 60 extends about 0 . 25 inches . in addition , bond 60 should extend around distal stem 32 for a distance sufficient to ensure a secure bond . see fig2 . preferably bond 60 extends from about 10 ° to about 350 ° around distal stem 32 . the exact bond angle depends on the size of distal inner tube 22 and distal stem 32 and the desired minimum unoccluded space for the inflation lumen . preferably , bond 60 extends around distal stem 32 about 30 ° to about 90 °. this leaves sufficient space in the inflation lumen for inflation fluid to pass therethrough and rapidly inflate and deflate balloon 40 . the exact combination of bond angle and bond length should be chosen to maximize the suppleness of bond 60 and maximize the unoccluded space of inflation lumen past bond 60 . although distal stem 32 and bond 60 are shown extending into balloon cavity 43 , it is also possible for distal stem 32 to terminate at its distal end at proximal neck 42 of balloon 40 so that bond 60 occurs at proximal neck 42 . however , it is preferable that the distal end of distal stem 32 , along with bond 60 , extend into balloon cavity 43 . this arrangement minimizes the material bonded at one point and thus maximizes the trackability of catheter 10 along a guidewire . thus , it is seen that a balloon dilatation catheter is provided that is flexible enough to negotiate a convoluted and tortuous path through the vascular system yet is stiff enough to be pushed through the vascular system and has a low profile yet has a inflation lumen that minimizes balloon inflation and deflation times . one skilled in the art will appreciate that the described embodiments are presented for purposes of illustration and not of limitation and that the present invention is only limited by the claims which follow .

a balloon dilatation catheter is disclosed having a multisectioned inner tube having a soft bumper tip , a multisectioned outer tube and a balloon with its distal neck connected to the bumper tip and its proximal neck connected to the outer tube . the various sections of the inner tube and outer tube may be formed from different materials or different grades of the same material . in addition , each section may have different outer diameters . the outer tube is bonded directly to the inner tube at the distal end of the outer tube . preferably this bond is accomplished by thermal bonding .

referring to fig1 the lancet device is shown generally labeled 10 . lancet device 10 has a proximal or patient contacting end generally labeled 16 and a distal end generally labeled 18 . the device 10 includes a lancet needle 12 having a lancet tip 14 at the proximal end . in the preferred embodiment , lancet needle 12 is about 0 . 031 &# 34 ; in diameter and about one inch long . the distal end of lancet needle 12 is encased in a distal needle piece 20 . in fig1 lancet needle 12 is shown in dotted lines encased in distal needle piece 20 . distal needle piece 20 encloses a significant length of lancet needle 12 . in the preferred embodiment , distal needle piece 20 is molded around lancet needle 12 to enclose more than half the length of lancet needle 12 . distal needle piece 20 includes a pair of opposed receptacles 22 , 24 extending into distal needle piece 20 on opposite sides of lancet needle 12 at approximately right angles to lancet needle 12 . receptacles 22 , 24 will be described in more detail hereafter . a proximal needle piece 26 is spaced away from and located proximal to distal needle piece 20 along lancet needle 12 . in manufacture , proximal needle piece 26 is molded to enclose and encase a portion of lancet needle 12 . the length of lancet needle 12 encased by proximal needle piece 26 is preferably considerably smaller than the portion of lancet needle 12 encased by distal needle piece 20 for a purpose that will be described hereafter . in the preferred embodiment , the length of lancet needle 12 enclosed by proximal needle piece 26 is approximately one fourth the length of lancet needle 12 enclosed by distal needle piece 20 . lancet needle 12 between distal needle piece 20 and proximal needle piece 26 is surrounded by a rigid sheath 54 . sheath 54 is preferably integrally molded with both distal needle piece 20 and proximal needle piece 26 at the time of manufacture . the distal end of sheath 54 is preferably rigidly connected to distal needle piece 20 while the proximal end of sheath 54 is preferably connected to proximal needle piece 26 by a frangible thin plastic piece 56 . thin plastic piece 56 preferably entirely surrounds the circumference of sheath 54 and is integrally formed with proximal needle piece 26 . thin plastic piece 56 may be made frangible by means including , but not limited to , having a narrow thickness , preferably not more than about 0 . 005 &# 34 ; thick , scoring , or perforating or a combination of these . although the preferred embodiment has the distal end of sheath 54 rigidly connected to distal needle piece 20 while the proximal end of sheath 54 is frangibly connected to proximal needle piece 26 , this may be reversed if desired so that the distal end of sheath 54 may be frangibly connected to distal needle piece 20 while the proximal end of sheath 54 may be rigidly connected to proximal needle piece 26 . thin plastic piece 56 precisely positions proximal needle piece 26 relative to distal needle piece 20 . this prevents proximal needle piece 26 from inadvertently moving away from distal needle piece 20 until desired as will be described hereafter . further , thin plastic piece 56 prevents proximal needle piece 26 from moving toward distal needle piece 20 . a pair of arms 28 , 30 connect of distal needle piece 20 with proximal needle piece 26 along opposite sides of lancet needle 12 . arms 28 , 30 are relatively thin and flexible . in the preferred embodiment , arms 28 , 30 extend from the distal end of distal needle piece 20 to the proximal end of proximal needle piece 26 . in this way , the overall length of lancet device 10 is minimized . each arm 28 , 30 has a catch 32 , 34 respectively , extending from arm 28 , 30 inwardly toward lancet needle 12 . in the preferred embodiment , catches 32 , 34 are arrow shaped so that a pair of edges 36 extend away from each catch 32 , 34 respectively . in a variation of the shape of catches 32 , 34 , catches 32 , 34 may be conical shaped so that a single annular ridge extends around catches 32 , 34 . receptacles 22 , 24 are shaped to correspond to the shape of the catches 32 , 34 . each arm 28 , 30 preferably has a finger pad 38 on the outer surface of each arm 28 , 30 directed away from lancet needle 12 . finger pads 38 are preferably cup shaped to allow arms 28 , 30 to be more easily grasped between the fingers of the user as will be explained hereafter . finger pads 38 may , in addition or in the alternative , include a friction producing surface such as a cross - hatched or rough surface to prevent the user &# 39 ; s fingers from slipping off of finger pads 38 . a cap 40 encloses lancet tip 14 . during manufacture , cap 40 is preferably integrally molded with proximal needle piece 26 and is formed around and encloses lancet tip 14 . a thin piece of plastic connects cap 40 to proximal needle piece 26 at breakoff point 42 at the proximal end of proximal needle piece 26 . in the preferred embodiment , the thickness of the plastic at breakoff point 42 is about 0 . 010 &# 34 ; and extends entirely around lancet needle 12 . as stated , during manufacture cap 40 is preferably integrally made with proximal needle piece 26 . in this way , cap 40 makes a seal with proximal needle piece 26 at breakoff point 42 so that lancet tip 14 is totally encapsulated within cap 40 to preserve the sterility of lancet tip 14 after the manufacturing process . cap 40 also includes a pair of opposed cap finger pieces 46 ( fig2 ) that allow cap 40 to be grasped . in the preferred embodiment , finger pieces 46 are concave extending into cap 40 from opposed sides . in addition or in the alternative , finger pieces 46 may also include a friction producing surface as a cross - hatched or rough surface to prevent the user &# 39 ; s fingers from slipping off of finger pieces 46 . in use , cap 40 is removed from its contact with proximal needle piece 26 . this is best done by the user grasping device 10 by finger pads 38 , preferably between the forefinger a and thumb b of one hand . thereafter , cap 40 is grasped between the thumb and forefinger of the other hand pinching cap finger pieces 46 . cap 40 is twisted relative to proximal needle piece 26 . at this time , the thin plastic connection at breakoff point 42 is broken so that cap 40 may be removed from proximal needle piece 26 as shown in fig4 . when cap 40 is removed from proximal needle piece 26 , lancet tip 14 is exposed ( fig4 ). with lancet tip 14 exposed , the user may move lancet tip 14 into contact with the skin so that a drop of blood may be drawn . thereafter , in order to cover lancet tip 14 , proximal needle piece 26 is moved over lancet tip 14 . proximal needle piece 26 is moved over lancet tip 14 by pinching arms 28 , 30 together between finger pads 38 as shown in fig5 . as arms 28 , 30 are pinched together , pressure is placed on distal needle piece 20 and proximal needle piece 26 to move away from each other . when sufficient pressure is placed on distal and proximal needle pieces 20 , 26 , thin plastic piece 56 will break thereby allowing distal needle piece 20 to move away from proximal needle piece 26 . because , in the preferred embodiment , the surface area of proximal needle piece 26 in contact with lancet needle 12 is considerably less than the surface area contacting lancet needle 12 within distal needle piece 20 , about one fourth the length , proximal needle piece 26 will break loose from its frictional contact with lancet needle 12 and move proximally away from distal needle piece 20 . as proximal needle piece 26 moves away from distal needle piece 20 , proximal needle piece 26 moves over and encloses lancet tip 14 as shown in fig5 . as arms 28 , 30 are pinched towards each other , catches 32 , 34 are moved into contact with receptacles 22 , 24 respectively . as catches 32 , 34 are moved farther into receptacles 22 , 24 , the material along the sides of receptacles 22 , 24 deforms around ridges 36 to allow catches 32 , 34 to move farther into receptacles 22 , 24 . when catches 32 , 34 are moved farthest into receptacles 22 , 24 , ridges 36 move into contact with the correspondingly shaped ledges 48 to securely hold catches 32 , 34 within receptacles 22 , 24 . because catches 32 , 34 are securely held or &# 34 ; locked &# 34 ; into receptacles 22 , 24 respectively , proximal needle piece 26 is &# 34 ; locked &# 34 ; into position enclosing lancet tip 14 , thereby preventing inadvertent contact with lancet tip 14 . as described above , arms 28 , 30 preferably extend from the distal end of distal needle piece 20 to the proximal end of proximal needle piece 26 . however , the invention will work with arms 28 , 30 attached to distal needle piece 20 and proximal needle piece 26 at any point along their respective surfaces parallel to lancet needle 12 so long as catches 32 , 34 may engage receptacles 22 , 24 as described above . as described above , because thin plastic piece 56 determines and maintains the distance between proximal needle piece 26 and distal needle piece 20 , the length of lancet tip 14 extending proximally beyond the proximal end of proximal needle piece 26 may be precisely set . this allows the lancet 10 to be manufactured so that lancet tip 14 protrudes various desired lengths from the proximal end of proximal needle piece 26 which desired protrusion length is maintained while lancet 10 is handled prior to pricking the patient &# 39 ; s skin with lancet tip 14 . by setting and maintaining precise lancet tip protrusion lengths , a desired depth of penetration may be consistently obtained . this allows lancets 10 to be manufactured according to desired lancet tip 14 penetration depths so that lancets 10 for special purposes , such as pediatric lancets , or lancets 10 corresponding to a patient &# 39 ; s optimal penetration depth to minimize pain are available . to aid in identifying the lancets 10 having the various penetration depths , the lancets 10 may be color coded or have other visual indicia representative of the depth of lancet tip 14 penetration presented . the thickness of thin plastic piece 56 may be varied to require differing amounts of pressure to be applied to arm 28 , 30 to break the connection between sheath 54 and proximal needle piece 26 . when thin plastic piece 56 is broken by pressure applied to arms 28 , 30 , an audible &# 34 ; pop &# 34 ; occurs . if , before the user has used lancet 10 to obtain a blood sample , pressure is inadvertently applied to arms 28 , 30 causing thin plastic piece 56 to break , the audible &# 34 ; pop &# 34 ; will alert the user that the desired depth of penetration by lancet tip 14 is no longer assured . the lancet 10 may then be appropriately discarded after locking the proximal needle piece 26 over lancet tip 14 as described above . in the invention , distal needle piece 20 , proximal needle piece 26 , arms 28 , 30 , sheath 54 and thin plastic piece 56 are preferably made of a flexible plastic material such as low density polyethylene . the material has sufficient stiffness to allow arms 28 , 30 to be pressed together while exerting pressure on proximal needle piece 26 to move proximally away from distal needle piece 20 . further , the material has sufficient rigidity to allow sheath 54 to prevent proximal needle piece 26 from moving toward distal needle piece 20 . preferably , the plastic material is molded around lancet needle 12 by techniques well understood in the art . however , distal needle piece 20 , proximal needle piece 26 , arms 28 , 30 , sheath 54 and thin plastic piece 56 may also be molded first and lancet needle 12 inserted into position later . in the invention , proximal needle piece 26 is molded around lancet needle 12 and contacts needle 12 along a relatively smaller distance than distal needle piece 20 contacts lancet needle 12 . this allows proximal needle piece 26 to break loose from its frictional contact with lancet needle 12 before distal needle piece 20 will break loose from frictional contact with lancet needle 12 when arms 28 , 30 are pinched together . however , in a variation of the embodiment shown , lancet needle 12 may have a lubricous coating applied along the area where proximal needle piece 26 will move to aid in proximal needle piece 26 breaking its frictional contact with lancet needle 12 . in the alternative or in addition , the surface of lancet needle 12 where proximal needle piece 26 will move may be provided with a much smoother , and consequently less friction producing surface , than the rest of lancet needle 12 , particularly the part of lancet needle 12 embedded in distal needle piece 20 . in these variations , the length of proximal needle piece 26 surrounding lancet needle 12 need not vary greatly from the length of distal needle piece 20 in contact with lancet needle 12 . when arms 28 , 30 are pinched together , proximal needle piece 26 will more easily slide along lancet needle 12 as described above . in another alternate embodiment , distal needle piece 20 , proximal needle piece 26 , and arms 28 , 30 may be molded at one time and lancet needle 12 inserted into position later . in this embodiment , proximal needle piece 26 may be manufactured with a bore extending through it through which lancet needle 12 will extend . this bore has a diameter slightly larger than the diameter of lancet needle 12 . after lancet needle 12 is positioned in distal needle piece 20 and extends through proximal needle piece 26 , when arms 28 , 30 are pinched together , proximal needle piece 26 will slide along lancet needle 12 as described above . as described above , catches 32 , 34 extend from arms 28 , 30 toward lancet needle 12 while recesses 22 , 24 extend into distal needle piece 20 . this configuration may be reversed so that catches , corresponding in shape to catches 32 , 34 , extend away from distal needle piece 20 toward arms 28 , 30 and are retained in recesses , corresponding in shape to recesses 22 , 24 , extending into arms 28 , 30 . in all the embodiments and variations thereof described above , the specific shape of the catches 32 , 34 and receptacles 22 , 24 may be varied from the &# 34 ; arrow &# 34 ; and conical shapes described herein to other shapes such as spherical or half - spherical , to name but a few of the possibilities . the key to the shapes of catches 32 , 34 and receptacles 22 , 24 is that catches 32 , 34 are securely retained within receptacles 22 , 24 once catches 32 , 34 are placed within receptacles 22 , 24 . consequently , any shape for catches 32 , 34 and receptacles 22 , 24 that performs this intended function is within the scope of the invention . further , the shapes for distal needle piece 20 , proximal needle piece 26 , finger pads 38 , and proximal and distal finger pads 50 , 52 , among other pieces described herein , may be varied so long as the elements perform their respective functions as described above . further , specific dimensions have been given for the lancet needle 12 . these dimensions have been given for the purpose of illustration and not for limiting the scope of the disclosure . lancet needles of other sizes and relative dimensions may be used in the invention as desired . the invention has been described in connection with specific embodiments . however , the disclosure given herein is intended for the purpose of illustration and not for the purpose of limitation . changes and modifications may be made to the description contained herein and still be within the scope of the invention . further , obvious changes and modifications will occur to those skilled in the art .

a blood lancet is disclosed having a lancet needle with a sharpened lancet tip . the lancet tip is covered before use . the lancet tip end of the lancet needle extends through a slidable proximal needle piece while the opposite end of the lancet needle is immovably embedded in a distal needle piece . the distal needle piece is connected to the proximal needle piece through a pair of opposed normally bowed flexible arms . a rigid sheath surrounds the lancet needle between the distal needle piece and the proximal needle piece . the sheath is rigidly attached to either the distal or proximal needle piece at one end and is frangibly connected to the proximal or distal needle piece , respectively , at its other end . the sheath precisely positions the proximal needle piece relative to the distal needle piece . a removable cap covers the lancet tip . in use , the cap is removed . after picking the user &# 39 ; s skin with the lancet tip , the bowed flexible arms are pinched towards each other which pushes the proximal needle piece into a position over and enclosing the lancet tip . the flexible arms each have an arrow shaped protrusion or catch that engages a correspondingly shaped receptacle on the distal needle piece to lock the proximal needle piece in position over the lancet tip .

in the accompanying drawings fig1 is a side perspective view of the cannula with a schematic diagram of a shoulder to which a ruptured tendon is to be attached ; fig2 is an exploded view of the apparatus of this invention ; fig3 is a cross sectional view of the cannula with the drill guide in place ; fig4 is a side elevational view of the apparatus of this invention with all parts assembled ; fig5 is a side schematic representation of an alternative embodiment of the suture pusher of this invention ; fig6 through 12 are a series of figures showing the sequence of steps performed in accordance with the invention . referring now in detail to the drawings and particularly to fig1 and 3 , a cannula 10 having a handle 12 is used to form a passageway for arthroscopic surgery to attach a tendon 14 to a bone 16 through overlying soft tissue 18 . the end of the cannula may contain a removable plug 20 to facilitate insertion of the cannula through the soft tissue , and the inner end of the cannula may contain teeth 22 by which the tendon 14 may be grasped by the cannula . a drill guide 24 has a handle 55 and contains two generally parallel bores 26 and 28 preferably 1 / 8 inch in diameter separated by a central web preferably 30 1 / 8 inch in diameter . the suture pusher 32 , which is constructed somewhat like a rongeur or arthroscopic grabber , is comprised of a pair of scissors handles 56 , 58 extending angularly from the distal ends of a pair of parallel arms 52 , 54 . a first embodiment of the suture pusher is shown in fig4 and fig9 through 12 . a suture pushing end 64 is connected to the proximal end of the parallel arms 52 , 54 . at the proximal end of the suture pushing end is an eye 38 through which a suture 41 is threaded as illustrated in fig9 . when the suture pushing member 64 is pivoted as described below , it carries the suture from one hole in the bone to the other as shown in fig1 . the distal end of the suture pushing end connects to parallel arm 52 at fixed pivot 70 . the suture pusher 32 of the first embodiment has four essential pivot points . fixed pivot 60 joins scissors handles 56 , 58 at their point of intersection . parallel arm 54 is connected to scissors handle 58 at pivot 62 on the distal end and is connected to suture pushing end 64 at pivot 68 . fixed pivot 70 joins suture pushing end 64 to parallel arm 52 . to pivot the suture 41 from the first hole 42 to the second hole 40 , scissors handle 58 is pivoted away from scissors handle 56 around fixed pivot 60 . this causes parallel arm 54 to slide in the distal direction , towards the scissors handles , thereby pulling on suture pushing end 64 at pivot point 68 . the suture pushing end 64 pivots about fixed pivot 70 , carrying the suture 41 into the second hole 40 . fig5 is a schematic side representation of an alternative embodiment of the suture pusher . this embodiment is quite similar to the first embodiment but may be preferred because it allows the surgeon to pivot the suture from the first hole into the second hole by closing the scissors handles rather than by opening them . a pair of scissors handles 56a , 58a extends angularly from the distal ends of a pair of parallel arms 52a , 54a . scissors handles 58a and 56a are joined by fixed pivot 60a , and scissors handle 58a is connected to parallel arm 52a at pivot 62a . at its proximal end , parallel arm 52a is attached to suture pushing end 64a at pivot point 68a . fixed pivot 70a joins parallel arm 54a to suture pushing end 64a . the proximal end of parallel arm 54 has a downwardly angled portion 72 which extends from the parallel arm at an obtuse angle and joins a second parallel portion 74 at the proximal end of the angled portion 72 . the second parallel portion 74 of parallel arm 54a is parallel to the proximal portion of the suture pushing end 64a . to use the alternative embodiment of the suture pusher , scissors handle 58a is pivoted around fixed pivot 60a in a distal direction , moving towards scissors handle 56a . this causes parallel arm 52a to slide in a proximal direction , thereby pushing suture pusher 64a at pivot 68a and causing the suture pushing end 64a to pivot around fixed pivot 70a . the suture ( not shown ) is thereby carried by the eye 38 into the second hole ( not shown ). as explained above this apparatus is used as follows : the cannula 10 is inserted into the tissue as illustrated in fig6 until it engages the bone where a suture is to be attached . where the tendon 14 is to be attached to the bone by the suture the tendon is grasped and held to the bone by the cannula as the cannula is inserted and the drill guide 24 is then inserted as shown in fig7 . a drill is then used as shown in fig8 to drill two holes 40 and 42 aligned with the bores 26 and 28 respectively of the drill guide . a suture 41 is then threaded through the eye 38 in the suture pusher 32 and the suture pusher is forced into the bore 28 of the drill guide and into the hole 42 , such that the two parallel arms 52 and 54 extend through one bore of the drill guide 24 as shown in fig9 . pivoting scissors handle 58 around pivot pin 60 as described above causes the suture pushing end 64 to push the suture 41 from one hole 42 to the other hole 40 . once the suture pushing member 64 penetrates from the hole 40 to the hole 42 as illustrated in fig1 and 11 , one end of the suture may be retrieved through the drill bore 26 by a suitable suture hook 50 as shown in fig1 . finally once the suture has been retrieved out through the bore 26 , the suture pusher and the drill guide may be withdrawn . knots are then tied in the suture and passed down the cannula to attach the tendon 14 to the bone 16 , and the excess ends of the suture may be cut off and the cannula withdrawn leaving the suture attached as shown in fig1 . while certain details of the invention have been illustrated and described herein it is obvious that many modifications thereof may be made .

an apparatus for use in arthroscopically attaching a suture to bone comprises a cannula and drill guide for use in drilling parallel holes in the bone and a scissors - like component for carrying a suture down one hole and pushing the suture through soft bone into the other hole where it can be retrieved .

although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention , the preferred methods are now described . however , before the present methods are described , it is to be understood that the present invention is not limited to the particular sizes , shapes , dimensions , materials , methodologies , protocols , etc . described herein , as these may vary in accordance with routine experimentation and optimization . it is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only , and is not intended to limit the scope of the present invention which will be limited only by the appended claims . the disclosure of each publication , patent or patent application mentioned in this specification is specifically incorporated by reference herein in its entirety . however , nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention . unless otherwise defined , all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs . in case of conflict , the present specification , including definitions , will control . in addition , the materials , methods , and examples are illustrative only and not intended to be limiting . the present invention relates to a method for preparing a composition comprising highly concentrated antibodies by ultrafiltration . the present invention comprises a method for preparing a composition comprising highly concentrated antibodies by ultrafiltration wherein a feed flow rate and a feed pressure applied to an ultrafiltration membrane are variable and changed during a filtration process . particularly preferred embodiments of the present invention are set forth below . a method for preparing a composition comprising highly concentrated antibodies by ultrafiltration , wherein the method comprises the steps of : 1 ) regulating a feed flow rate to allow the value of feed pressure applied to an ultrafiltration membrane to increase to 85 - 100 % of a specified maximum feed pressure of an ultrafiltration membrane ; and 2 ) decreasing the feed flow rate to maintain or decrease the value of the feed pressure applied to the ultrafiltration membrane after the step ( 1 ). the term “ ultrafiltration ” which is used within the present invention denotes a membrane - based separation process that separates molecules in solution on the basis of size . the term “ tangential flow filtration ( tff )” denotes a specific filtration method wherein a fluid flows tangentially to a membrane . the solution containing protein molecules is concentrated by flowing along , i . e . tangential to , the surface of an ultrafiltration membrane under pressure . the ultrafiltration membrane has a pore size with a certain cut off value . in one embodiment the cut off value is in the range of 50 kda or less , preferably of 30 kd or less . the term “ feed flow ” denotes the flow of fluid from the feed pump to the membrane . the term “ feed flow rate ” denotes the volumetric rate of flow of the solution to the membrane . the feed flow rate is usually given in terms of volume per unit time as liter / minute and normalized in terms of volume per unit membrane area per unit time as liter / m 2 / h ( lmh ). the term “ flux ” denotes the normalized permeate flow through the membrane in terms of volume per unit membrane area per unit time as liter / m 2 / h ( lmh ). the term “ feed pressure ” denotes the pressure applied to the inlet of an ultrafiltration membrane . the expression “ maximum feed pressure ” denotes the acceptable maximum value of the feed pressure which is specified by a vendor as a product specification of the ultrafiltration membrane . the term “ retentate pressure ” denotes the pressure applied to the outlet of an ultrafiltration membrane . the term “ permeate pressure ” denotes the pressure applied to the permeate side of the ultrafiltration membrane . the term “ transmembrane pressure ( tmp )” denotes the pressure which drives the fluid to filtrate across an ultrafiltration membrane . the value of tmp can be calculated as : tmp is an average of the feed pressure and the retentate pressure in the case where the permeate side is open in the tff equipment . the value of pressure is usually given in terms of “ bar ” or “ mpa ” or “ psi ”. the term “ antibody ” refers to a protein specifically recognizing an antigen . the antibody may be monoclonal or polyclonal . the antibody may exist in a variety of formats , including , for example , fv , fab , and f ( ab ) 2 as well as single chains ( scfv ) or diabodies . furthermore , any fragment or modification ( e . g ., chimeric antibody , humanized antibody , etc .) of the antibody may be used for the present method . methods to prepare these kinds of antibodies are well known in the art , and any method may be employed in the present invention to prepare such antibodies and fragments thereof . the monoclonal antibodies used in the present invention include not only those derived from animals such as humans , mice , rats , hamsters , rabbits , sheep , camels , and monkeys , but also artificially modified gene recombinant antibodies such as chimeric antibodies , humanized antibodies , and bispecific antibodies . the antibodies of the present invention also include gene recombinant antibodies that result from artificially modifying the antibody constant regions to alter the physical properties of the antibody molecule ( specifically , alteration of the isoelectric point ( pi ), improvement of the affinity for fc receptor , etc ) for the purpose of improving the blood persistence and in vivo pharmacokinetics . the immunoglobulin class of the antibodies used in the present invention is not particularly limited ; and the class may be any class , including igg such as igg1 , igg2 , igg3 , and igg4 , iga , igd , ige , and igm . however , igg and igm are preferred . antibodies used in the present invention include , but are not limited to , anti - tissue factor antibodies , anti - il - 6 receptor antibodies , anti - il - 6 antibodies , anti - hm1 . 24 antigen monoclonal antibodies , anti - parathyroid hormone - related peptide antibodies ( anti - pthrp antibodies ), anti - glypican - 3 antibodies , anti - ganglioside gm3 antibodies , anti - tpo receptor agonist antibodies , antibodies as a functional substitute for coagulation factor viii , anti - il31 receptor antibodies , anti - hla antibodies , anti - axl antibodies , anti - cxcr4 antibodies , anti - nr10 antibodies , and bispecific antibodies against factor ix and factor x . preferred humanized antibodies used in the present invention include anti - humanized interleukin 6 ( il - 6 ) receptor antibodies ( tocilizumab , hpm - 1 , and mra ) ( see wo 92 / 19759 ), humanized anti - hm1 . 24 antigen monoclonal antibodies ( see wo 98 / 14580 ), humanized anti - parathyroid hormone - related peptide antibodies ( anti - pthrp antibodies ) ( see wo 98 / 13388 ), humanized anti - tissue factor antibodies ( see wo 99 / 51743 ), humanized anti - glypican - 3 igg1kappa antibodies ( see pct / jp05 / 013103 ), and anti - nr10 humanized antibodies ( see wo2009 / 072604 ). particularly preferred humanized antibodies used in the present invention are humanized anti - il - 6 receptor antibodies . preferred human igm antibodies include recombinant human anti - ganglioside gm3 igm antibodies ( see wo 05 / 05636 ). preferred minibodies include anti - tpo receptor agonist diabodies ( see wo 02 / 33072 ) and anti - cd47 agonist diabodies ( see wo 01 / 66737 ). furthermore , antibodies with an improved isoelectric point include , for example , mab1 which is an anti - il - 6 receptor antibody described in wo 2011 / 090088 ( h chain / seq id no : 1 therein ; l chain / seq id no : 2 therein ), and fully humanized ns22 antibody , which is an anti - nr10 humanized antibody , produced by the method described in example 12 of wo2009 / 072604 . the present invention also relates to a method for preparing a composition comprising highly concentrated proteins other than antibodies by ultrafiltration . the present invention comprises a method for preparing a composition comprising highly concentrated proteins by ultrafiltration wherein a feed flow rate and a feed pressure applied to an ultrafiltration membrane are variable and changed during a filtration process . the proteins used in the present invention include , but are not limited to , enzymes , cytokines , and peptide aptamers . the expression “ a composition comprising highly concentrated antibodies ” as used within the present application denotes an aqueous , buffered solution containing the highly concentrated antibodies . the term “ buffer ” as used within the present application denotes a solution in which changes of ph due to the addition or release of acidic or basic substances is leveled by a buffer substance . any buffer substance resulting in such an effect can be used . in one embodiment pharmaceutically acceptable buffer substances are used , such as e . g . phosphoric acid or salts thereof , acetic acid or salts thereof , citric acid or salts thereof , morpholine or salts thereof , 2 -( n - morpholino ) ehanesulfonic acid or salts thereof , or tris ( hydroxymethyl ) aminomethane ( tris ) or salts thereof . in a preferred embodiment the buffer composition of the antibody preparation is between 10 to 30 mmol / l histidine . in more preferred embodiment the buffer composition of the antibody preparation is 20 mmol / l histidine . optionally the buffered solution may comprise an additional salt , such as e . g . sodium chloride , and / or sodium sulphate , and / or potassium chloride , and / or potassium sulfate , and / or sodium citrate , and / or potassium citrate . in one embodiment of the present invention , the ph of the antibody preparation is between ph 3 . 0 and ph 10 . 0 , preferably between ph 5 . 5 and ph 6 . 5 , more preferred ph 6 . 0 . in one embodiment of the present invention , the antibody preparation is processed at ambient temperature , preferably at a temperature from 10 to 30 degrees c ., more preferred at a temperature from 15 to 30 degrees c . in one embodiment , the highly concentrated antibodies have a protein concentration of above 100 g / l or a viscosity above 2 mpa · s . in a preferred embodiment , the highly concentrated antibodies have a protein concentration of above 200 g / l or a viscosity above 10 mpa · s . in more preferred embodiment , the highly concentrated antibodies have a protein concentration of above 250 g / l or a viscosity above 40 mpa · s . in one embodiment , the feed flow rate in step ( 1 ) is maintained at 200 lmh ( l / m 2 / hour ) or higher . in a preferred embodiment , the feed flow rate in step ( 1 ) is maintained at 250 lmh ( l / m 2 / hour ) or higher . in these embodiments the feed flow rate in step ( 1 ) is preferably maintained at a constant rate . in one embodiment , the maximum value of the feed pressure applied to an ultrafiltration membrane in step ( 1 ) is within 85 - 100 % of the specified maximum feed pressure of the ultrafiltration membrane . in a preferred embodiment , the maximum value of the feed pressure is from 2 . 0 bar to 4 . 0 bar . in a more preferred embodiment , the maximum value of the feed pressure applied to an ultrafiltration membrane in step ( 1 ) is 3 . 5 bar . in one embodiment , step ( 1 ) is transitioned to step ( 2 ) when the retentate solution is concentrated to a protein concentration greater than 200 g / l . in a preferred embodiment , step ( 1 ) is transitioned to step ( 2 ) when the retentate solution is concentrated to a protein concentration equal or greater than 220 g / l . in a more preferred embodiment , step ( 1 ) is transitioned to step ( 2 ) when the retentate solution is concentrated to a protein concentration equal to 240 g / l . in this embodiment , the feed flow rate after the value of the feed pressure is decreased in step ( 2 ) is maintained at a constant rate , preferably 120 lmh ( l / m 2 / hour ) or lower , or more preferred 80 lmh ( l / m 2 / hour ) or lower . in one embodiment , the value of the feed pressure applied to the ultrafiltration membrane in step ( 2 ) is maintained at a constant value . in one embodiment , the value of the feed pressure applied to the ultrafiltration membrane in step ( 2 ) is maintained within 85 - 100 % of the specified maximum feed pressure of the ultrafiltration membrane by ramping down the feed flow rate . in one embodiment , the feed flow rate is automatically regulated in a manner to maintain the feed pressure within 85 - 100 % of the specified maximum feed pressure of the ultrafiltration membrane by a feedback control between a feed pressure and a feed flow rate . in one embodiment of the production method according to the present invention further comprises between step ( 1 ) and step ( 2 ), the following step of : 3 ) recirculating the antibody preparation through the membrane with a permeate valve closed . in this embodiment , the antibody preparation is recirculated with a retentate pressure control valve fully open . in this embodiment , the feed flow rate in step ( 3 ) is preferably maintained at a constant flow rate between 5 to 120 lmh ( l / m 2 / hour ), and more preferably between 10 to 80 lmh ( l / m 2 / hour ). the present invention also relates to a liquid composition that comprises highly concentrated antibodies prepared by the methods of the present invention . the present invention also relates to pharmaceutical liquid compositions . the pharmaceutical liquid compositions of the present invention may include pharmaceutically acceptable carriers . in the present invention , pharmaceutical liquid compositions ordinarily refer to agents for treating , preventing , testing , or diagnosing diseases . the pharmaceutical liquid compositions of the present invention can be formulated by methods known to those skilled in the art . for example , they can be used parenterally , in the form of injections of sterile solutions or suspensions including water or other pharmaceutically acceptable liquid . for example , such liquid compositions may be formulated by mixing in the form of unit dose required in the generally approved medicine manufacturing practice by appropriately combining with pharmaceutically acceptable carriers or media , specifically with sterile water , physiological saline , vegetable oil , emulsifier , suspension , surfactant , stabilizer , flavoring agent , excipient , vehicle , preservative , binder , or such . in such formulations , the amount of active ingredient is adjusted to obtain an appropriate amount in a pre - determined range . sterile compositions for injection can be formulated using vehicles such as distilled water for injection , according to standard formulation practice . aqueous solutions for injection include , for example , physiological saline and isotonic solutions containing dextrose or other adjuvants ( for example , d - sorbitol , d - mannose , d - mannitol , and sodium chloride ). it is also possible to use in combination appropriate solubilizers , for example , alcohols ( ethanol and such ), polyalcohols ( propylene glycol , polyethylene glycol , and such ), non - ionic surfactants ( polysorbate 80 ™, hco - 50 , and such ). oils include sesame oil and soybean oils . benzyl benzoate and / or benzyl alcohol can be used in combination as solubilizers . it is also possible to combine buffers ( for example , phosphate buffer and sodium acetate buffer ), soothing agents ( for example , procaine hydrochloride ), stabilizers ( for example , benzyl alcohol and phenol ), and / or antioxidants . appropriate ampules are filled with the prepared injections . the pharmaceutical liquid compositions of the present invention are preferably administered parenterally . for example , the liquid compositions may be in the dosage form for injections , transnasal administration , transpulmonary administration , or transdermal administration . for example , they can be administered systemically or locally by intravenous injection , intramuscular injection , intraperitoneal injection , subcutaneous injection , or such . administration methods can be appropriately selected in consideration of the patient &# 39 ; s age and symptoms . the dose of a pharmaceutical liquid composition containing an antigen - binding molecule may be , for example , from 0 . 0001 to 1000 mg / kg for each administration . alternatively , the dose may be , for example , from 0 . 001 to 100 , 000 mg per patient . however , the present invention is not limited by the numeric values described above . the doses and administration methods vary depending on the patient &# 39 ; s weight , age , symptoms , and such . those skilled in the art can set appropriate doses and administration methods in consideration of the factors described above . the following examples serve to more fully describe the manner of using the above - described disclosure , as well as to set forth the best modes contemplated for carrying out various aspects of the disclosure . it is understood that these examples in no way serve to limit the true scope of this disclosure , but rather are presented for illustrative purpose . fig1 illustrates the major components of an apparatus used to perform an ultrafiltration process . a recycle tank contains initial material and retentate . a mixing apparatus ensures uniform mixing between the initial pool added via a transfer line and the retentate that returns back to the recycle tank from ultrafiltration membrane . a feed pump creates tangential flow over the membrane . feed pressure is measured at the inlet of the membrane . a retentate pressure control valve is used on the retentate side , downstream of the membrane , to adjust a retentate pressure , for example under transmembrane pressure ( tmp ) control . between the membrane and the retentate pressure control valve , a pressure sensor measures a retentate pressure . on the permeate side of the membranes , a pressure of the liquid filtered through the membrane is monitored by a permeate pressure sensor . for lab - scale ultrafiltration processing an automated tff system aktacrossflow ( ge healthcare , us ) was used . the ultrafiltration process was performed using a 0 . 02 m 2 sartocon slice cassette with a hydrosart membrane of regenerated cellulose , a nominal molecular weight cut - off of 30 kda and a maximum feed pressure specification of 4 . 0 bar ( sartorius , germany ). prior to use , the membrane cassette was cleaned with 1 mol / l sodium hydroxide and rinsed with purified water . the normalized flux was determined to ensure comparable membrane properties . the membrane cassette was equilibrated with 30 mmol / l histidine buffer ph 5 . 8 prior to process . ultrafiltration was operated at ambient temperature . the starting material was prepared from a purified pool of a humanized anti - human interleukin - 6 receptor ( il - 6r ) monoclonal antibody ( tocilizumab ( registered trade mark : actemra , roactemra ) see pct pub . no . wo92 / 19759 , u . s . pat . no . 5 , 795 , 965 ). the purified pool was concentrated up to 60 mg / ml and buffer exchanged into 30 mmol / l histidine buffer ph 5 . 8 . the buffer exchanged pool ( df pool ) was loaded into the tff system with 625 g antibody / m 2 . the feed flow rate was set to a constant rate of 250 lmh ( l / m 2 / hour ) during the entire process . the tmp was controlled at 1 . 0 bar until the retentate pressure control valve came to a fully open . the ultrafiltration process was operated with the permeate side open - ended . the operation was terminated when the feed pressure exceeded 3 . 5 bar . after ultrafiltration processing , the concentrated solution was circulated with the permeate side closed for 15 minutes under a constant retentate flow rate of 10 ml / min and then recovered into a graduated cylinder . the recovered pool was stirred until visually homogeneous . for protein concentration measurement , the recovered pool was diluted gravimetrically using a density value measured by a density meter dma 4500 ( anton paar , austria ). uv absorbance at 280 nm was measured with a uv / vis spectrophotometer du800 ( beckman coulter , us ). fig2 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 1 shows the result of protein concentration measurement . comparative example 1 was repeated with the following exception . the feed flow rate was reduced to 80 lmh when the retentate volume reached the value that corresponds to protein concentration of 100 g / l . fig3 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 2 shows the result of protein concentration measurement . comparative example 1 was repeated with the following exception . the feed flow rate was reduced to 80 lmh when the retentate volume reached the value that corresponds to protein concentration of 200 g / l . fig4 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 3 shows the result of protein concentration measurement . comparative example 1 was repeated with the following exception . the feed flow rate was reduced to 80 lmh when the feed pressure exceeded 3 . 5 bar . the value of the retentate volume at that point corresponds to protein concentration of 240 g / l . fig5 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 4 shows the result of protein concentration measurement . example 4 was repeated with the following exception . once the feed pressure exceeded 3 . 5 bar under a constant feed flow rate of 250 lmh , the feed flow rate was set to automatic flow control in a manner to maintain the feed pressure of 3 . 5 bar . the operation was terminated when the feed flow rate decreased to 80 lmh . fig6 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 5 shows the result of protein concentration measurement . example 4 was repeated with the following exception . the flow path was switched into the mode of circulation once the feed pressure exceeded 3 . 5 bar . in the circulation mode , the retentate was circulated through the membrane with the retentate pressure control valve fully open and the permeate closed . after the circulation for 20 minutes under a constant feed flow rate of 80 lmh , ultrafiltration was resumed under the same feed flow rate . fig7 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 6 shows the result of protein concentration measurement . the viscosity of a concentrated pool of a humanized il - 6r monoclonal antibody was measured using a ar1000 rheometer and a cone and plate geometry with 40 mm diameter , 2 degree angle and 53 micrometer truncation ( ta instruments , us ). fig1 shows the plot of viscosity against concentration at temperatures of 15 degrees c ., 25 degrees c . and 35 degrees c . for a scale - up study , the uf / df process was performed at pilot scale . the process was operated in two stages with different sizes of tff system . a larger tff system , using 1 . 20 m 2 sartocon cassettes , was used to process the uf1 / df / uf2 steps . a smaller tff system , using 0 . 30 m 2 sartocon cassettes , was used to process the uf3 / uf4 steps . the entire process was operated at ambient temperatures with the permeate side open - ended . the sartocon cassettes used were 30 kda ( cut - off ) hydrosart membranes ( sartorius , germany ). prior to use , the membrane cassettes were cleaned with 1 mol / l sodium hydroxide and rinsed with purified water . the normalized flux was determined to ensure comparable membrane properties . prior to process , the membrane cassettes were equilibrated with 30 mmol / l histidine buffer ph 5 . 8 in the large system and 20 mmol / l histidine buffer ph 6 . 1 in the small system respectively . the whole process was performed at ambient temperature . in the large system , a purified pool of a humanized anti - human il - 6r monoclonal antibody was loaded with 259 g antibody / m 2 . the feed flow rate was set to a constant rate of 710 lmh . the tmp was controlled at 1 . 0 bar . the purified pool was concentrated to 20 g / l in uf1 step and then diafiltered with 7 diavolumes of 30 mmol / l histidine buffer ph 5 . 8 . after the diafiltration , the pool was further concentrated to 60 g / l in uf2 step . the uf2 pool was circulated through the membrane for 15 minutes under a low differential pressure of 5 psi and then recovered into a separate container . in the small system , the recovered uf2 pool was loaded with 990 g antibody / m 2 . in uf3 step , the feed flow rate was set to a constant rate of 250 lmh . the uf3 step was ended when the retentate volume reached the value that corresponds to protein concentration of 100 g / l . the feed flow rate was set to a constant rate of 80 lmh in uf4 step . the tmp was controlled at 1 . 0 bar until the retentate pressure control valve came to a fully open . the operation was terminated when the retentate volume decreased to the value that corresponds to protein concentration of 240 g / l . it is of significant note that the feed flow rate was manually reduced after 80 minutes since the feed pressure was approaching the upper limit before the retentate volume reached the target volume . the uf4 pool was circulated through the membrane for 15 minutes under a low differential pressure of 15 psi and then recovered into a separate container . the recovered uf4 pool was mixed well by inverting the container . for protein concentration measurement , the recovered uf4 pool was diluted gravimetrically using a density value measured by a density meter densito 30px ( mettler toledo , switzerland ). uv absorbance at 280 nm was measured with a uv / vis spectrophotometer uv - 1700 ( shimadzu , japan ). fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp and retentate volume in uf1 / df / uf2 steps . fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp in uf3 / uf4 steps . comparative example 9 was repeated with the following exceptions . uf3 / 4 steps were performed using 0 . 40 m 2 sartocon cassettes with a hydrosart membrane of 30 kda cut - off ( sartorius , germany ). in the large system , the purified pool was loaded with 274 g antibody / m 2 . in the small system , the recovered uf2 pool was loaded with 804 g antibody / m 2 . the process transitioned from uf3 step to uf4 step when the retentate volume reached the value that corresponds to protein concentration of 220 g / l . fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp and retentate volume in uf1 / df / uf2 steps . fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp and retentate volume in uf3 / uf4 steps . example 10 was repeated with the following exceptions . production scale tff systems were used in a gmp manufacturing facility . uf1 / df / uf2 steps were performed using 35 . 10 m 2 sartocon cassettes and uf3 / 4 steps were using 17 . 55 m 2 sartocon cassettes with a hydrosart membrane of 30 kda cut - off ( sartorius , germany ). in a large system , the purified pool was loaded with 243 g antibody / m 2 . in a small system , the recovered uf2 pool was loaded with 478 g antibody / m 2 . df buffer was changed to 39 mmol / l histidine buffer ph 5 . 8 . the target protein concentration of uf2 pool was increased to 75 g / l . at the end of uf2 step , the feed flow rate was reduced to prevent foaming in the recycle tank . to maximize the recovery , uf2 pool and uf4 pool were recovered with buffer displacement of 70 l and 1 l respectively . the recovered uf4 pool was formulated at 180 g / l in 20 mmol / l histidine buffer ph 6 . 0 , mmol / l methionine , 100 mmol / l arginine and 0 . 2 % polysorbate 80 ( see pct pub . no . wo 2009 / 084659 ). for protein concentration measurement , uf4 pool and recovered uf4 pool were diluted gravimetrically using a density reference . uv absorbance at 280 nm was measured with a uv / vis spectrophotometer uv - 2450 ( shimadzu , japan ). fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp and retentate volume in uf1 / df / uf2 steps . fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp and retentate volume in uf3 / uf4 steps . the monomer contents in the in - process pools were measured using a hplc system alliance 2695 ( waters , us ) and a tsk g3000sw xl column ( tosoh , japan ). table 15 shows the result of sec assay . example 11 was repeated with the following exception . in the large system , the purified pool was loaded with 246 g antibody / m 2 . in the small system , the recovered uf2 pool was loaded with 482 g antibody / m 2 . fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp and retentate volume in uf1 / df / uf2 steps . fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp in uf3 / uf4 steps . the monomer contents in the in - process pools were measured using a hplc system alliance 2695 ( waters , us ) and a tsk g3000sw xl column ( tosoh , japan ). table 19 shows the result of sec assay . an automated lab - scale tff system aktacrossflow ( ge healthcare , us ) was used for ultrafiltration processing . the ultrafiltration process was performed using two 88 cm 2 pellicon 3 cassettes with ultracel membranes of regenerated cellulose , a nominal molecular weight cut - off of 30 kda ( merck millipore , germany ). prior to use , the membrane cassettes were cleaned with 0 . 5 mol / l sodium hydroxide and rinsed with purified water . the normalized flux was determined to ensure comparable membrane properties . the membrane cassettes were equilibrated with 20 mmol / l tris , 150 mmol / l arginine buffer ph 7 . 0 prior to process . ultrafiltration was operated at ambient temperature . the starting material was prepared from a purified pool of a monoclonal anti - nr10 humanized antibody ( fully humanized ns22 antibody prepared according to the method shown in example 12 of wo 2009 / 072604 ) which belongs to the antibody class of igg2 . this is an antibody whose amino acid sequence was modified such that the pi is reduced to 5 . 6 . the purified pool was concentrated up to 20 mg / ml and buffer exchanged into 20 mmol / l tris , 150 mmol / l arginine buffer ph 7 . 0 . the buffer exchanged pool ( df pool ) was loaded with 625 g antibody / m 2 . the feed flow rate was operated at a constant rate of 250 lmh ( l / m 2 / hour ) and then reduced to 80 lmh when the retentate volume reached the value that corresponds to protein concentration of 60 g / l . the tmp was controlled at 1 . 0 bar until the retentate pressure control valve came to a fully open . the ultrafiltration process was operated with the permeate side open - ended . the operation was terminated when the feed pressure exceeded 3 . 5 bar . after ultrafiltration processing , the concentrated solution was circulated with the permeate side closed for 15 minutes under a constant feed flow rate of 10 ml / min and then recovered into a graduated cylinder . the recovered pool was stirred until visually homogeneous . for protein concentration measurement , the recovered pool was diluted gravimetrically using a density value measured by a density meter dma 4500 ( anton paar , austria ). uv absorbance at 280 nm was measured with a uv / vis spectrophotometer du800 ( beckman coulter , us ). fig1 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 20 shows the result of protein concentration measurement . comparative example 13 was repeated with the following exception . the feed flow rate was reduced to 80 lmh when the feed pressure exceeded 3 . 5 bar . the value of the retentate volume at that point corresponds to protein concentration of 145 g / l . fig2 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 21 shows the result of protein concentration measurement . example 14 was repeated with the following exception . once the feed pressure exceeded 3 . 5 bar under a constant feed flow rate of 250 lmh , the feed flow rate was set to automatic flow control in a manner to maintain the feed pressure of 3 . 5 bar . the operation was terminated when the feed flow rate decreased to 80 lmh . fig2 shows the measured process values over time for the feed flow rate , feed pressure , retentate pressure , tmp . table 22 shows the result of protein concentration measurement .

the present invention provides a method for preparing a composition comprising highly concentrated antibodies by ultrafiltration in batch concentration mode having a first constant feed rate step and a second controlled feed rate step .

fig3 shows a portion of a sole member 10 of a sports shoe , e . g . a football shoe or a baseball shoe . the sole member 10 may consist of a thermoplastic synthetic polymer . on ground - contacting face 11 , the sole member 10 is fitted with a plurality of gripping elements for example the football studs 12 shown in fig1 or 13 shown in fig2 or the irons 14 of a baseball shoe as shown in fig4 . sole member 10 comprises a bead 15 beneath gripping elements 12 , 13 or 14 , the bead having a metal insert 16 cast or moulded therein and comprising a flange 17 to ensure secure retention in the sole member 10 . each insert 16 possesses a central smooth bore 18 to hold an attachment element for the gripping element 12 , 13 or 14 . in the embodiments shown in fig1 and 2 , a cylindrical shell 19 slit along one side to form a continuous longitudinal slot 20 serves as the attachment element and in the example given is a standard engineering component . the wall thickness of the collar 19 is shown by the broken lines 21 . th gripping element 12 of fig1 is a stud made for example of cast aluminium alloy . it comprises a blind recess 22 into which the end of the cylindrical shell 19 is pressed . the other end of the shell 19 is pressed into the bore 18 of the insert 16 , but exerts a different gripping friction since the two recesses 18 and 22 are of slightly different diameters . the gripping element 13 is also a stud of a football shoe and consists in this instance of synthetic polymer . the upper portion of the shell 19 in this case is embedded by casting or moulding in situ within the material of the stud 13 . the upper end of the cylindrical shell 19 is opened out at 23 , 24 in order to ensure secure retention in the stud 13 . while , in the embodiments according to fig1 and 2 , the gripping element and the cylindrical shell are separate components , the embodiment according to fig3 - 5 shows the gripping element 14 integrally constructed with the attachment elements , as a single component . a cylindrical shell portion comprises at its lower end two diametrically opposite longitudinal slots 25 and 26 occupying a common plane with the axis and thus serving to hold the component in the insert bore 18 . the gripping element 14 is flattened at the portion 28 which projects beyond the holder sleeve 16 also to occupy a common plane with the axis at 90 ° to the first mentioned such plane and thus serves as an iron for a baseball shoe . in fig1 to 4 , the bore 18 , which receives the shell 19 or 27 is shown as a cylindrical bore of uniform diameter . however , it may be enlarged at its outer end in a lightly conical manner , i . e . tapered in order to facilitate the insertion and fixing of the gripping elements 12 , 13 or 14 . the gripping element can be inserted manually into the bore 18 and thereafter pushed completely into its assembled position by stamping the shoe on the ground . the following features of the invention are to be noted as a comparison with the prior art . studs fixed as shown may be interchanged more rapidly than screw - connected studs . simple resilient compression of the cylindrical shell is sufficient , e . g . by means of a pair of flat pliers . moreover , the fixing system according to the invention does not comprises screw - threads to become blocked or damaged . also twisting the stud or iron in use does not loosen it . since the shell according to the invention is hollow , the total weight of the gripping element is low , and it is simple , quick and economical to produce . it is no longer necessary for the gripping element to have gripping edges ( for example , have a hexagonal cross - section ) and it can therefore be produced in a simple manner . since the gripping element e . g . the stud , need not possess any more gripping edges for assembly , it can have a completely smooth surface so that considerably less dirt can adhere to the gripping element . this in turn reduces the risk off accident or injury . if during use the gripping element should become loose the resilience of the cylindrical shell reasserts itself after relief of the load . moreover , during the next following step by the user the gripping element can be pressed into its operative position again . additionally , a smooth bore can serve as a holder for the attachment element in the sole . not only can such a bore be produced simply and economically , but also it is not sensitive to damage to use . the absence of screw threads also means that excessive tightening during the fixing is avoided with improvement in the quality of the sole assembly . finally , should the cylindrical shell become distorted it can readily be bent back into shape .

a sports shoe has a sole assembly with cylindrical recesses which grip longitudinally slit generally cylindrical shells of slightly larger initial diameter . the projecting ends of these shells can serve as attachments for gripping elements such as studs , attached thereto for example in the same manner . alternatively , these projecting ends can be so shaped as to constitute integral gripping elements .

referring to the figures , wherein like numerals indicate like parts , and in particular to fig1 , a playard 20 is shown with a changing table 30 mounted thereto in accordance with the present invention . the playard 20 can be any conventional playard having at least one upper end rail member 21 and a pair of upper side rail members 23 . in general , the upper side rail members 23 are connected to the upper end rail member 21 directly or via other structural members , such as legs , corner pieces 22 , 24 etc . each of the corner pieces 22 , 24 is provided with a slot 25 to receive the rod - like supporting member 31 of the changing table 30 so as to secure the changing table 30 to the playard 20 . changing table 30 includes front and rear rails 32 , 34 and a pair of side rails 36 , 36 ′ respectively connected to the front and rear rails 32 , 34 to form a platform 38 rectangular or elliptical in shape . the front rail 32 and the pair of side rails 36 - 36 ′ may be separate components or integral formed . the changing table 30 is movable between an operation position and a storage position by the operation of a folding mechanism , which will be described in detail hereinafter . fig2 is an exploded view of the folding mechanism 50 in accordance with a preferred embodiment of the present invention . the folding mechanism 50 primarily comprises a first joint 51 connected to a side rail 36 at one end of the side rail 36 , and a second joint 52 connected to the rear rail 34 at the rear end thereof ( refer to fig1 ). referring to fig2 , the first joint 51 is a substantially hollow cylindrical body with a closed end 511 , and has an opening through which a fastener 59 may pass to connect the first joint 51 to the second joint 52 . a pair of opposed arcuate plates 512 , 514 extend upwardly ( outwardly and toward the left as seen in fig2 ) from the bottom wall of the closed end 511 of the first joint 51 and positioned opposite to each other . the pair of arcuate plate 512 - 514 extend beyond the cylindrical body of the first joint 51 , and the upper arcuate plate 512 bends downwardly , the lower arcuate plate 514 bends upwardly . a stop 513 extends from the upper side wall of the arcuate plate 512 , and is cooperative with and corresponds to the stop 523 to be mentioned hereinafter . the second joint 52 is also a substantially hollow cylindrical body with a closed end . a fastener receiving portion 525 in a form of cylindrical post protrudes from the center of the second joint 52 for receiving the fastener 59 . by inserting the fastener 59 through the opening ( not shown ) of the first joint 51 , and then into the fastener receiving portion 525 of the second joint 52 , the first joint 51 can be pivotally connected with the second joint 52 . furthermore , the first joint 51 includes a receiving portion 515 at one side thereof to receive a portion of the side rail 36 . the receiving portion 515 extends laterally from the one side of the first joint 51 and is formed of substantially hollow , cylindrical body , so that one end of the side rail 36 can be inserted and received therein . the side rail 36 is formed of a substantially hollow , and elongated cylindrical tube and includes a pair of opposed , horizontally extending and rectangular - shaped slots 361 near one end . furthermore , an aperture 362 is provided at a predetermined distance from the slots 361 at the same level with the slots 361 , for the insertion of a pin 53 therethrough and received therein . the slots 361 are configured to receive the fastener 59 . it is appreciated that the elongate slots 361 can also be formed of a channel having an open end and a close end , so that a passage is provided to allow the side rail 36 to move to and fro when a force is applied to the side rails 36 . in assembly , a spring 54 is mounted on the side rail 36 , and inserted along with the side rail 36 into the first joint 51 and received therein . fig3 is a perspective view showing the first joint 51 and second joint 52 are assembled and fig4 is a sectional - view thereof . the fastener 59 is passed through the opening ( not shown ) of the first joint 51 , and then into the fastener receiving portion 525 of the second joint 52 , so that the first joint 51 is pivotally connected to the second joint 52 . when the folding mechanism 50 is assembled , the side rail 36 is accommodated in the side rail receiving portion 515 of the first joint 51 , the pin 53 is abutted against the side wall of the first joint 51 and the second joint 52 , and the spring 54 located between the fastener 59 and the pin 53 . with reference to fig4 , the second joint 52 includes a cavity wall 521 at about half the axial length of the cylindrical body . an arcuate plate 522 substantially in the shape of a semi - circle extends upwardly ( laterally as seen in fig2 ) from the cavity wall 521 , and is spaced from the peripheral wall 526 of the second joint 52 at a predetermined distance . the arcuate plate 522 of the second joint 52 corresponds to the arcuate plates 512 , 514 of the first joint 51 , and thus the arcuate plates may contact with each other . therefore , arcuate plates 512 , 514 may cooperate with arcuate plate 522 , and serve the purpose of guiding when the first joint 51 rotates relative to the second joint 52 . in other words , when the two joints rotate relative to each other , arcuate plates 512 , 514 will rotate along the inner wall of arcuate plate 522 , so that the two joints are in alignment with each other . fig5 is a sectional view taken along line a - a of fig4 , which illustrates the assembly of the first and second joints 51 , 52 . referring to fig4 and 5 , the arcuate plate 522 of the second joint 52 is formed of a stop 523 at one end thereof ( at the upper right corner in fig5 ), while the other end is formed of a stop 524 ( at the lower position in fig5 ). as mentioned above , the fastener receiving portion 525 formed of a substantially hollow , cylindrical body protrudes from the center of the second joint 52 for receiving the fastener 59 . fig5 also shows the state of the folding mechanism 50 in which the changing table 30 is in the operation position . in this state , the pin 53 is blocked by the stop 523 of the second joint 52 to prevent the side rails 36 ( and hence the changing table 30 ) from being lifting , so that the changing table 30 is kept in the operation position . besides , the stop 513 of the first joint 51 and the stop 523 of the second joint 52 engage with each other , and thus the first joint 51 cannot rotate with respect to the second joint 52 , thereby preventing the changing table 30 from being pressed downwards , and this is the bearing point for the load of the changing table 30 . at this state , the user or caretaker can change a child &# 39 ; s diaper or perform other baby caretaking tasks on the changing table 30 at ease . referring to fig6 , after the user or caretaker has finished changing a child &# 39 ; s diaper or performing baby caretaking tasks , to move the changing table 30 to its storage position , the user only has to press the front rail 32 by one hand . as the side rail 36 is forced , to move inwards ( leftwards in fig5 ) in the folding mechanism 50 , so that the spring 54 is compressed . as the side rail 36 has a horizontally extending slot 361 at one end , the side rail 36 may move with respect to the first joint 51 . the pin 53 secured in the opening 362 of the side rail 36 also moves inwards ( leftwards ) simultaneously , causing the pin 53 to remove away from the stop 523 of the second joint 52 . subsequently , the side rails 36 can be lifted along in the direction as shown by the arrow in fig7 and the changing table is further to be in the folding / storage position . referring to fig8 , when the changing table 30 is swung to move to the storage position by the rotation movement of the side rail 36 , one end of the side rail 36 will move outwardly ( substantially downwards as seen in fig8 ) in the folding mechanism 50 to restore to its original position due to the restoring force of the compression spring 45 . the pin 53 mounted within the opening 362 of the side rail 36 moves outwards ( downwards ) simultaneously , resulting in the engagement of the pin 53 with the stop 524 of the second joint 52 , to thereby locking the changing table 30 in the storage position . when it is desired to swing the changing table 30 back to its operation position , the user only has to press the front rail 32 by one hand to subject a force on the side rail 36 , causing the pin 53 to disengage from the stop 524 of the second joint 52 . in this manner , the changing table 30 can be raised along with the side rails 36 and rotated to return to its operation position . fig9 is an exploded view of the folding mechanism 60 in accordance with an alternate embodiment of the present invention . this folding mechanism 60 is somewhat similar to the folding mechanism 50 of the first embodiment , and primarily comprises a first joint 61 and a second joint 62 . the first joint 61 is similar to the first joint 51 of the folding mechanism 50 in the aforementioned embodiment in structure , and is formed of a substantially hollow and cylindrical body , and is attached to a second joint 62 by a fastener 69 . the first joint 61 also has a pair of opposed arcuate plates 612 , 614 , in which the upper arcuate plate 612 curves downwardly , and the lower arcuate plate 614 curves upwardly . a stop 613 extends from the upper side wall of the arcuate plate 612 , and abutted against a stop 623 to be mentioned hereinafter . the second joint 62 is also formed of a substantially cylindrical body closed at one end and opened at the other end . the second joint 62 includes a cavity wall 621 at about half the axial length of the cylindrical body . an arcuate plate 622 substantially in the shape of a circle extends upwardly from the cavity wall 621 , and is spaced from the peripheral wall 626 of the second joint 62 at a predetermined distance . the arcuate plate 622 of the second joint 62 corresponds to the arcuate plates 612 , 614 of the first joint 61 . therefore , arcuate plates 612 , 614 may cooperate with arcuate plate 622 , and serve the purpose of guiding when the first joint 61 rotates relative to the second joint 62 . in other words , when the two joints rotate relative to each other , arcuate plates 612 , 614 will rotate along the inner wall of arcuate plate 622 , so that the two joints are in alignment with each other . a stop 623 extends from the upper side wall of the arcuate plate 622 , and is abutted against the stop 613 to be mentioned hereinafter . a fastener receiving portion 625 protrudes from the center of the cavity wall 621 of the second joint 62 . the fastener receiving portion 625 includes an opening 6253 in the center thereof to receive a fastener 69 . the fastener 69 is passed through the opening ( not shown ) of the first joint 61 , and then into the opening 6253 of the fastener receiving portion 625 of the second joint 62 , so that the first joint 61 is pivotally connected to the second joint 62 . the fastener receiving portion 625 is formed of a substantially cylindrical body , but chamfered at the right lower corner . referring to fig9 and 11 , it can be seen that the fastener receiving portion 625 includes a horizontally face 6251 and a vertically face 6252 , which may serve as stops ( to be described hereinafter ). the first joint 61 is similar to the first joint 51 of the previous embodiment in that it also has a side rail receiving portion 615 to accommodate one end of the side rail 36 ′. the side rail 36 ′ is also formed of a substantially hollow tube , and includes a pair of opposed , horizontally extending slots 365 . furthermore , an aperture 362 is provided at a predetermined distance from the slots 365 at the same level with the slots 365 , for the insertion of a pin 63 therethrough and received therein . the slots 365 are configured to receive the fastener 69 . it is appreciated that the slots 365 can also be formed of a channel having an open end and a close end , so that a passage is provided to allow the side rail 36 ′ to move to and fro when a force is applied to the side rails 36 ′. in assembly , the spring 64 is mounted on the side rail 36 ′, and inserted along with the side rail 36 ′ into the first joint 61 and received therein . besides , the spring 64 is located between the pin 63 and the peripheral wall of the first joint 61 . fig1 and 11 illustrate respectively the perspective view and sectional - view of the first joint 61 and second joint 62 after assembly . the assembly is achieved by inserting the fastener 69 through an opening ( not shown ) of the first joint 61 , and then into opening 6253 of the fastener receiving portion 625 of the second joint 62 , so that the first joint 61 is pivotally connected to the second joint 62 . in the assembled state , the side rail 36 ′ is accommodated in the side rail receiving portion 615 of the first joint 61 , in which the slot 365 thereof receives the fastener 69 which is then secured in the fastener receiving portion 625 of the second joint 62 . fig1 is a sectional view taken along line a - a of fig1 , which illustrates in detail the assembly of the first and second joints 61 , 62 . fig1 also shows the state of the folding mechanism 60 for rotatably folding / unfolding the changing table in which the changing table 30 is in the operation position . in this state , the pin 63 is blocked by the horizontally face 6251 of the fastener receiving portion 625 of the second joint 62 to prevent the side rails 36 ′ ( and hence the changing table 30 ) from being lifting , so that the changing table 30 is kept in the operation position . besides , the stop 613 of the first joint 61 and the stop 623 of the second joint 62 engage with each other , and thus prevents the changing table 30 from being pressed downwards . at this state , the user or caretaker can change a child &# 39 ; s diaper or perform other baby caretaking tasks on the changing table 30 at ease . referring to fig1 , after the user or caretaker has finished changing a child &# 39 ; s diaper or performing baby caretaking tasks , to move the changing table 30 to its storage position ( as shown in fig1 ), the user only has to pull the front rail 32 by one hand . as the side rail 36 ′ is forced to move outwards ( rightwards in fig1 ) in the folding mechanism 60 , so that the spring 64 is compressed . as the side rail 36 ′ has a slot 365 at one end , the side rail 36 ′ may move with respect to the fastener 69 outwards ( rightwards ) until the left side wall of the slot 365 urges against the fastener 69 . the pin 63 secured in the opening 366 of the side rail 36 ′ also moves outwards ( rightwards ) simultaneously , causing the pin 63 to remove away from the horizontally face 6151 of the fastening receiving portion 625 of the second joint 62 . subsequently , the side rails 36 ′ can be lifted along the direction as shown by the arrow in fig1 and the changing table 30 is further to be in the folding / storage position . referring to fig1 , when the changing table 30 is swung to move to the storage position by the rotation movement of the side rail 36 , 36 ′, one end of the side rail will move inwardly ( substantially upwards as seen in fig1 ) in the folding mechanism 60 to restore to its original position due to the restoring force of the spring 64 . the pin 63 secured in the opening 366 of the side rail moves inwards ( upwards ) simultaneously , resulting in the engagement of the pin 63 with the vertically face 6252 of the fastening receiving portion 625 of the second joint 62 , to thereby locking the changing table 30 even when it is in the storage position . when it is desired to swing the changing table 30 back to its operation position , the user only has to pull the front rail 32 by one hand to subject a force on the side rails 36 , 36 ′ causing the pin 63 to disengage from the vertically face 6252 of the fastening receiving portion 625 of the second joint 62 . in this manner , the changing table 30 can be raised along with the side rails 36 , 36 ′ and rotated to return to its operation position . furthermore , the above embodiments can be modified in a number of ways . for example , the front end of the rail 36 does not necessarily to have a slot or opening , nor have to connect to the fastener 69 , and the spring 64 does not necessarily have to be located between the pin 63 and the peripheral wall . such modified embodiment includes a spring to connect the pin 63 and fastener 69 instead . in the general state , the rail 36 moves inwardly due to the spring , and when it is intended to fold the changing table , it is only necessary to pull the rail 36 outwards . although the foregoing has been described in terms of presently preferred and alternate embodiments , those skilled in the art will recognize that the invention is not limited to the embodiments described . the apparatus of the present invention can be practiced with modification and alteration within the spirit and scope of the appended claims . the description is thus to be regarded as illustrative instead of limiting the present invention .

this invention relates to a folding mechanism for a playard , which comprises first and second joints substantially cylindrical in shape . the joints have arcuate plates and stops that cooperative with each other to effect the rotation between the joints , so that the changing table can be moved between an operation position and a storage position . this invention may avoid accidental collapse of the changing table , and enable the users to conveniently fold / unfold the changing table single handed .

the following detailed description of heart valve prostheses and systems and methods of delivering heart valve prostheses refers to the accompanying figures that illustrate exemplary embodiments . other embodiments are possible . modifications can be made to the embodiments described herein without departing from the spirit and scope of the present invention . therefore , the following detailed description is not meant to be limiting . further , it would be apparent that the systems and methods described below can be implemented in many different embodiments of hardware . any actual hardware described is not meant to be limiting . the operation and behavior of the systems and methods presented are described with the understanding that modifications and variations of the embodiments are possible given the level of detail presented . for example , while the description provided is directed to heart valve prostheses and systems and methods of delivering heart valve prostheses , the systems and methods described herein should not be limited to delivery of heart valve prostheses . one of skill in the art would readily understand how to incorporate the features and structures described herein into delivery systems and methods for other types of prostheses . for example , the systems and methods described herein can be used for other types of procedures , such as delivery of stents , valves , or other prostheses to a variety of areas in the body . fig1 is a schematic illustration of a fully - assembled valve prosthesis 10 in accordance with an embodiment of the present invention . typically , valve prosthesis 10 comprises exactly three commissural posts 11 , arranged circumferentially around a central longitudinal axis 13 of valve prosthesis 10 . valve prosthesis 10 can also be provided with two commissure posts , e . g ., for placement in a native mitral valve annulus , or could be provided with more than three commissural posts . valve prosthesis 10 further comprises a prosthetic valve 104 coupled to commissural posts 11 . valve 104 typically comprises a pliant material 105 . pliant material 105 can include , e . g ., animal pericardial tissue or artificial tissue . pliant material 105 of valve 104 is configured to collapse inwardly ( i . e ., towards central longitudinal axis 13 ) during diastole , in order to inhibit retrograde blood flow , and to open outwardly during systole , to allow blood flow through the prosthesis . for some applications , valve prosthesis 10 comprises a collapsible inner support structure 12 that serves as a proximal fixation member , and a collapsible outer support structure 14 that serves as a distal fixation member . the commissural posts 11 are shaped so as define therethrough respective openings 16 that serve as radiographic identifiers during an implantation procedure , as described hereinbelow . although fig1 illustrates openings 16 on each of the three commissural posts , it is understood that openings 16 may be provided only on one or two of the commissural posts . the openings may assume any convenient shape , for example , slits , as shown in fig1 and 2a - b . in some embodiments , the openings are shaped to be reflection - asymmetric along respective post axes generally parallel with central longitudinal axis 13 of prosthesis 10 when the posts assume their collapsed position . for some applications , in addition to serving as the radiographic identifiers , openings 16 are used for coupling valve 104 to support structures 12 and 14 . although pliant material 105 of valve 104 at least partially fills openings 16 , the pliant material is substantially more radiolucent than commissural posts 11 , and thus does not reduce the radiographic visibility of the radiographic identifiers . one or more of posts 11 can be formed without openings 16 , and the one or more posts can instead comprise radiographic identifiers comprising a material having a radiopacity different from ( greater or less than ) the radiopacity of posts 11 , such as gold or tantalum . valve prosthesis 10 is configured to be placed in a native diseased valve of a subject , such as a native stenotic aortic or pulmonary valve , using a minimally - invasive approach , such as a beating heart transapical procedure , or a retrograde transaortic procedure . as used in the present application , including in the claims , a “ native valve ” is to be understood as including : ( a ) native valves that include their native leaflets , and ( b ) native valves in which one or more of the native leaflets have been surgically excised , are otherwise absent , or are damaged or stenosed . reference is made to fig2 a , which is a schematic illustration of collapsible outer support structure 14 prior to assembly with inner support structure 12 , in accordance with an embodiment of the present invention . in this embodiment , outer support structure 14 is shaped so as to define a plurality of distal diverging strut supports 20 , from which a plurality of proximal engagement arms 22 extend radially outward in a proximal direction . engagement arms 22 are typically configured to be at least partially disposed within aortic sinuses of the subject , and , for some applications , to engage and / or rest against floors of the aortic sinuses , and to apply an axial force directed toward a left ventricle of the subject . outer support structure 14 comprises a suitable material that allows mechanical deformations associated with crimping and expansion of valve prosthesis 10 , such as , but not limited to , nitinol or a stainless steel alloy ( e . g ., aisi 316 ). reference is made to fig2 b , which is a schematic illustration of collapsible inner support structure 12 prior to assembly with outer support structure 14 , in accordance with an embodiment of the present invention . for some applications , inner support structure 12 is shaped so as to define a plurality of distal diverging inner struts 30 , and a bulging proximal skirt 32 that extends from the struts . a proximal portion 34 of proximal skirt 32 is configured to engage a left ventricular outflow tract ( lvot ) of the subject and / or periannular tissue at the top of the left ventricle . a relatively narrow throat section 36 of proximal skirt 32 is configured to be positioned at a valvular annulus of the subject , and to engage the native valve leaflets . inner support structure 12 comprises , for example , nitinol , a stainless steel alloy , another metal , or another biocompatible material . inner support structure 12 also includes one or more fixation hooks 38 extending from the proximal end of inner support structure 12 . preferably , inner support structure 12 includes three fixation hooks 38 . however , it is understood that fewer or greater than three fixation hooks 38 can be provided with inner support structure 12 . fixation hooks 38 extend from the proximal end of inner support structure 12 and include eyelets at their proximal end . fixation hooks 38 , which are optional , can be formed in various configurations other than that shown . for example , fixation hooks 38 can be j - shaped hooks or eyelets 38 , and can take on any number of sizes or shapes while remaining compatible with the delivery methods and systems described herein . reference is again made to fig1 . inner and outer support structures 12 and 14 are assembled together by placing outer support structure 14 over inner support structure 12 , such that outer strut supports 20 are aligned with , and typically support , respective inner struts 30 , and engagement arms 22 are placed over a portion of proximal skirt 32 . inner struts 30 and outer strut supports 20 together define commissural posts 11 . although exactly three commissural posts 11 are shown in the figures , for some applications valve prosthesis 10 comprises fewer or more posts 11 , such as two posts 11 , or four or more posts 11 . typically , valve prosthesis 10 further comprises a graft covering 106 which is coupled to proximal skirt 32 , such as by sewing the covering within the skirt ( configuration shown in fig1 ) or around the skirt ( configuration not shown ). inner support structure 12 thus defines a central structured body for flow passage that proximally terminates in a flared inlet ( proximal skirt 32 ) that is configured to be seated within an lvot immediately below an aortic annulus / aortic valve . for some applications , graft covering 106 is coupled at one or more sites to pliant material 105 . in an embodiment of the present invention , a portion of valve prosthesis 10 other than commissural posts 11 , e . g ., proximal skirt 32 , is shaped so as to define openings 16 that serve as radiographic identifiers . alternatively or additionally , the commissural posts or the selected other portion of the prosthesis comprise radiographic identifiers comprising a material having a radiopacity different from ( greater or less than ) the radiopacity of other portions of the prosthesis . for some applications , the radiographic identifiers are radially aligned with commissural posts 11 . additional features of valve prostheses suitable for use in conjunction with the present invention are described in u . s . patent publication nos . 2008 / 0071361 , 2008 / 0071366 , 2008 / 0071368 , 2008 / 0071369 , 2010 / 0131054 , 2010 / 0137979 , and 2010 / 0262231 , each of which is incorporated , in its entirety by reference herein . fig3 is a schematic illustration of a subject 200 undergoing a transapical or percutaneous valve replacement procedure in accordance with an embodiment of the present invention . a fluoroscopy system 210 comprises a fluoroscopy source 213 , a fluoroscopy detector 212 , and a monitor 214 . fluoroscopy source 213 is positioned over subject 200 so as to obtain a left anterior oblique ( lao ) projection . preferably , the lao projection is at an angle between 30 and 45 degrees , such as between 30 and 40 degrees , with a 30 - degree cranial tilt ( for orthogonal projection of the annulus ). typically , imaging is enhanced using an ultrasound probe 216 . it is understood that alternate fluoroscopy systems can be used in conjunction with the delivery systems and methods described herein . fig4 - 6 show exemplary transverse plane mris of an aortic root . right coronary sinus r is generally positioned on the anterior side of the annulus . left coronary sinus l and non - coronary sinus n are also shown . fig4 - 6 further illustrate a commissure r / l between the right and left coronary sinuses r and l , a commissure n / r between the non - coronary sinus n and the right coronary sinus r , and a commissure n / l between the non - coronary sinus n and the left coronary sinus l . commissure r / l is best shown in a lao projection , as illustrated in fig4 . commissure n / r is best shown in a right anterior oblique ( rao ) projection , as illustrated in fig5 . commissure n / l is best shown in an anteroposterior ( ap ) projection , as illustrated in fig6 . commissures r / l , n / r , and n / l serve as clear anatomical landmarks during the replacement procedure , enabling the physician to readily ascertain the layout of the aortic root . fig7 is a schematic view of valve prosthesis 10 in a collapsed , position in a catheter 300 inserted transapically and extending through a native annulus . devices and methods for introducing a delivery system into a heart through the apex area of the heart are described by u . s . patent application publication 2010 / 0121436 , which is incorporated by reference herein in its entirely . in this embodiment , openings 16 in commissure posts 11 are shaped as slits . as noted above , openings 16 are clearly visible by fluoroscopy . valve prosthesis 10 is contained within sleeve 314 at its distal end . valve prosthesis 10 is held at its proximal end by valve retainer 308 , which is connected to inner delivery member 306 . preferably , fixation hooks 38 on valve prosthesis 10 are engaged with valve retainer 308 . an auxiliary catheter 310 is introduced into the aortic root . auxiliary catheter 310 is preferably a pigtail catheter for introducing dyes into the aortic root area to facilitate imaging of the aortic root area . when the valve prosthesis 10 has been inserted , to the position illustrated in fig7 , the distal ends of engagement arms 22 are positioned downstream of the tips 320 of native valve leaflets 312 . because fig7 is a two - dimensional view , only two native valve leaflets 312 are illustrated . it is also understood that the implantation devices and methods described herein can be used to implant prostheses in a native annulus that does not have three leaflets . for example , the devices and methods described herein can be used to implant prostheses in a mitral or pulmonary valve annulus . in addition , it is understood that the implantation devices and methods described herein can be used to implant prostheses in a native annulus from which one or more native leaflets have already been removed , or in which one or more of the native leaflets has been damaged . after valve prosthesis 10 has been inserted through a native annulus , the valve prosthesis is rotationally aligned with the native commissures and sinuses of the native valve . preferably , an rao projection is used for the rotational alignment procedure . once an rao projection has been established , initial alignment proceeds generally in the manner described in u . s . patent application publication 2010 / 0121436 , which is incorporated , by reference herein in its entirely . specifically , the physician selects one of the commissural posts 11 having a radiographic identifier , and attempts to rotationally align the selected post with one of the native commissures , such as the commissure between the left and right coronary sinuses . because the radiographic image is two - dimensional , all of the posts appear in the image as though they are in the same plane . the physician thus cannot distinguish between two possible rotational positions of the posts : ( 1 ) the desired rotational position , in which the selected post faces the desired native commissure , and ( 2 ) a rotational position 180 degrees from the desired rotational position , in which the selected , post faces the side of the native valve opposite the desired native commissure . for example , if the desired native commissure is the commissure between the left and right coronary sinuses , in position ( 2 ) the post is rotationally aligned with the non - coronary sinus , although this undesired rotation is not apparent in the radiographic image . to ascertain whether the posts are in rotational position ( 1 ) or ( 2 ), the physician slightly rotates the valve prosthesis . if the radiographic identifier on the selected post appears to move in the radiographic image in the same direction as the rotation , the selected post is correctly rotationally aligned in the desired position ( 1 ). if , on the other hand , the radiographic identifier appears to move in the direction opposite the direction of rotation , the selected post is incorrectly rotationally aligned in position ( 2 ). to correct the alignment , the physician may rotate the valve prosthesis approximately 60 degrees in either direction , thereby ensuring that one of the two other posts is now rotationally aligned in position ( 1 ). after rotational alignment has been achieved , the physician verifies that the distal end 316 of the valve retainer 308 is still approximately at the level of the curl of the pigtail catheter 310 , and that proximal ends 318 of the engagement arms 22 are still positioned downstream of the tips 320 of the native valve leaflets 312 . once this position has been confirmed , sleeve 314 is moved in a distal direction , i . e ., away from valve retainer 308 , to release engagement arms 22 . engagement arms 22 are configured to radially expand when released from sleeve 314 , as shown in fig8 . inner delivery member 306 , and thereby valve retainer 308 , are then retracted in a proximal direction ( i . e ., generally towards the apex of the heart ) in order to position engagement arms 22 in their respective sinuses , as illustrated in fig9 . although engagement arms 22 are shown in fig9 and 10 as not fully extending to the base of the sinuses , it is understood that the arms can be formed in a variety of shapes and lengths , and may contact the base of the sinuses and / or contact the native leaflets 312 when implanted in a native annulus . u . s . patent publication nos . 2008 / 0071361 , 2008 / 0071366 , 2008 / 0071368 , 2008 / 0071369 , 2010 / 0131054 , 2010 / 0137979 , and 2010 / 0262231 , each of which is incorporated , in its entirety by reference herein , disclose heart valve prostheses having engagement arms suitable for use with the present invention . at this stage , commissural posts 11 can be released from sleeve 314 by further moving sleeve 314 in a distal direction relative to valve retainer 308 . delivery catheter 300 is then moved proximally with respect to valve retainer 308 , thereby releasing the proximal skirt 32 of valve prosthesis 10 . once released , proximal skirt 32 contacts the upper ventricle of the heart below the sinuses . proximal skirt can contact the underside of native leaflets 312 in addition to or instead of contacting the upper ventricle . sleeve 314 , valve retainer 308 , and inner delivery member 306 can then be withdrawn from the heart . fig1 is a profile view of a valve retainer 408 according to another embodiment of the present invention . unlike valve retainer 308 , which , as shown in fig7 - 9 , is substantially radially symmetrical , valve retainer 408 is formed with a rotational identifier on one side thereof . as shown in fig1 - 11 , the rotational identifier can be a physical identifier such as a notch 422 formed on one side of valve retainer 408 . as illustrated in fig1 - 11 , notch 422 preferably extends from the proximal end 424 of valve retainer 408 towards distal end 416 , and extends approximately 180 degrees around the outer surface of valve retainer 408 . however , it is understood that notch 422 can be formed in a variety of shapes and locations consistent with the present invention . for example , notch 422 can be a narrow notch on one side of valve retainer 408 , i . e ., a notch that extends only a small fraction of the length of valve retainer 408 . notch 422 can extend to the proximal end 424 of valve retainer or can be formed only in the middle region of valve retainer 408 . it is also understood that other physical markings can be used consistent with the present invention . the term notch is used herein to refer to any of a variety of notch , slit , groove , or other physical alteration that is visible during a fluoroscopy procedure and that provides information on the rotational alignment of the valve retainer . for example , a hole formed in the valve retainer can serve as the physical alteration . as shown in fig1 , valve retainer 408 also includes three slots 426 at its distal end 416 . slots 426 are configured to receive fixation hooks 38 of valve prosthesis 10 . fixation hooks 38 serve to secure valve prosthesis 10 to valve retainer 408 when fixation hooks 38 are placed within slots 426 and valve retainer 408 is placed within a catheter , such as delivery catheter 300 . as shown in fig1 , slots 426 are evenly positioned around the perimeter of the distal end 416 of valve retainer 408 . although three evenly spaced slots 426 are shown in fig1 , it is understood that fewer or more than three slots can be provided with retainer 408 , and that the slots can be spaced unevenly . fig1 and 13 illustrate valve prosthesis 10 , in its crimped configuration , connected to valve retainer 408 . in fig1 , notch 422 is positioned to the right . it should be noted that the circumferential locations of the commissure posts 11 of valve prosthesis 10 relative to the fixation hooks 38 of valve prosthesis 10 are known due to the geometry of valve prosthesis 10 . specifically , commissure posts 11 and fixation hooks 38 are formed on valve prosthesis 10 such that when fixation hooks 38 are inserted , into slots 426 of valve retainer 408 , the circumferential position of each commissure post 11 is known based on the geometry of valve prosthesis 10 and valve retainer 408 . thus , when valve prosthesis 10 is loaded into valve retainer 108 and viewed in a two - dimensional profile view , such as during an angiography procedure , and , when notch 422 is visible on the right side of valve retainer 408 in the profile view , as shown in fig1 , a user can identify that the central commissure post 428 is rotationally positioned on the anterior side of valve prosthesis 10 . this is because the location of the central commissure post 428 relative to fixation hooks 38 is known , and because the location of central commissure post 428 relative to slots 426 is known because the fixation hooks 38 are secured within slots 426 . as noted above , radiographic images are two - dimensional . because of this , absent the additional information provided by the position relationship between notch 422 and central commissure post 428 , a user would be unable to distinguish between two possible rotational positions of the posts : ( 1 ) the desired rotational position , in which the selected central commissure post 428 faces the desired native commissure , and ( 2 ) a rotational position 180 degrees from the desired rotational position , in which the selected central commissure post 428 faces the side of the native valve opposite the desired native commissure . although a particular commissure post 11 has been identified as a central commissure post 428 for purposes of describing fig1 , it is understood that any of the three commissure posts 11 can serve as a central commissure post during an implantation procedure . in any particular implantation procedure , the commissure post 11 that serves as the central commissure post is determined by aligning the opening 16 of one of the commissure posts 11 with the tip of the center of coaptation 440 ( see fig1 ) of the native valve leaflets 312 . it is understood that the center of coaptation 440 refers to the point where the tips of the native valve leaflets 312 meet when the native valve is in a closed position . once the opening 16 of one of the commissure posts 11 is aligned , with the center of coaptation in a chosen radiographic view , for example , using an rao projection , that particular commissure post 11 serves as central commissure post 428 for that procedure . it is also understood that more or fewer than three commissure posts , fixation hooks 38 , and slots 426 can be utilized in the delivery devices described , herein while maintaining the advantages of the present invention . valve retainers 408 and the delivery devices and methods described herein utilizing the described valve retainers 408 can be used to implant valve prostheses that are structurally different from the valve prostheses described , herein . for example , the delivery devices and , methods described herein can be utilized to delivery valve prostheses with no engagement arms . it is understood that openings 16 may be provided only on one or two of the commissural posts . the openings may assume any convenient , shape , for example , slits , as shown in fig1 - 14 . in some embodiments , the openings are shaped , to be reflection - asymmetric along respective post axes generally parallel with central longitudinal axis 13 of prosthesis 10 when the posts assume their collapsed position . for some applications , in addition to serving as the radiographic identifiers , openings 16 are used for coupling valve 104 to support structures 12 and 14 . although pliant material of a valve at least partially fills openings 16 , the material is substantially more radiolucent than commissural posts 11 , and thus does not reduce the radiographic visibility of the radiographic identifiers . as detailed above , one or more of posts 11 can be formed without openings 16 , and the one or more posts can instead comprise radiographic identifiers comprising a material having a radiopacity different from ( greater or less than ) the radiopacity of posts 11 , such as gold or tantalum . in the profile view of loaded valve prosthesis 10 shown in fig1 , notch 422 of valve retainer 408 is visible on the left , i . e ., rotated approximately 180 degrees from the position shown in fig1 . when valve prosthesis 10 is loaded into valve retainer 408 and viewed in a two - dimensional profile view , such as during an radiography procedure , and when notch 422 is visible on the left side of valve retainer 408 in the profile view , as shown in fig1 , a user can identify that the central commissure post 428 is rotationally positioned on the posterior side of valve prosthesis 10 . this is because the location of the central commissure post 428 relative to fixation hooks 38 is known , and because the location of central commissure post 428 relative to slots 426 is known because the fixation hooks 38 are secured within slots 426 . it is understood that the rotational orientation of the identified central commissure post 428 with respect to notch 422 can be reversed , that is , notch 422 can be formed in valve retainer 408 such that when notch 422 is visible on the right side of an angiography projection , central commissure post 428 is posterior instead of anterior . in this configuration , when notch 422 is visible on the left side of an angiography projection , central commissure post 428 is anterior instead of posterior . fig1 is a schematic view of valve prosthesis 10 in a collapsed position in a catheter 300 inserted transapically and extending through a native annulus . devices and methods for introducing a delivery system into a heart through the apex area of the heart are described by u . s . patent application publication 2010 / 0121436 , which is incorporated by reference herein in its entirely . in this embodiment , openings 16 in commissure posts 11 are shaped as slits . as noted above , openings 16 are clearly visible by fluoroscopy . valve prosthesis 10 is contained within sleeve 314 at its distal end . valve prosthesis 10 is held at its proximal end by valve retainer 408 which is connected to inner delivery member 306 . valve retainer 408 is provided with notch 422 , which is visible on the right side of valve retainer 408 . preferably , fixation hooks 38 on valve prosthesis 10 are engaged with valve retainer 308 . an auxiliary catheter 310 is introduced into the aortic root . auxiliary catheter 310 is preferably a pigtail catheter for introducing dyes into the aortic root area to facilitate imaging of the aortic root area . when the valve prosthesis 10 has been inserted to the position illustrated in fig1 , the distal ends of engagement arms 22 are positioned downstream of the tips 320 of native valve leaflets 312 , and therefore downstream of the center of coaptation 440 . because fig1 is a two - dimensional view , only two native valve leaflets 312 are illustrated . it is understood that the implantation devices and methods described herein can be used to implant prostheses in a native annulus that does not have three leaflets . for example , the devices and methods described herein can be used to implant prostheses in a mitral or pulmonary valve annulus . in addition , it is understood that the implantation devices and methods described herein can be used to implant prostheses in a native annulus from which one or more native leaflets have already been removed , or in which one or more of the native leaflets has been damaged . after valve prosthesis 10 has been inserted through a native annulus , the valve prosthesis is rotationally aligned with the native commissures and sinuses of the native valve . preferably , an rao projection is used for the rotational alignment procedure . this rotational alignment is achieved by lining up the opening 16 of one of the commissure posts 11 with the center of coaptation 440 of the native valve leaflets 312 using an rao projection to visualize the aortic root area ( this post is marked as central commissure post 428 in fig1 for description purposes ). commissure n / r is the native commissure visible in an rao projection , as shown in fig5 , and it is positioned on the anterior side of the heart . thus , a user can properly align the commissure posts 11 of valve prosthesis 10 by first aligning an opening 16 of a commissure post 11 ( thereafter designated central commissure post 428 ) with the native commissure n / r and verifying that notch 422 of valve retainer 408 is visible on the right side of the angiographic projection . as described with reference to fig1 , a user can identify that the central commissure post 428 is rotationally positioned on the anterior side of valve prosthesis 10 when notch 422 is visible to the right side of the profile view of valve retainer 408 . because native commissure n / r is anterior in an rao projection , rotationally aligning central commissure post 428 to the anterior position ensures that commissure 428 is aligned with native commissure n / r . the remaining commissure posts 11 are evenly distributed around the circumference of valve prosthesis 10 to approximately match the normal spacing of the native commissures a heart such that properly rotationally aligning one commissure post 11 is sufficient to ensure that the remaining two commissure posts 11 are also properly aligned with a respective one of the remaining two native commissures r / l or nit . alternately , an lao or rao projection can be used in conjunction with the implantation devices and methods disclosed herein . native commissure r / l is visible when an lao projection is utilized , as shown in fig4 . therefore , when an lao projection is used , a central commissure 428 is identified by alignment with the native commissure r / l . because native commissure r / l is anterior in an lao projection , central commissure 428 is properly rotationally positioned when notch 422 of valve retainer 408 is visible on the right side of valve retainer 408 . native commissure n / l is visible when an ap projection is utilized , as shown in fig6 . therefore , when an ap projection is used , a central commissure 428 is identified by alignment with the native commissure n / l . because native commissure n / l is posterior in an ap projection , central commissure 428 is properly rotationally positioned when notch 422 of valve retainer 408 is visible on the left side of valve retainer 408 . in other embodiments , the rotational identifier of valve retainer 408 can include one or more radiopaque identifiers applied on the outer surface of valve retainer 408 or formed integrally with valve retainer 408 . when a radiopaque identifier is applied to the outer surface , valve retainer 408 may or not be formed with a notch or other physical rotational identifier . for example , instead of physically notching valve retainer 408 , a radiopaque identifier can be applied on one side of valve retainer 408 . the radiopaque identifier can , for example , be a vertical or a dot that contrasts with the rest of valve retainer 408 during radiographic imaging . the radiopaque identifier can extend approximately 180 degrees around the outer surface of valve retainer 408 . the radiopaque identifier can be positioned on valve retainer 408 in a known location relative to a commissure post of a valve prosthesis when the valve prosthesis is secured to valve retainer 408 for an implantation procedure . if the radiopaque identifier is visible when the commissure post is aligned with a native commissure , the user knows that the central commissure post is on the anterior side of the valve prosthesis . if the radiopaque identifier is not visible when the commissure post is aligned with a native commissure , the user knows that the central commissure post is on the posterior side of the valve prosthesis . as with the positioning of the notch 422 described above , the relation between the location of the radiopaque identifier and the anterior / posterior position of the commissure post can be reversed . that is , the radiopaque identifier can be positioned on valve retainer 408 such that if the radiopaque identifier is not visible when the commissure post is aligned with a native commissure , the user knows that the central commissure post is on the anterior side of the valve prosthesis . the foregoing description of the invention has been presented for purposes of illustration and description . it is not intended to be exhaustive or to limit the invention to the precise form disclosed . other modifications and variations may be possible in light of the above teachings . the embodiments and examples were chosen and described in order to best explain the principles of the invention and its practical application and to thereby enable others skilled in the art to best utilize the invention in various embodiments and various modifications as are suited to the particular use contemplated . it is intended that the appended claims be construed to include other alternative embodiments of the invention .

a valve retainer is connected to an elongate delivery member . the valve retainer is configured to releasably secure a prosthesis to the delivery member during delivery to a target site in a body . the valve retainer includes a rotational identifier that identifies the rotational orientation of the valve retainer when the valve retainer is positioned proximate to the target site . a heart valve prosthesis can include a commissural post that has a predetermined rotational position relative to the rotational identifier , such that the heart valve prosthesis can be rotationally aligned with the native commissures of the native valve by rotating the delivery member and the valve retainer until the commissural post is aligned with a native valve commissure and the rotational identifier is visible .

the present invention is based upon the finding that triflusal and its metabolite , htb , are potent inhibitors of the activation of the transcription factor nf - κb . as mentioned above , nf - κb is an ubiquitous transcription factor that acts by binding to dna , activating in this manner the expression of various genes , many of them involved in the immune and inflammatory response . the present invention shows that triflusal and htb inhibit the activation of nf - κb induced by various agents such as tnf - α immune complexes and lps in several types of cells , such as human umbilical vein endothelial cells ( huvec ), macrophages and monocytes . moreover , it is also shown that triflusal and htb inhibit the expression of several proteins in whose transcriptional regulation nf - κb is involved , such as for example vcam - 1 , inos , cox - 2 , mcp - 1 and tnf - α . therefore , triflusal and htb are useful as therapeutic or preventive agents in those pathological situations where nf - κb and / or the proteins whose expression is regulated by this transcription factor are involved . triflusal and htb can be generically represented by means of formula i : it is an object of the present invention to provide the use of a compound of formula i for the manufacture of a medicament useful for inhibiting the activation of the transcription factor nf - κb . the use of a pharmaceutically acceptable salt of a compound of formula i or of a prodrug thereof are also encompassed within the scope of the present invention . another object of the present invention is to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of genes which are dependent on and / or regulated by , at least partially , the transcription factor nf - κb . in a preferred embodiment , the gene encodes il - 1β , il - 2 , il - 6 , tnf - α , gm - csf , il - 8 , rantes , mip - 1α , mcp - 1 , eotaxin , inos , cox - 2 , 5 - lo , cpla 2 , icam - 1 , vcam - 1 , e - selectin , il - 2 receptor or t - cell receptor , and more preferably encodes vcam - 1 , inos , cox - 2 , mcp - 1 or tnf - α . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of disorders associated with the activation of the transcription factor nf - κb and / or the expression of genes which are dependent on this transcription factor . in a preferred embodiment , the disorder is inflammation ; asthma ; adult respiratory distress syndrome ( ards ); immunoinflammatory and autoimmune diseases such as rheumatoid arthritis and other arthritic conditions , multiple sclerosis , psoriasis , inflammatory bowel disease , lupus and glomerulonephritis ; arthrosis ; septic shock ; atherosclerosis ; cancer ; osteoporosis ; preterm labour ; transplant rejection ; neurodegenerative diseases such as dementia , including alzheimer &# 39 ; s disease , parkinson &# 39 ; s disease and amyotrophic lateral sclerosis ; and viral infections . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of cox - 2 . another object of the present invention is to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cox - 2 . in a preferred embodiment , the disease mediated by cox - 2 is rheumatoid arthritis and other arthritic conditions , arthrosis , preterm labour , dementia or cancer . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of vcam - 1 . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by vcam - 1 . in a preferred embodiment , the disease mediated by vcam - 1 is atherosclerosis , rheumatoid arthritis , lupus , multiple sclerosis , inflammatory bowel disease , asthma , allergic rhinitis and tumor metastasis . another object of the present invention is to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of inos . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by inos . in a preferred embodiment , the disease mediated by inos is inflammation , septic shock , inflammatory bowel disease and neurodegenerative diseases . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of tnf - α . another object of the present invention is to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by tnf - α . in a preferred embodiment , the disease mediated by tnf - α is rheumatoid arthritis , rheumatoid spondylitis , gouty arthritis and other arthritic conditions , arthrosis , sepsis , septic shock , endotoxic shock , toxic shock syndrome , to adult respiratory distress syndrome , cerebral malaria , chronic pulmonary inflammatory disease , silicosis , pulmonary sarcoidosis , pulmonary fibrosis , hepatitis , osteoporosis and other bone resorption diseases , reperfusion injury , transplant rejection , multiple sclerosis , lupus , fever and myalgias due to infections , cachexia , acquired immune deficiency syndrome ( aids ), inflammatory bowel disease and pyresis . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of mcp - 1 . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by mcp - 1 . in a preferred embodiment , the disease mediated by mcp - 1 is atherosclerosis , glomermlonephritis , rheumatoid arthritis , pulmonary fibrosis , restenosis , asthma , psoriasis , inflammatory bowel disease , multiple sclerosis and transplant rejection . it is also an object of the present invention to provide the use of a compound of formula ii or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of neurodegenerative diseases , particularly dementia , parkinson &# 39 ; s disease and amyotrophic lateral sclerosis . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of immunoinflammatory and autoimmune diseases , preferably rheumatoid arthritis and other arthritic conditions , multiple sclerosis , psoriasis , inflammatory bowel disease , lupus and glomerulonephritis . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of arthrosis . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of cancer . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of atherosclerosis . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of al medicament for the prevention of preterm labour . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of inflammation . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of asthma or adult respiratory distress syndrome . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of septic shock . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of osteoporosis . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of viral infections . it is also an object of the present invention to provide the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of transplant rejection . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the activation of the transcription factor nf - κb . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of genes which are dependent on and / or regulated by , at least partially , the transcription factor nf - κb . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of disorders associated with the activation of the transcription factor nf - κb and / or the expression of genes which are dependent on this transcription factor . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of cox - 2 . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by cox - 2 , preferably rheumatoid arthritis and other arthritic conditions , arthrosis , preterm labour , dementia or cancer . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of vcam - 1 . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by vcam - 1 , preferably atherosclerosis , rheumatoid arthritis , lupus , multiple sclerosis , inflammatory bowel disease , asthma , allergic rhinitis and tumor metastasis . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of inos . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by inos , preferably inflammation , septic shock , inflammatory bowel disease and neurodegenerative diseases . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of tnf - α . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by tnf - α , preferably rheumatoid arthritis , rheumatoid spondylftis , gouty arthritis and other arthritic conditions , arthrosis , sepsis , septic shock , endotoxic shock , toxic shock syndrome , adult respiratory distress syndrome , cerebral malaria , chronic pulmonary inflammatory disease , silicosis , pulmonary sarcoidosis , pulmonary fibrosis , hepatitis , osteoporosis and other bone resorption diseases , reperfusion injury , transplant rejection , multiple sclerosis , lupus , fever , and myalgias due to infections , cachexia , acquired immune deficiency syndrome ( aids ), inflammatory bowel disease and pyresis . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of mcp - 1 . the present invention also provides the use of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by mcp - 1 , preferably atherosclerosis , glomerulonephritis , rheumatoid arthritis , pulmonary fibrosis , restenosis , asthma , psoriasis , inflammatory bowel disease , multiple sclerosis and transplant rejection . the present invention also provides a method for inhibiting the activation of the transcription factor nf - κb in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the mammal is preferably a human being . the present invention also provides a method for inhibiting the expression of genes which are dependent on and / or regulated by , at least partially , the transcription factor nf - κb in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for the treatment or prevention of disorders associated with the activation of the transcription factor nf - κb and / or the expression of genes which are dependent on this transcription factor in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for inhibiting the expression of cox - 2 in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for the treatment or prevention of diseases mediated by cox - 2 , preferably rheumatoid arthritis and other arthritic conditions , arthrosis , preterm labour , dementia or cancer , in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for inhibiting the expression of vcam - 1 in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for the treatment or prevention of diseases mediated by vcam - 1 , preferably atherosclerosis , rheumatoid arthritis , lupus , multiple sclerosis , inflammatory bowel disease , asthma , allergic rhinitis and tumor metastasis , in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for inhibiting the expression of inos in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for the treatment or prevention of diseases mediated by inos , preferably inflammation , septic shock , inflammatory bowel disease and neurodegenerative diseases , in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for inhibiting the expression of tnf - α in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for the treatment or prevention of diseases mediated by tnf - α , preferably rheumatoid arthritis , rheumatoid spondylitis , gouty arthritis and other arthritic conditions , arthrosis , sepsis , septic shock , endotoxic shock , toxic shock syndrome , adult respiratory distress syndrome , cerebral malaria , chronic pulmonary inflammatory disease , silicosis , pulmonary sarcoidosis , pulmonary fibrosis , hepatitis , osteoporosis and other bone resorption diseases , reperfusion injury , transplant rejection , multiple sclerosis , lupus , fever and myalgias due to infections , cachexia , acquired immune deficiency syndrome ( aids ), inflammatory bowel disease and pyresis , in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for inhibiting the expression of mcp - 1 in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . the present invention also provides a method for the treatment or prevention of diseases mediated by mcp - 1 , preferably atherosclerosis , glomerulonephritis , rheumatoid arthritis , pulmonary fibrosis , restenosis , asthma , psoriasis , inflammatory bowel disease , multiple sclerosis and transplant rejection , in a mammal in need thereof , which comprises administering to said mammal a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . it is also encompassed within the scope of the present invention a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of disorders associated with the activation of the transcription factor nf - κb and / or the expression of genes which are dependent on this transcription factor , and more preferably for the treatment or prevention of inflammation ; asthma ; adult respiratory distress syndrome ( ards ); immunoinflammatory and autoimmune diseases such as rheumatoid arthritis and other arthritic conditions , multiple sclerosis , psoriasis , inflammatory bowel disease , lupus and glbmerulonephritis ; arthrosis ; septic shock ; atherosclerosis ; cancer ; osteoporosis ; preterm labour ; transplant rejection ; neurodegenerative diseases such as dementia , including alzheimer &# 39 ; s disease , parkinson &# 39 ; s disease and amyotrophic lateral sclerosis ; and viral infections . the pharmaceutically acceptable salts of a compound of formula i include any of the salts commonly used in pharmaceutical chemistry , such as for example the salts with inorganic cations such as sodium , potassium , calcium , magnesium , lithium , aluminium , zinc , etc as well as the salts formed with ammonia and other pharmaceutically acceptable amines . throughout the present description , the term prodrug of a compound of formula i means any precursor compound of a compound of formula i that is capable of being metabolized and release in vivo a compound of formula i , that is triflusal or htb . by nf - κb it is to be understood any member of the family of proteins known by this name . by gene which is dependent on and / or regulated by , at least partially , the transcription factor nf - κb it is to be understood any gene having in its promoter region one or more nf - κb binding sites . the list of genes regulated by nf - κb mentioned above under the heading “ description of the prior art ” is cited only as an example and it is not to be understood as limiting the scope of the invention in any way . by disorder associated with the activation of the transcription factor nf - κb and / or the expression of genes which are dependent on this transcription factor it is to be understood any disease or pathological state where the activation of nf - κb and / or the proteins whose expression ( i . e . the expression of the gene that encodes them ) is regulated by this transcription factor are involved , at least partially . the lists of these diseases mentioned above are cited only as examples and thus are not to be understood as limiting the scope of the present invention in any case . the term neurodegenerative diseases includes , among others , dementias , such as alzheimer &# 39 ; s disease ; diseases involving movement dysfunction , such as parkinson &# 39 ; s disease ; progressive ataxias ; and amyotrophies of neuronal origin , such as amyotrophic lateral sclerosis . by the term dementia it is to be understood any pathology characterized by an impairment of the cognitive functions , such as for example alzheimer &# 39 ; s disease , post - traumatic dementia or dementia following infection as well as mixed situations . the term inflammatory bowel disease includes both ulcerative colitis and crohn &# 39 ; s disease as well as any other type of variant of inflammatory bowel disease . the term transplant rejection refers both to tissue transplant rejection , such as for example graft - versus - host disease , as well as organ transplant rejection . processes for preparing triflusal or htb are disclosed in the above - mentioned ( u . s . pat . no . 4 , 096 , 252 ). as mentioned above , the compounds of formula i inhibit the activation of the transcription factor nf - κb and therefore can be used to inhibit said activation in mammals , preferably in human beings . the dose of a compound of formula i necessary to modulate the activation of the transcription factor nf - κb , or any other use herein described , will depend upon the disorder to be treated , the severity of the symptoms , the age and body weight of the patient as well as the chosen route of administration . any person skilled in the art will be able to readily determine the appropriate doses depending on these factors without having to incur in undue experimentation . in human therapy , doses will generally be in the range between about 30 mg and about 3000 mg daily of a compound of formula i which can be administered in one or several dosage units . depending on the particular disease to be treated and the patient &# 39 ; s situation , however , doses outside this range might be needed , which , as mentioned above , may be readily determined by those skilled in the art without requiring undue experimentation . the compounds of formula i can be administered in the form of any pharmaceutical formulation , the nature of which will depend , as it is well known , upon the route of administration and the nature of the disease to be treated . these pharmaceutical compositions can be prepared by conventional methods , using compatible , pharmaceutically - acceptable excipients or vehicles . examples of such compositions include capsules , tablets , syrups , powders and granulates for the preparation of extemporaneous solutions , injectable preparations , etc . a preferred route of administration , for the compounds of formula i is by the oral route . for example , they can be , administered as hard gelatine capsules containing for example 50 , 100 , 200 , 300 , 400 or 500 mg of a compound of formula i or a pharmaceutically acceptable salt or a prodrug thereof . fig1 shows the inhibitory effect of triflusal and htb on the activation of the transcription factor nf - κb induced by tnf - α in human umbilical vein endothelial cell ( huvec ) cultures . fig2 shows the inhibitory effect of triflusal and htb on the activation of the transcription factor nf - κb induced by immune complexes ( ic ) in rat macrophages . fig3 ( a and b ) shows the inhibitory effect of htb on the activation of the transcription factor nf - κb induced by bacterial lipopolysaccharide ( lps ) in human peripheral blood mononuclear cells . fig4 shows the inhibitory effect of triflusal and htb on the expression of vcam - 1 mrna induced by tnf - α in huvec . fig5 shows the inhibitory effect of htb ( 5a ) and triflusal ( 5b ) on the production of nitrite induced by immune complexes in rat macrophages . fig6 shows the effect of triflusal and htb on lps - induced cox - 2 in human mononuclear cells : ( 6a ) inhibitory effect of triflusal on cox - 2 expression ; ( 6b ) inhibitory effect of htb on cox - 2 expression ; ( 6c ) inhibition of prostaglandin e 2 ( pge 2 ) production elicited by triflusal ; ( 6d ) inhibition of pge 2 production elicited by htb . fig7 shows the inhibitory effect of triflusal administered orally on cox - 2 expression ( 7a ) and on pge 2 production ( 7b ) in a carrageenan - induced inflammation model in the rat . fig8 shows the inhibitory effect of htb on mcp - 1 expression induced by immune complexes ( ic ) in human monocytic cell line thp - 1 . fig9 shows the inhibitory effect of triflusal and htb on tnf - α expression induced by bacterial lipopolysaccharide ( lps ) in human peripheral blood mononuclear cells . the following examples illustrate the utility of triflusal and htb as inhibitors of the activation of nf - κb and its dependent genes . in any case are they to be construed as limiting the scope of the present invention . the following abreviations have been used in the examples : human umbilical vein endothelial cells ( huvec ) were obtained by the procedure of dejana et al . ( j . cell biol 1987 , 104 ( 5 ), 1403 - 1411 ) by treatment of the umbilical vein with . 0 . 2 % collagenase p from c . histolyticum ( boehnnger manheim gmbh , manheim , germany ) for 20 minutes at 37 ° c . next , cells were cultured in m199 medium ( flow lab , herts , u . k .) containing 100 u / ml penicillin , 100 μg / ml streptomycin , 2 . 5 μg / ml amphotercin b and 20 % fetal calf serum . primary cultures were plated in 25 cm 2 plastic flasks . after 24 hours cells were washed to remove those cells which had not adhered to the flask surface . then , the same medium containing 10 % fetal calf serum , 50 μg / ml endothelial cell growth supplement factor and 100 μg / ml heparn was added . after culturing for 5 - 7 days , cells reached confluence and were detached from the flask surface with 0 . 05 % trypsin and 0 . 02 % edta ( flow lab ). the reaction was inhibited by the addition of fetal calf serum , and then cells were washed and plated again in culture medium . cells were grown to confluence in gelatin - coated flasks . cells used for the experiments were from passages 2 - 7 . b . treatment of huvec cells with tnf - α electrophoretic mobility shift assay ( emsa ) in this experiment , huvec cells were preincubated with triflusal and htb , at concentrations in both cases of 2 and 4 mm . then these cells were stimulated with 100 u / ml tnf - α ( genzyme diagnostics , cambridge , mass . usa ) for 90 minutes . next , huvec cells were washed with cold - hypotonic lysis buffer ( 10 mm hepes - koh , ph 7 . 9 , 10 mm kcl , 1 . 5 mm mgcl 2 , 0 . 5 mm dtt ( 1 , 4 - dithiothreitol ), 0 . 5 mm phenylmethylsulfonyl fluoride , 5 μg / ml aprotinin , 5 μg / ml leupeptine and 0 . 6 % nonidet p - 40 ) and were kept on ice for 10 minutes . then , they were vortexed vigorously for 10 seconds . unbroken cells were eliminated by centrifugation at 1 , 000 × g for 10 minutes . the nuclei were collected by centrifugation at 15 , 000 × g for 1 minute in a microcentrifuge . the nuclear pellet was resuspended in a high salt extraction buffer ( 25 % glycerol and 0 . 5 m kcl ). the nuclear extract was obtained by centrifugation for 30 minutes at 105 , 000 × g in a optima ti ultracentrifuge ( beckmann ) using a tla 100 . 2 rotor . a 22 bp double - stranded oligonucleotide containing nf - κb sequences was used as probe . this probe was end - labeled with ( γ - 32 p ) atp using t4 polynucleotide kinase and was purified by minicolumn chromatography . the κb sequence used was , 5 ′- agttcaggggmattcccaggc - 3 ′ and the complementary 5 ′- gcctgggmattcccctgmct - 3 ′. 10 μg of the purified nuclear protein was incubated for 20 minutes on ice with the radiolabeled oligonucleotide probe ( 2 - 6 × 10 4 cpm ) in 25 μl of reaction buffer consisting of 2 μg poly ( di - dc ), 10 mm tris hcl ph 7 . 5 , 100 mm nacl , 1 mm edta , 1 mm dtt , 8 % ficoll and 4 % glycerol . nucleoprotein - oligonucleotide complexes were resolved by electrophoresis in a nondenaturing polyacrylamide gel in tris - borate / edta buffer for 3 hours at 175 v and at 4 ° c . the gel was dried and autoradiographed with an intensifying screen at − 80 ° c . and for 2 to 12 hours . the specificity of the dna ( probe )- protein complex was confirmed by competition of the 32 p - labeled probe with a 300 - fold excess of unlabeled probe , which showed no presence of the labeled probe in the dna - protein complex ( data not shown ). the lane labeled as control corresponds to cells incubated for 90 minutes in the absence of tnf - α . the results of this experiment are shown in fig1 . both triflusal and htb concentration - dependently inhibit the activation of nf - κb induced by tnf - α in huvec . inhibition of the activation of nf - κb induced by immune complexes ( ic ) in rat macrophages rat peritoneal cavity cells were extracted and resuspended in dmem culture medium in the absence of serum previously supplemented with 100 u / ml penicillin , 100 μg / ml streptomycin , 50 μg / ml gentamycin , 2 mm glutamine and 0 . 5 mm l - arginine . cells were incubated for 2 hours in culture plates at 37 ° c . and those which had not adhered to the plates were removed by washing three times with the same fresh medium . more than 95 % of the adherent cells were macrophages , as assessed by their ability to engulf zymosan particles and nonspecific esterase staining . macrophages were kept at 37 ° c . under a 5 % co 2 atmosphere and two hours later non - adherent cells were removed and the peritoneal macrophages adhered to the plates were incubated with 100 μg / ml igg / ovalbumin immune complexes prepared from ; rabbit antiserum for 2 hours in the presence or absence ( vehicle ) of triflusal or htb ( 4 mm , both ). after incubation , macrophages were washed twice with pbs and the degree of activation ( binding to dna ) of the transcription factor nf - κb was determined using the emsa assay , described in detail in example 1 . fig2 shows the results obtained with triflusal and htb in this experiment . a representative example of the obtained in two independent experiments is shown . both triflusal and htb markedly inhibit the activation of nf - κb induced by immune complexes in rat macrophages . inhibition of the activation of nf - κb induced by bacterial lipopolysaccharide ( lps ) in human peripheral blood mononuclear cells ( pbmc ) mononuclear cells ( pbmc ) were obtained from blood of healthy donors from the hospital de sant pau ( barcelona ) who had not taken any antiinflammatory drug during a period of not less than 2 weeks before blood extraction . starting from a volume of about 80 ml of heparinized human blood ( 10 u / ml ), this was diluted ( 1 : 1 ) with pbs ( ph 7 . 4 ; dulbecco ) without calcium , magnesium nor sodium bicarbonate . 15 ml of ficoll solution ( d = 1 . 077 at 20 ° c . ; biochrom kg ) were placed in 50 - ml falcon tubes . to this solution a volume of about 25 ml per tube of the blood previously diluted with pbs was carefully added and the tubes were then centrifuged at 1 , 200 g for 20 minutes . mononuclear cells concentrate on a whitish interphase between the plasma and the ficoll solution . this interphase was collected with a pasteur pipette and was diluted 1 : 1 with pbs . it was then centrifuged at 300 g for 10 min . the resulting pellet was resuspended in 50 ml pbs and was again centrifuged at 200 g for 10 min , in order to remove platelet contamination . finally , the resulting pellet was resuspended in 20 ml of rpmi - 1640 culture medium ( gibcobrl ) supplemented with 10 % fetal calf serum . isolated pbmcs were analyzed by standard wright - giemsa staining to examine if the cells displayed the morphological features of viable mononuclear cells and determine the different types of cells isolated ( an average of 90 % lymphocytes and 10 % monocytes ). prior to the various treatments , cell viability was determined by the trypan blue exclusion assay . cells were diluted at a concentration of 2 . 5 million / ml with rpmi medium containing 10 % fetal calf serum and were incubated ( 37 ° c ., 5 % co 2 ) 1 hour in 6 - well plates ( 2 ml / well , 5 million pbmc ) without adding any drug ( control ) or adding htb ( 1 - 3 mm ). next , cells were incubated for further 10 minutes in the presence of 10 μg / ml e . coli lipopolysaccharide ( lps , 026 : b6 serotype ; sigma ). after incubation , a sample ( 100 μl ) was taken in order to carry out a cell count as well as cell viability controls by measuring the ability of mitochondrial dehydrogenases to convert the soluble tetrazolium salt , mtt the insoluble product formazan ( mtt assay ). cells were also incubated with htb ( 3 mm ) in the absence of lps . in all cases , cell viability was equal to or higher than 95 %. after incubation , pbmcs were washed twice with pbs and the degree of activation ( binding to dna ) of the transcription factor nf - κb was determined using the emsa assay , described in detail in example 1 . fig3 shows the results obtained with htb in this experiment . a representative example of the obtained in two independent experiments is shown . htb markedly inhibits the activation of nf - κb induced by lps in human pbmcs . primers used for the detection of vcam - 1 mrna by rt - pcr were designed from the human gene sequence ( embugenbank ac : m30257 ), using the wisconsin package version 9 . 1 , genetics computer group ( gcg ), madison , wis . their sequences were 5 ′- tgtcactgtmgctgcmg - 3 ′ and 5 ′- ttccagcctggttaattc - 3 ′, corresponding to nucleotides 1090 - 1108 and 1589 - 1572 ( l . osbom et al ., cell 1989 , 59 ( 6 ), 1203 - 1211 ). total rna was extracted from cultured cells using the guanidium isothiocyanate method ( p . chomczynski and n . sacchi , anal biochem . 1987 , 162 ( 1 ), 156 - 159 ). cdna first strand was synthesized from total rna by reverse transcription reaction . the reaction was carried out using 0 . 2 mg / ml total rna ( preheated at 68 ° c . for 10 minutes ), 2 . 5 μl h 2 o , 20 u of rnaase inhibitor , 4 μl buffer 5 ×, 2 μl 0 . 1 m dtt , 4 μl 2 . 5 mm dntp , 1 μl 0 . 1 mm hexanucleotides and 200 u of moloney - murine leukemia virus reverse transcriptase . the reaction was carried out at 37 ° c ., for 60 minutes in a volume of 20 μl . vcam - 1 cdna was amplified by pcr in a reaction mixture containing 2 μl dna , 10 μl h 2 o , 2 . 5 μl buffer 10 ×, 0 . 75 μl 50 mm mgcl 2 , 1 . 0 μl 2 . 5 mm dntp , 1 . 25 μl of each primer ( sense and antisense ) and 0 . 25 μl taq dna polymerase 5 u / ml . a negative control using water was included in each pcr reaction . the amplification conditions were as follows : an initial cycle of denaturation at 94 ° c . for 5 minutes , and then 30 cycles comprising : denaturation at 94 ° c . for 30 seconds , primer annealing at 59 ° c . for 30 seconds , and extension at 72 ° c . for 1 minute ; and finally a cycle of extension at 72 ° c . for 7 minutes . the relative amounts of each amplified cdna were determined by measuring the density of the bands stained with ethidium bromide using the gel doc documentation system and the molecular analyst software from bio - rad laboratories , hercules , calif . the expression of β - actin was used as control for assaying the expression of a constitutively expressed gene . specifically , the effect of triflusal ( 4 mm ) and htb ( 4 mm ) on the regulation of the expression of vcam - 1 mrna induced by tnf - α ( 100 u / ml ) in huvec was studied . thus , cells were incubated in the presence or absence of tnf - α and with triflusal and htb . after one hour , total rna was extracted and subjected to the reverse transcription reaction . then , an amplification reaction by pcr was carried out with the primers designed for the sequences of the molecules vcam - 1 and human β - actin . the pcr products were separated by electrophoresis in a 1 . 8 % agarose gel and were later quantified . the molecular weight of the amplification products was determined from the electrophoretic migration of dna size standards . the results obtained in this experiment are shown in fig4 . both triflusal and htb at a concentration of 4 mm completely inhibit the expression of vcam - 1 mrna induced by tnf - α in huvec . the absence of effect on the expression of β - actin mrna shows the selectivity of the tested compounds for the transcription factor nf - κb . inhibition of the expression of inos in rat peritoneal macrophages induced by immune complexes rat peritoneal cells were obtained and resuspended in dmem culture medium in the absence of serum and supplemented with antibiotics . macrophages were isolated by their ability to adhere to culture plates following incubation for 2 hours at 37 ° c . non - adherent cells were removed and it was then checked that more than 95 % of the adherent cells were macrophages , as assessed by their ability to engulf zymosan particles and nonspecific esterase staining . culture plates were kept at 37 ° c . under a 5 % co 2 atmosphere , and the peritoneal macrophages adhered to the plates were incubated with 100 μg / ml igg / ovalbumin immune complexes in the presence or absence ( control ) of triflusal or htb ( 0 . 1 - 20 mm , both ). drugs were added 10 minutes before the addition of igg / ovalbumin and the production of no was determined as the nitrite present after 24 hours . inos expression was indirectly measured as the production of no . no released from macrophage cultures was determined indirectly by the accumulation of nitrites . to one milliliter of cell culture ( 0 . 5 million cells in medium without phenol red ) was added 100 μl of a solution of 1 mm sulphanilic acid and 100 mm hcl ( final concentration ). after incubation for five minutes , the medium was aspirated and centrifuged in an eppendorf microcentrfuge . 50 μl naphthylenediamine ( 1 mm final concentration ) were added and after 15 minutes of incubation the absorbance of the sample was measured at 548 nm and was compared with a nano 2 standard . the production of no was expressed as nmol no 2 − / mg protein . the results obtained in this experiment are shown in fig5 a for htb and in fig5 b for triflusal . points represent the mean ± standard error of the mean ( sem ) from 7 to 9 experiments , each performed in duplicate . ic 50 values calculated for triflusal and htb from the corresponding graphs were 1 . 13 ± 0 . 12 and 1 . 84 ± 0 . 34 mm , respectively . similar results were obtained when macrophages were incubated with lps instead of immune complexes . inhibition of cox - 2 expression induced by bacterial lipopolysaccharide ( lps ) in human peripheral blood mononuclear cells ( pbmc ). mononuclear cells ( pbmc ) were obtained from blood of healthy donors from the hospital de sant pau , ( barcelona ) who had not taken any antiinflammatory drug during a period of not less than 2 weeks before blood extraction . starting from a volume of about 80 ml of heparinized human blood ( 10 u / ml ), this was diluted ( 1 : 1 ) with pbs ( ph 7 . 4 ; dulbecco ) without calcium , magnesium nor sodium bicarbonate . 15 ml of ficoll solution ( d = 1 . 077 at 20 ° c . ; biochrom kg ) were placed in 50 - ml falcon tubes . to this solution a volume of about 25 ml per tube of the blood previously diluted with pbs was carefully added and the tubes were then centrifuged at 1 , 200 g for 20 minutes . mononudear cells concentrate on a whitish interphase between the plasma and the ficoll solution . this interphase was collected with a pasteur pipette and was diluted 1 : 1 with pbs . it was then centrifuged at 300 g , 10 min . the resulting pellet was resuspended in 50 ml pbs and was again centrifuged at 200 g for 10 min in order to remove platelet contamination . finally , the resulting pellet was resuspended in 20 ml rpmi - 1640 culture medium ( gibcobrl ) supplemented with 10 % fetal calf serum . isolated pbmcs were analyzed by standard wright - giemsa staining to examine if the cells displayed the morphological features of viable mononuclear cells and determine the different types of cells isolated ( an average of 90 % lymphocytes and 10 % monocytes ). cells were diluted at a concentration of 2 . 5 million / ml with rpmi medium containing 10 % fetal calf serum and were incubated ( 37 ° c ., 5 % co 2 ) 19 hours in 6 - well plates ( 2 ml / well , 5 million pbmc ). incubations were carried out in the presence of 10 μg / ml e . coli lipopolysaccharide ( lps , 026 : b6 serotype ; sigma ) without adding any drug ( control ) or adding triflusal or htb ( 0 . 1 - 5 mm ). prior to incubations , cell viability controls were performed using the trypan blue exclusion assay . after incubation , a sample ( 100 μl ) was taken in order to perform a cell count as well as cell viability controls by measuring the ability of mitochondrial dehydrogenases to convert the soluble tetrazolium salt , mtt , into the insoluble product formazan ( mtt assay ). cells were also incubated with htb and triflusal at the same concentrations but without adding lps . in all cases , cell viability was equal to or higher than 95 % both at the beginning of the experiment and after 19 hours incubation . after incubation , cells were centrifuged for 5 min at 1 , 000 g . the supernatant was collected and stored at − 70 ° c . for later determination of pge 2 levels as a measure of cox - 2 activity , and the pelleted cells were resuspended in 5 ml pbs and centrifuged again ( 5 min , 1 , 000 g ). the resulting pellet was resuspended in 50 μl cell lysis buffer ( pbs with 1 % nonidet - 40 and 1 mm edta ) and incubated in ice for 15 minutes . the resulting mixture was centrifuged at 20 , 000 g for 15 min and the supernatant was collected . 5 μl of the supernatant were taken and diluted 1 / 20 with pbs in order to determine the concentration of protein using the bca protein assay reagent ( pierce ). the remaining supernatant was then mixed in a 1 : 1 ratio with electrophoresis gel loading buffer ( 50 mm tris ; sds , 2 % w / v ; glycerol , 10 % v / v ; β - mercaptoethanol , 50 μl / ml and bromophenol blue , 2 mg / ml ) and boiled for 5 min . samples were centrifuged at 10 , 000 g for 2 min and then subjected to discontinuous electrophoresis in sds - polyacrylamide gel ( 4 % stacking gel / 7 . 5 % separating gel ) at a variable intensity and a fixed voltage of 200v , until the front was only a few millimeters from the gel end ( about 1 hour ). proteins were transferred to a nitrocellulose membrane , using a cooled te 22 mighty small transfer unit ( hoefer ) system , at a voltage of 100 v for 2 hours . when the transfer was finished , membranes were stirred overnight at 4 ° c . in blocking buffer ( 1 : 4 dried fat - free milk in tbs containing 0 . 1 % tween 20 ). blocked membranes were incubated 1 hour under stirring with a goat polyclonal antibody raised against human cox - 2 ( santa cruz biotechnology , inc . ), and after washing were incubated 1 hour with a horseradish peroxidase - labeled antibody ( rabbit anti - goat igg - horseradish peroxidase , immunopure , pierce ) and the antibody bound to the protein was visualized by chemoluminescence ( ecl , amershan ). finally , the supernatants from each experiment that had been stored at − 70 ° c . were defrozen and the amount of pge 2 in solution was determined using specific elisa kits ( amershan - biotrak rpn22 ). the results obtained in this experiment are shown in fig6 . the results shown correspond to two representative immunoblots from the obtained in five independent experiments ( fig6 a : triflusal ; fig6 b : htb ) and the mean ± sem of the quantification of pge 2 in the supernatants of the cultures corresponding to said experiments ( fig6 c : triflusal ; fig6 d : htb ). both triflusal and htb concentration - dependently inhibit cox - 2 expression as well as pge 2 production . lewis rats ( 175 - 200 g ) were used in this study . rats were randomly distributed in groups of 5 animals . an , air pouch was produced by subcutaneous injection of 20 ml of sterile air into the intrascapular area of animals in each group . every two days , 10 ml of air were injected again into the cavity to keep the space open . seven days after the first injection of air , 2 ml of a 1 % carrageenan solution was injected into the air pouch in all groups to produce an inflammatory reaction . test compound was administered orally 30 min before carrageenan administration . the animals were killed 6 h later and the volume of exudate was measured . the type and number of cells present were determined using standard wright - giemsa staining and a coulter counter cell counter , respectively . the exudate was centrifuged at 400 g at 4 ° c . for 7 min and pge 2 concentration was determined by enzyme - immunoassay ( amershan - biotrak rpn222 ). the cell pellet was resuspended in 2 ml cold 0 . 85 % nacl . to eliminate red cell contamination , cells were subjected to a selective cellular lysis by the addition of 6 ml cold water for 20 seconds . the isotonicity of the cellular suspension was restored by the addition of 2 ml 3 . 5 % nacl . finally , the cellular suspension was centrifuged under the same conditions mentioned above and the pellet was resuspended in lysis buffer at a density of 2 × 10 8 cells for immunoblot assays ( see example 6 ). the results are shown in fig7 . fig7 a corresponds to a representative immunoblot and fig7 b shows the mean ± sem of the quantification of pge 2 in the rat exudate ( n = 4 ). the oral administration of triflusal ( 3 - 30 mg / kg ) dose - dependently inhibits cox - 2 expression in the cells present in the exudate as well as pge 2 production . inhibition of the expression of monocyte chemotactic protein - 1 ( mcp - 1 ) induced by immune complexes in the human monocytic cell line thp - 1 human monocytic thp - 1 cells ( 3 × 10 6 cells / well ) were cultured in plastic dishes in rpmi 1640 culture medium supplemented with penicillin ( 100 u / ml ), streptomycin ( 100 μg / ml ), gentamycin ( 50 μg / ml ), glutamine ( 2 mm ) and 2 % heat - inactivated fetal calf serum . cells were cultured in the presence of htb ( 2 and 4 mm ) or vehicle and were activated with 100 μg / ml immune complex aggregates ( a - igg ). the production of soluble mcp - 1 was determined by elisa using a commercially available kit ( r & amp ; d systems inc . ; minneapolis , minn .). the detection limit of the system was 5 pg / ml . the results obtained in this assay are shown in fig8 . htb , both at a concentration of 4 mm , and 2 mm , causes a complete inhibition of mcp - 1 expression induced by immune complexes in thp - 1 . inhibition of the expression of tnf - α induced by bacterial lipopolysaccharide ( lps ) in human peripheral blood mononuclear cells ( pbmc ) mononuclear cells ( pbmc ) were obtained from blood of healthy donors from the hospital de sant pau ( barcelona ) following the procedure described in example 3 . cells were diluted at a concentration of 2 million / ml in rpmi medium supplemented with 10 % fetal calf serum and were incubated ( 37 ° c ., 5 % co 2 ) with triflusal , htb or vehicle ( dmso ) in the presence of 10 μg / ml e . coli lipopolysaccharide ( lps , 026 : b6 serotype ; sigma ), for 19 hours . the cell suspension was then centrifuged at 2 , 000 g for 10 minutes at 4 ° c ., and the resulting supernatant was stored at − 70 ° c . for later analysis . the cytokine content was determined by enzymatic immunoassay , after 1 / 100 dilution of the samples . the results obtained with triflusal and htb in this experiment are shown in fig9 . both triflusal and htb ( 1 and 0 . 3 mm ) almost completely inhibit the lps - induced tnf - α production . the results are expressed as the mean ± standard error of the mean from 2 - 5 separate experiments , each performed in triplicate . inhibition of the activation of nf - κb in post natal long evans black - hooded rat glial cells this study was carried out using post - natal ( p9 ) long evans black - hooded rats . each group consisted of 6 animals subjected to an experimental lesion , plus two control animals of the same age . the experimental lesion was induced by intracortical injection ( sensorimotor area ) of n - methyl - d - aspartate ( nmda ), which causes a marked local neuronal degeneration . triflusal ( 30 mg / kg ) was administered orally in three doses ( from day 7 to 9 ) every 24 hours . glial reactivity was induced by nmda injection at postnatal day 9 , one hour after the last triflusal dose . at different times ( 2 - 24 h ) after this last dose , animals were killed , brains were extracted and cut in a cryostat and sections were processed using immunocytochemical and histochemical techniques to determine nf - κb activation in microglia and astroglia using double staining : nf - κb - lectin and nf - κb - gfpa . in parallel , slices were cut on a vibratome to determine the degree of microglial and astroglial reactivity by histoenzymatic techniques ( b . castellano et al ., j . histochem . cytochem ., 1991 , 39 ( 5 ), 561 - 568 ). in control animals , cortical neurons but not glial cells showed constitutively activated nf - κb . this basal activation is inhibited by pretreatment with triflusal . in those animals where an excitotoxic lesion was performed with nmda , a rapid activation of nf - κb was observed in glial cells . pretreatment with triflusal at 30 mg / kg p . o . completely inhibited nf - κb activation , both in astroglial and microglial cells . triflusal prevents neuronal cell death in cocultures of neurons and astrocytes induced by oxygentglucose deprivation ( ogd ) to carry out this study , an in vitro model of neuronal ischemia based on cocultures of neurons and glial cells was used . primary cultures of type 1 astrocytes were prepared from 1 - day old wistar rats . astrocytes were plated onto 60 mm , poly - d - lysine - coated plates . these cells were allowed to grow until they were confluent ( about 11 days ) and then rat primary neurons were plated onto them and were allowed to grow for 10 days . in addition , separate cultures of each one of the two types of cells were prepared . half of the cultures were exposed for four hours to oxygenlucose deprivation ( ogd ), followed by a 24 - hour recovery period . both the cells exposed to ogd and control cells , were treated at the start of ogd with 0 , 10 and 30 μg / ml triflusal in a series of experiments and with 0 , 20 and 100 μg / ml htb in another series . after the 24 - hour recovery period , the release of lactate dehydrogenase ( ldh ) into the medium was determined as a measure of cellular death , as well as the degree of apoptosis in the cultures ( using the tunel assay ) and total neuron and astrocyte counts present in the coculture ( using hoescht staining ). in the cultures exposed to ogd a marked increase in ldh release as well as in the number of apoptotic neurons was observed , as compared to controls . the various concentrations of triflusal or htb tested in this study completely inhibited both effects . therefore , in this model both triflusal and its metabolite htb can prevent apoptosis and neuronal degeneration induced by oxygen and glucose deprivation . adjuvant - induced arthritis is characterized by the development , from day 14 after adjuvant injection , of a chronic inflammation of immunological origin in several joints , with accumulation of inflammatory cells and release of cytokines . for this study , male lewis rats with body weight between 100 and 150 g were used . before the start of the study animals were acclimated for a period of at least 5 days . animals were fasted for 18 hours before the study , with water ad libitum . throughout the study , animals were allowed free access to drinking water , except during observation periods . groups of five animals were randomized ( sham , control and triflusal ). the duration of the study was 28 days . arthritis was induced on day 1 of the study by subplantar administration of 0 . 1 ml of an emulsion formed with 10 mg m . butyricum and 10 ml freund &# 39 ; s incomplete adjuvant ( difco ) to the right hindpaw of the animals from the control and triflusal groups . sham animals received 0 . 1 ml freund &# 39 ; s incomplete adjuvant . triflusal was administered daily from day 1 of the study at a dose of 10 mg / kg p . o . in tween 80 ( 1 %). on day 28 of the development of arthritis , the volume of the contralateral paw to that receiving the adjuvant injection was determined using a ugo basile 7150 plethysmometer . the inhibition of the increase in volume was calculated as follows : oral administration of triflusal for 28 days at the dose of 10 mg / kg produced a 63 . 1 ± 8 . 0 % inhibition of the increase in volume of immunological origin induced by m . butyricum and adjuvant in control animals , several cell lines obtained from the american type culture collection ( atcc ) were cultured at 37 ° c . and under a 5 % co 2 atmosphere . each cell line was grown in an appropriate culture medium and within the exponential phase ( table i ). for the cell viability studies 24 - well plates were used , where 0 . 5 × 10 6 cells / ml ( for 24 - hour studies ), 0 . 25 × 10 6 cells / ml ( for 48 - hour studies ) or 0 . 125 × 10 6 cells / ml ( for 72 - hour studies ) were incubated . next , different concentrations of htb ( 1 - 3 mm ) were added and cells were incubated for different time periods ( 37 ° c ., 5 % co 2 ). after incubation , the supernatant from each well was extracted , and cells were washed with culture medium without fetal calf serum . then , the supernatant was extracted and 200 μl culture medium without fetal calf serum were added to each well . in addition , 20 μl substrate were added to determine cell viability . this method is based on the ability of viable cells to transform the colourless substrate into a coloured substance that is excreted to the supernatant ( ez4u , biomedica gmbh .). after incubating cells for 1 hour at 37 ° c . and 5 % co 2 , 200 μl supernatant were collected and the absorbance was measured at 450 nm . the absorbance was also determined at 620 nm as a measure of the existing non - specific value . the results of cell viability determinations are shown on table ii . incubation with htb leads to the cell death of the various tumoral cell lines tested . this cell death is concentration - and time - dependent . the results from the assays described in examples 1 , 2 and 3 show that triflusal and htb inhibit the activation of the transcription factor nf - κb . they also show that this inhibition is independent of the inducing agent and the type of cell . these results show the : utility of triflusal and htb in the treatment or prevention of those disorders where nf - κb is involved . the results from example 4 show that triflusal and htb inhibit vcam - 1 expression . it has been described that the vcam - 1 gene has nf - κb binding sites ( c . weber et al ., arterioscler . thromb . 1994 , 14 ( 10 ), 1665 - 1673 ). it has been shown that adhesion molecules such as vcam - 1 are involved in disorders such as atherosclerosis ( k . d . o &# 39 ; brien et al ., j . clin . invest . 1993 , 92 , 945 - 951 ), rheumatoid arthritis , lupus , multiple sclerosis , inflammatory bowel disease , asthma , allergic rhinitis and tumor metastasis . by inhibiting nf - κb activation and vcam - 1 expression , both triflusal and htb may be of particular utility in the treatment or prevention of vcam - 1 - mediated disorders such as all those mentioned above and specially atherosclerosis . in example 5 it is shown that triflusal and htb also inhibit inos expression , which is regulated at transcriptional level , at least partially , by nf - κb ( u . förstermann et al ., biochem . pharnacol . 1995 , 50 ( 9 ), 1321 - 1332 ). it has been shown that inos is involved in pathologies such as inflammation , septic shock , inflammatory bowel disease and neurodegenerative diseases such as dementia and parkinson &# 39 ; s disease ( j . e . ogden and p . k . moore , trends biotechnol . 1995 , 13 ( 2 ), 70 - 78 ). by inhibiting nf - κb activation and inos expression , triflusal and htb may be of particular utility in the treatment or prevention of inos - mediated disorders and specially inflammation , septic shock , inflammatory bowel disease and neurodegenerative diseases such as dementia and parkinson &# 39 ; s disease . the results of examples 6 and 7 show that triflusal and htb inhibit cox - 2 expression both in vitro and in vivo . it has been described that the gene encoding cox - 2 has nf - κb binding sites ( s . b . appleby et al ., biochem . j . 1994 , 302 , 723 - 727 ). cox - 2 has been associated with pathologies such as rheumatoid arthritis and other arthritic conditions , arthrosis , preterm labour , dementia , particularly alzheimer &# 39 ; s disease ( t . a . sandson and o . felician , exp . opin . invest . drugs 1998 , 7 ( 4 ), 519 - 526 ), and cancer ( m . oshima et al ., cell 1996 , 87 ( 5 ), 803 - 809 ; k . subbaramaiah et al ., cancer res . 1996 , 56 ( 19 ), 44244429 ). by inhibiting nf - κb activation and cox - 2 expression , triflusal and htb may be of particular utility in the treatment or prevention of cox - 2 - mediated disorders and specially rheumatoid arthritis and other arthritic conditions , arthrosis , preterm labour , dementia and cancer . the results from example 8 show that htb inhibits also mcp - 1 expression , which is regulated at transcriptional level , at least partially , by nf - κb ( t . martin et al ., eur . j . immunol . 1997 , 27 ( 5 ), 1091 - 1097 ). it has been described that an excessive or unregulated mcp - 1 production is involved in disorders such as glomerulonephritis ( b . h . rovin et al ., lab . invest . 1994 , 71 ( 4 ), 536 - 542 ), rheumatoid arthritis ( p . m . villiger et al ., j . immunol . 1992 , 149 ( 2 ), 722 - 727 ), pulmonary fibrosis ( h . n . antoniades et al ., proc . natl . acad . sci . usa 1992 , 89 ( 12 ), 5371 - 5375 ), restenosis , asthma , psoriasis , inflammatory bowel disease , multiple sclerosis and transplant rejection , and it is the most potent chemotactic factor detected in macrophage - rich atherosclerotic plaques ( s . yla - herttuala et al ., proc . natl . acad . sci . usa 1991 , 88 ( 12 ), 5252 - 5256 ). by inhibiting nf - κb activation and mcp - 1 expression , triflusal and htb may be of particular utility in the treatment or prevention of mcp - 1 - mediated disorders such as those mentioned above . the results from example 9 show that triflusal and htb inhibit also the expression of tnf - α , which is regulated at transcriptional level , at least partially , by nf - κb ( j . yao et al , j . biol . chem . 1997 , 272 ( 28 ), 17795 - 17801 ). it has been described that an excessive or unregulated tnf - α production is involved in a broad range of disorders such as rheumatoid arthritis , rheumatoid spondylitis , gouty arthritis and other arthritic conditions , arthrosis , sepsis , septic shock , endotoxic shock , toxic shock syndrome , adult respiratory distress syndrome , cerebral malaria , chronic pulmonary inflammatory disease , silicosis , pulmonary sarcoidosis , pulmonary fibrosis , hepatitis , osteoporosis and other bone resorption disorders , reperfusion ; injury , transplant rejection , multiple sclerosis , lupus , fever and myalgias due to infections , cachexia , acquired immune deficiency syndrome ( aids ), inflammatory bowel disease and pyresis ( l . sekut and k . m . connolly , drug news perspect . 1996 , 9 ( 5 ), 261 - 269 ). by inhibiting nf - κb activation and tnf - α expression , triflusal and htb may be of particular utility in the treatment or prevention of tnf - α - mediated disorders such as those mentioned above . the results from examples 11 , 12 and 13 further show the usefulness of triflusal and htb for the treatment or prevention of neurodegenerative diseases , arthritis and cancer , respectively . the concentrations at which effects are observed in the experiments described in examples 1 to 13 are reached at the therapeutic doses of triflusal commonly used in humans by the oral route . without wishing to be bound by what is herein stated , it is believed that the inhibition of the expression of proteins such as vcam - 1 , inos , cox - 2 , mcp - 1 and tnf - α by triflusal and htb is mediated , at least partially , by an inhibition of the activation of the transcription factor nf - κb . this notwithstanding , it is known that the expression of the genes that encode these proteins may be activated by other agents . since we have shown that triflusal and htb inhibit the expression of these genes ( both in vitro and in vivo , in the case of cox - 2 ), both products may also be useful in the treatment or prevention of disorders where there is an elevated expression of these genes that is independent of nf - κb , which is also encompassed by the scope of the present invention .

a method for inhibiting the activation of transcription factor nf - κb in a warm - blooded animal in need thereof , comprises administering to said animal an effective amount of a compound of formula i wherein r represents hydrogen or coch 3 , or a pharmaceutically acceptable salt or a prodrug thereof .

in one embodiment , the present invention is a 3 - number bingo game and method of playing the game that ensures that there is only one winner . each card eligible to play the game is printed with a unique 3 - number combination . therefore , the first player to match all three numbers on his card must be the only winner . fig2 a and 2b are flashboards suitable for use with the bingo game of the present invention . fig2 a illustrates a vertically oriented flashboard , and fig2 b illustrates a horizontally oriented flashboard . in the vertical orientation of fig2 a , there are five columns ; each headed by one of the letters of the word bingo , and each containing 15 sequential numbers . in the vertical orientation , each row contains five numbers , one from each of the five columns . in the horizontal orientation of fig2 b , there are five rows , each headed by one of the letters of the word bingo , and each containing 15 sequential numbers . in the horizontal orientation , each column contains five numbers , one from each of the five rows . fig3 is a flow chart illustrating the steps of an embodiment of a method of playing bingo in accordance with the teachings of the present invention . at step 21 , ten unique 3 - number combinations are determined for each of the fifteen 5 - number columns of the flashboard ( assuming a horizontally oriented flashboard as shown in fig2 b ). it can be shown mathematically that any set of five different numbers can be combined three at a time to form ten unique combinations . mathematically , this is shown as follows : since the dashboard has fifteen 5 - number columns , there are a total of 150 unique 3 - number combinations , when combinations are formed one column at a time . assuming once again that 1 , 000 cards are to be distributed to players , 850 cards are printed at step 22 with an indication that the card is not a hold card ( or alternatively , these cards are printed without an indication that the card is a hold card ). at step 23 , 150 cards are printed with a hold indication . each hold card includes a different one of the 150 unique 3 - number combinations . at step 24 , the house distributes the 1 , 000 cards to the players . at step 25 , the bingo game is played with the hold cards only . a winner may be determined in alternative ways . at step 26 , the house randomly calls numbers from in the range of 1 - 75 , until one unique winner with a hold card is determined . since each of the 150 3 - number combinations on the hold cards is unique , there can be only one winner . additionally , when combinations are formed one column at a time as described above , the house can quickly determine that there has been a winner whenever three numbers in any one column have been drawn . this is because each 3 - number combination has been uniquely assigned to a single hold card . in an alternative embodiment , a winner may be determined at step 27 by opening a predetermined sealed card matching one of the 150 unique 3 - number combinations on the hold cards . once again , there can be only one winner . from step 26 or 27 , the method proceeds to step 28 , where the house pays out to the one unique winner . in the embodiment shown and described above , each hold card has a 1 in 150 chance of being a winner . the odds may be changed in other embodiments by computing different combinations and printing a set of hold cards reflecting the new combinations . for example , still referring to fig2 b , combinations may be computed for the number of combinations of the 15 numbers in each row taken three at a time . mathematically , this is shown as follows : thus , there are 455 unique 3 - number combinations in each row of the flashboard illustrated in fig2 b . since the flashboard has five 15 - number rows , there are a total of 455 × 5 = 2 , 275 unique 3 - number combinations , when combinations are formed one row at a time . thus in this embodiment , each hold card has a 1 in 2 , 275 chance of being a winner . other combinations of the numbers on the flashboard may also be utilized to achieve different odds of winning . at one extreme , if combinations are computed for all 75 numbers on the flashboard taken three at a time , it is found that there are 67 , 525 unique 3 - number combinations . in such an embodiment , each hold card has a 1 in 67 , 525 chance of being a winner . in another exemplary embodiment , intermediate odds of winning may be achieved by computing combinations on a per column basis for a predefined number of columns , and then computing combinations for the remaining partial rows . for example , combinations may be computed for the first eight 5 - number columns in the manner shown in the first embodiment above . this calculation results in a total of 80 unique 3 - number combinations . combinations may then be calculated on a row - by - row basis for the remaining seven positions . for each partial row ( i . e ., positions nine through 15 ), there are 35 combinations of the seven numbers taken three at a time . since there are five such partial rows , there are an additional 175 unique 3 - number combinations . thus , the total number of unique combinations in this embodiment is 80 + 175 = 255 . if a hold card is printed for each unique 3 - number combination , each hold card has a 1 in 255 chance of being a winner . in each embodiment , since each hold card includes a unique 3 - number combination , there can be only one winner . fig4 is a game card with a set of three numbers between 1 and 75 printed thereon . fig5 is a sealed card for use by the house that contains the winning 3 - number combination . as will be recognized by those skilled in the art , the innovative concepts described in the present application can be modified and varied over a wide range of applications . for example , the pool of numbers being played may be greater or lesser than 75 , and the hold cards may include greater or lesser than three numbers . the invention may also be utilized with indicators other than numbers such as letters or other symbols . accordingly , the scope of patented subject matter should not be limited to any of the specific exemplary teachings discussed above , but is instead defined by the following claims .

a 3 - number bingo game adapted to ensure there can be only a single winner . the numbers from 1 to 75 are divided into fifteen groups of five numbers each . for each group , the unique 3 - number combinations of the five numbers taken three at a time are determined and printed on game cards . a single winner is determined if the unique 3 - number combination on a player &# 39 ; s game card matches a winning set of three numbers randomly determined by the house .

with reference to the figures , a patient warming system in accordance with an embodiment of the present invention is illustrated , particularly being designed for use in veterinary medicine . the patient warming system comprises a heating unit 1 ( to be described in more detail later ) and a patient warming blanket 2 . the patient warming blanket 2 includes first 3 and second 4 layers of material which form a hollow air space 5 between them . in this embodiment , when the warming blanket 2 is not being used , it will lie substantially flat as no air is being pumped into the air space 5 . in use , however , when air is being pumped into the air space 5 , the blanket “ inflates ” to give the profile shown in the cross - section of fig2 . the first layer 3 is substantially non porous to air . the second layer 4 , however , is made of porous material and is substantially porous over its entire surface area . warm air pumped into the hollow air space 5 , therefore , escapes via the entire surface of the second layer 4 . the warming blanket 2 may be made of any appropriate material and in this embodiment is made from polyester . the second surface 4 being of porous polyester . the arrangement of the first 3 and second layers 4 in operation in this embodiment forms a tubular arrangement which extends about three sides of a patient receiving space 6 . in this embodiment , a continuation 7 of the first layer 3 provides a blanket base on which the patient may lie . in operation , warmed air is provided from the heating unit 1 via a flexible heat delivery tube 8 into a port 9 to the interior space 5 of the blanket . the warmed air inflates the blanket to give the profile illustrated in fig2 . the patient is positioned within the patient receiving space 6 . warm air escapes via the porous second layer 4 into the patient receiving space maintaining the patient receiving space 6 at a substantially even temperature . the shape of the blanket maximises the convective surface area for heating . the material of the warming blanket 2 is treated to be fluid repellent , so that any liquid contamination rolls off the blanket . in an alternative embodiment , the blanket may consist of the same main material over all of its surface . warmed air is therefore delivered over all of the exposed surface of the blanket . this blanket may be cheaper to make . the heating unit 1 includes a feedback means which in this embodiment is a pressure sensor . the pressure sensor is arranged to sense a certain amount of back pressure on a delivery port 10 of the heating unit which delivers warmed air to the delivery tube 8 . the existence of this back pressure implies that a warming blanket 2 is attached to the delivery tube 8 . if the back pressure signal is not received by the pressure sensor , then delivery of warmed air 10 via the port is disabled . this prevents any operative attempting to provide warmed air directly to a patient via the delivery tube 8 , without using a warming blanket . the heating unit 1 includes control and selection means 12 , 13 , 14 that enables a selection of plurality of temperatures for the warmed air , and in this embodiment warmed air can be delivered at temperatures of 34 , 37 , 40 , 43 or 46 degrees centigrade . the heating unit 1 is based on a conventional heating unit , but adapted to deliver the above temperatures . a further adaptation is the addition of the pressure sensor and feedback to temperature control circuitry ( not shown ) to switch off the delivery of warmed air if a back pressure is not sensed ( implying that the warming blanket 2 is not attached to the delivery tube 8 ). fig3 and fig4 show an alternative embodiment of the patient warming blanket . the alternative patient warming blanket 20 comprises an air inlet 21 which is on one “ leg ” 22 of the blanket . otherwise , the blanket is of similar construction to the patient warming blanket of fig1 and 2 . similar reference numerals have been used for similar components as the embodiment of fig1 and 2 . in the above - described embodiment the patient warming blanket will be appropriately dimensioned for veterinary care . example dimensions include 560 mm width , 1110 mm length , with width of each of the arms when inflated being 110 mm . note that these dimensions are examples only and , the present invention is not limited to these dimensions . while the above description refers to application of the warming system with animal patients , the system of the present invention is not limited to use with animal patients and can be used with human patients eg . small human patients . modifications and variations as would be apparent to a skilled addressee are deemed to be within the scope of the present invention .

the present invention relates to a patient warming system and in particular a patient warming blanket for warming patients undergoing medical care . the patient warming blanket is particularly for use in veterinary medicine . the warming blanket includes a porous surface from which warmed air can escape over the entire porous surface , evenly warming the patient .

several methods for assessing and modifying the circadian cycle of a human subject are disclosed and claimed in the patents and applications listed in the related u . s . applications section of this document . the disclosures of the listed patents are incorporated , in their entirety , into the present application by reference . while the circadian cycle of a human subject may be successfully assessed and modified by the methods disclosed in each of these patents , subsequent research has shown that the circadian cycle may be modified more efficiently by a model based on a photic transducer which reflects the recent finding that humans appear to sum circadian photic responses progressively . although not fully addressed in the present disclosure , it must be remembered that prior to modifying the circadian phase of a human subject to a desired state , the present circadian cycle of the subject must first be assessed . the subject &# 39 ; s present circadian cycle may be successfully assessed using any of the techniques disclosed in the patents previously listed in this document and such assessing techniques are specifically incorporated into the present disclosure by reference . prior to discussing the improved model of the present invention , it may be helpful to briefly discuss the development of circadian models over the past several years . it was originally thought that in order to rapidly shift the circadian phase the subject must be exposed to a bright light stimulus of high intensity ( e . g ., 10 , 000 lux ) for a long period of time ( e . g ., 5 hours ). as shown in fig1 it was believed that the circadian pacemaker was immediately responsive to exposure to light and that such a level of responsiveness was maintained until exposure to the light stimulus was interrupted . as the light stimulus was interrupted , it was thought that no further response of the circadian pacemaker could be evoked and that the circadian pacemaker was instantaneous in nature , as its responsiveness to a light stimulus was initiated and terminated precisely with the timing ( or onset and offset ) of the light stimulus . subsequent research indicated , however , that the circadian pacemaker did not respond to light stimuli as previously thought . with reference now to fig2 a second theory was developed which was based on the premise that an increase in retinal light exposure requires a measurable duration of time ( time ramp a ) to initiate the neurophysiologic or neurohumoral chain of events responsible for mediating the circadian response to enhanced light exposure and that these biological effects of enhanced light on the circadian pacemaker will persist on a diminishing trajectory ( time ramp b ) for some duration of time following a reduction in the level of retinal light exposure . thus it was thought that the circadian pacemaker continued to respond on a diminishing scale to the previous light stimulus even though the subject was being exposed to an episode of darkness ( or an interruption of the light stimulus that need not be total darkness ). based on this perceived response of the circadian pacemaker , it was thought that intermittent exposure to bright light could be nearly as effective as continuous exposure to bright light . while it is true that intermittent exposure to bright light can be nearly as effective as continuous exposure to bright light , the representation of the responsiveness of the circadian pacemaker as shown in fig2 was not accurate . on the contrary , it has been recently discovered that the circadian pacemaker responds to light stimuli in the manner shown in fig3 and that only intermittent pulses of light are required to effectively shift the circadian phase . the response curves of fig3 are based on studies performed where the subjects were exposed to 5 hour episodes of an intermittent light stimulus with only 5 minutes of enhanced light per 25 minute cycle . each 25 minute cycle consisted of 1 minute of transition up to enhanced light , a four minute pulse of enhanced light , 1 minute of transition down to darkness , and a 19 minute pulse of darkness . the phase shifts of those exposed to this intermittent light stimulus were approximately half of those seen when giving subjects 5 hours of continuous lighting , even though the subjects were exposed to light for only 20 % of the episode of the light stimulus . referring now to fig3 it can be seen that during the first 5 minutes of the stimulus cycle the responsiveness of the circadian pacemaker is initially high , but subsequently declines throughout the duration of the 5 minute stimulus pulse . during the 19 minute pulse of darkness , no response of the circadian pacemaker is evoked . when the 5 minute light stimulus pulse is resumed , the response of the circadian pacemaker is again initially high and subsequently declines throughout the duration of the 5 - minute stimulus pulse . with the onset of the second 19 minute darkness episode , the circadian pacemaker again becomes unresponsive . the responsiveness of the circadian pacemaker to light ( as shown in fig3 ) is based on the phenomenon of a &# 34 ; photic transducer &# 34 ; which is comprised of a population of neuronal elements which are responsive to light for a limited time period to &# 34 ; drive &# 34 ; or shift the circadian pacemaker . these elements are not perpetually responsive to light , as these elements are &# 34 ; burnedup &# 34 ; or &# 34 ; spent &# 34 ; after an exposure period to light . this burning up of neuronal elements is illustrated in fig3 by downward sloping response ramp a which elapses during the first 5 minutes of the stimulus episode . after a certain period of time ( which occurs during the darkness episode ) these elements are &# 34 ; recycled &# 34 ; at a predetermined rate , so that they are once again responsive to light during the application of the second 5 minute light stimulus pulse . the dynamic photic transducer briefly described above with respect to fig3 is embodied in the improved method of the present invention and will now be described in more detail below . to accommodate the pseudo - saturation found in rodent responses , the improved model of the present invention postulates a finite population of potentially active neuronal elements that , in the absence of light , i , are inactive , but are ready to be activated . these are said to be in the &# 34 ; ready &# 34 ; state . exposure to light activates these neuronal elements . activation of any particular element is a probabilistic process and we let α ( i ) represent the rate at which activation occurs for the population ( i . e ., the fraction of the &# 34 ; ready &# 34 ; elements activated per minute ). the stronger i is , the larger α is . when activated , each element rapidly initiates a chain of chemoelectric events which delivers a &# 34 ; quantum &# 34 ; of drive to the circadian pacemaker , whereupon the element is used - up and enters a subpopulation called &# 34 ; spent &# 34 ; elements . a recycling process restores the &# 34 ; spent &# 34 ; elements to the &# 34 ; ready &# 34 ; state at a rate β ( the fraction of &# 34 ; spent &# 34 ; elements that are recycled per minute ) which is independent of the light intensity i . this population of elements constitutes a dynamic photic transducer which receives the light intensity pattern i ( t ) as an input and delivers quantal flux , δ ( t ) as drive to the circadian pacemaker . in the present model , the drive to the pacemaker depends on the history of i ( t ), not simply its current value . letting n represent the fraction of all elements which are &# 34 ; spent &# 34 ; at any given time , then ( 1 - n ) represents the fraction which are &# 34 ; ready &# 34 ;. the described rate processes lead to the differential equation ## equ1 ## any protracted light level , i , will give a constant value for α ( i ) and , in time , n will achieve a steady level , n : ## equ2 ## in particular , if i = 0 we expect α ( i )= 0 and n = 0 . that is , in the absence of photic stimulation all elements revert to the &# 34 ; ready &# 34 ; state . for a steady i ≠ 0 there will be a steady rate , δ , at which quanta are delivered to the pacemaker ( the continuing rate at which recycled elements are activated ). the drive rate onto the pacemaker may be represented as ## equ3 ## where the coefficient c is the product of the absolute number of elements and the absolute drive strength of each quantum . the right - hand - side of equation ( 3 ) has the standard form of the logistic function ( sometimes called the naka - rushton function or the michaelis function ). however large the activation rate α may be , δ can never exceed cb . in physical terms , when α & gt ;& gt ; β almost all the elements are in the &# 34 ; used &# 34 ; state ( n ≅ 1 ) and it is the recycle rate that limits the rate at which elements can be continuously reactivated . a most important feature of the photic transducer is its transient response to the switching - on of light after extended darkness when essentially all of the elements are in the &# 34 ; ready &# 34 ; state . letting time , t , be zero at the switch - on to light intensity , i , the transient is given by the right - side of equation ( 5 ) conveniently separates into two terms . the first term is what would be expected from the steady - state drive rate alone . we will call this the &# 34 ; sustained response &# 34 ; rate , δ sustained . the second term represents the rapid activation of the reservoir of &# 34 ; ready &# 34 ; elements which accumulated during the preceding darkness . we will call this the &# 34 ; acute response &# 34 ; rate ( to an acute stimulus ), δ acute . if the light remains at i for some duration of time so that ( α ( i )+ β ) t & gt ;& gt ; 1 , the acute response will die out . the cumulative drive due to the acute response is ## equ4 ## the cumulative acute response &# 34 ; saturates &# 34 ;. if the stimulus is applied for a duration , t , the cumulative sustained drive is simply ## equ5 ## the cumulative sustained drive will equal the cumulative acute drive for a time , t , which we denote by t critical : the significance of this critical time value is that for stimulus duration shorter than t critical the acute component dominates the response while for durations longer than t critical the sustained component dominates . with this model the pseudo - saturation of rodent response corresponds to a dominance of the acute component while the proportionality of response to stimulus duration seen in humans corresponds to a dominance of the sustained component . for strong stimuli , so that α ( i )& gt ;& gt ; β , n ≅ 1 and t critical is dictated by β . we conclude that β for humans is considerably larger than for rodents . it is equally important to understand the prediction of this photic transducer model in the case where a sustained light stimulus is interrupted by an episode of darkness ( i = 0 ). let the darkness begin at t = 0 and last for a duration , t . before and after the darkness the light has intensity i for which the corresponding n is given by equation ( 2 ). since i = 0 implies α = 0 , no further activations from the &# 34 ; ready &# 34 ; state occur once darkness is initiated . consequently the drive onto the pacemaker , δ , is zero throughout the dark episode 0 ≦ t ≦ t . however , the &# 34 ; spent &# 34 ; elements continue to be recycled during darkness , so n decreases and the fraction of &# 34 ; ready &# 34 ; elements , 1 - n , increases : ## equ6 ## when the light is once again brought up to i at the end of the dark episode there will be an acute drive component in addition to the sustained drive . for t & gt ; t we have for which the cumulative acute drive is ## equ7 ## during the dark episode there is a cumulative loss of sustained drive given by cβnt . this loss is partially offset by acute drive which occurs when i is brought back . the net loss is then ## equ8 ## for βt & lt ;& lt ; 1 and a strong stimulus ( so n ≅ 1 ) the net loss of drive is very small . this explains how there may be very little penalty for turning off the stimulus completely for moderately long episodes provided light is subsequently reinstated and the increased pool of &# 34 ; ready &# 34 ; elements is utilized . moreover , this model makes a specific prediction of the manner in which the loss of drive depends on the duration of the episode of darkness . the value of the recycle rate , β , can be estimated from a single experiment as described in detail below . the functional form can be validated by a series of experiments with varying duration of darkness or diminished light . it should be understood that the intensity of light during a pulse of enhanced light exposure may fall within a variety of ranges . for example , the intensity of a pulse of enhanced light could fall within a variety of ranges , including ranges of approximately 500 - 1 , 000 lux ; 1 , 000 - 2 , 000 lux ; 2 , 000 - 4 , 000 lux ; and 4 , 000 - 100 , 000 lux . as stated previously , as the intensity increases the light stimulus pulse would be able to activate more neuronal elements . the intensity of light during a pulse of reduced or diminished light exposure may also fall within a variety of ranges . for example , the intensity of a diminished light stimulus could fall within the range of approximately 0 - 200 lux ; 0 - 10 lux ; or 50 - 200 lux . nothing in the foregoing disclosure is intended to limit the intensity range of an enhanced or diminished light stimulus to the intensity ranges enumerated above . the key to determining whether a particular intensity of light should be characterized as &# 34 ; enhanced &# 34 ; or &# 34 ; diminished &# 34 ; with regard to a particular subject is the effect of that light intensity on the circadian rhythm of the particular subject to which it is applied , as well as the length of the pulse . due to the &# 34 ; noise &# 34 ; in the assay of human circadian phase ( random fluctuations of temperature ) experiments should be designed to produce anticipated phase shifts of a few hours , at least . consequently bright light stimuli are commonly extended for 5 hours . based on the evidence that response is approximately proportional to stimulus duration when 3 hour and 5 hour durations are compared , it is clear that in model terms both 3 hour and 5 hour & gt ;& gt ; t critical . the magnitude of t critical ( and consequently the size of β ) can best be estimated by embedding darkness episodes of duration approximately equal to t critical within the total stimulus window . the loss of cumulative drive ( evidenced as reduced phase shift compared to that achieved with no darkness episodes ) leads to an estimate of β via equation ( 12 ). to enhance the phase shift reduction and thereby improve experimental accuracy , several darkness episodes should be embedded within the stimulus window , provided the duration of brightness between the dark episodes is long enough to return the elements to the steady - state level where the fraction of spent elements is n , implying that the full cumulative acute drive given by equation ( 11 ) is realized . this means that the duration of light between the dark episodes should be long compared to the ( α ( i )) - 1 . since we expect α & gt ;& gt ; β , this full realization of the acute drive should be achieved if the intervening light episodes are also approximately equal to t critical . once the estimate of β is obtained from experiments in which the stimulus consists of light and darkness episodes of approximately equal duration , the value of α ( i ) can be assessed by a pattern of interspersed light and dark episodes within the stimulus window in which the duration of light episodes is brief ( somewhat less than ( α ( i )) - 1 so that acute response is not fully realized . the dark episodes should have a duration about half of t critical so that reduction of phase shift , when it occurs , can be ascribed to incomplete acute response . as postulated , the activation rate , α , depends on i and so too does the sustained drive rate δ with a line ( see equation ( 8 )). by comparing phase shifts produced by 5 hour stimuli of different intensity ( for which the acute component represents little of the total drive ) we are approximately comparing the sustained drive rates at the different intensities . equation ( 3 ) enables us to infer the corresponding α ( i ). in a wide variety of studies of phototransduction where data are fit by a logistic function such as equation ( 3 ) it has proven useful to let wherein i o establishes the reference intensity for which α = 1 ( in whatever units of time have been chosen ; minutes here ) while the exponent p is typically less than 1 and usually in the range 0 . 6 ≦ p ≦ 0 . 9 . for humans , we estimate p = 0 . 85 and i o = 30 , 000 lux . ( these parameters are estimated by fitting phase shift data at various light intensities with the logistic equation ( 2 ). the value of β is found from experiments in which light and dark episodes alternate within the stimulus window .) with i = 30 , 000 lux , the activation rate , α , will be 1 min - 1 . for comparison , the hamster data from nelson et al . are best fitted by p = 0 . 6 and i o = 10 lux , the latter corresponding to the enhanced visual sensitivity of rodents vis - a - vis humans . in neuronal processes , response to a stimulus often is found only after some threshold stimulus is attained . we anticipate that at very low levels of i the transition rate α ( i ) may be zero , so that only after i is raised to some critical level will any response be observed . since , in a population of potentially active neuronal elements the individual elements would very likely have different threshold levels , distributed statistically , the transition between α ( i )=( i / i o ) p and α ( i )= 0 will not be abrupt . there is evidence that hamster response has a threshold at about 0 . 1 lux . human response shows no threshold behavior for i as low as 150 lux . we have performed experiments in which a single 5 hour stimulus is subdivided into 4 bright light ( 10 , 000 lux ) episodes with three interspersed dark ( less than 1 lux ) episodes all of approximately equal duration (≅ 42 minutes ). from these we have inferred that the recycle rate , β , is approximately 0 . 02 min - 1 . no other comparable experiments for hamsters are known , but by comparing phase shifts obtained ( by various investigators ) with sustained light durations of 5 , 10 , 15 , and 60 minutes , we infer that β is approximately 0 . 01 min - 1 or about 50 % of the human recycle rate . the essential equation is ( 1 ) ## equ9 ## the activation rate constant α is a function of i for which we have selected the form where i o and p are constants . for any specified temporal pattern of light , i ( t ), equation ( 13 ) gives α ( t ). integration of equation ( 1 ) gives n ( t ). the drive onto the pacemaker is then given by in general the integration of ( 1 ) must be done numerically . selected analytic integrals for i ( t ) that change stepwise have been developed above . i o = 30 , 000 lux ( with α measures in min - 1 ) the coefficient c is evaluated by making the steady drive , δ , for 10 , 000 lux match the value b = ci 1 / 3 = 0 . 018 ( 10 , 000 ) 1 / 3 = 0 . 388 , of the direct - drive model : the photic transducer model described above very simply encompasses two of the most important nonlinear aspects of the response of the circadian pacemaker to photic stimulation . one is the temporal pseudo - saturation seen in those animals for which the pacemaker drive is dominated by the acute component . the other is the intensity saturation effect found in the sustained component ( see equation ( 2 )) and evidenced in human response that is typically dominated by sustained drive effects . it is useful to examine the consequences of interposing a linear temporal filter between the photic transducer output , δ ( t ), and the pacemaker . one of the simplest filters is described by a first - order differential equation , ## equ10 ## where b is the filter output ( and hence represents the drive onto the pacemaker ). t f is the filter time constant . this filter has the properties of smoothing the δ ( t ) and , in an approximate sense , delaying the smoothed version by t f . the long - time integral of b is equal to that of δ , so the integrated strength of the drive to the pacemaker is unchanged by the filter . in the case of a hamster exposed to a 5 minute pulse of 20 lux of brightness , the acute response of δ ( t ) will be essentially complete at the end of the pulse . moreover , the turning - off of the light at the end of the pulse means that no further drive can be generated . the interposition of a filter of the type described implies that the filter output drive to the pacemaker , b , may be considerably extended , declining exponentially with a time constant t f . a very interesting situation arises if t f is matched to the recycle rate constant δ : equation ( 1 ) can be simply rearranged ## equ11 ## so that the right side is exactly δ ( t ). the left side can be rewritten ## equ12 ## comparison of equation ( 15 ) with equation ( 14 ) shows that in this special case that is , the output of the matched filter is equal to n ( the fraction of &# 34 ; spent &# 34 ; e elements ) multiplied by the recycle rate constant , β . the combination of the photic transducer with following matched filter leads to a second model interpretation . in this interpretation , we suppose that transducer elements , upon activation , enter a state of sustained drive onto the pacemaker ( rather than delivering only a quantum of drive ). in such a case , the drive to the pacemaker at any time will be proportional to n ( the fraction of elements which have been activated ). the recycle rate , β , now represents the rate at which active elements cease being active . in this view , when an episode of light is initiated from a state of protracted darkness , the drive to the pacemaker will progressively increase as elements are activated ( moved to the state represented by the fraction n ) up to the level n . when the light is then turned off , drive to the pacemaker will continue while the fraction n declines exponentially with the time constant β - 1 . this model may be called an &# 34 ; element recruitment &# 34 ; model wherein the &# 34 ; ready &# 34 ; elements are recruited into extended activation . equations ( 15 ) and ( 16 ) show that the &# 34 ; expenditure &# 34 ; model with the matched filter added is the mathematical equivalent of the &# 34 ; recruitment &# 34 ; view . the question of whether a filter such as ( 14 ) exists in the signal pathway is difficult to appraise experimentally and is largely moot . first , the response processes within the pacemaker itself are integrative , and so change very little with input signal smoothing . secondly , any delay produced by the filter can simply be accommodated as a change in the presumed timing of the phase response curve ( prc ) relative to other circadian markers . only when the physiology of the internal pacemaker mechanism is elucidated can this question be properly addressed it is important to observe that light input mediating other biological effects such as melatonin suppression or alertness enhancement may operate via the same photic transduction mechanism as that which mediates effects on the circadian pacemaker . heretofore , the conventional view of the action of light on the circadian pacemaker implied that a brief reduction of stimulus ( such as might be produced by directing one &# 39 ; s gaze away from a bright light source ) would invoke a penalty in the cumulative stimulus effect . through a series of experiments employing unique temporal patterns of bright and dark episodes contained within the overall stimulus time - window we have demonstrated that even long ( e . g ., 30 minute ) intervals in which light is completely absent can be accommodated with relatively little penalty , provided these are followed by sufficiently long ( e . g ., 5 - 10 minute ) episodes of bright light . this discovery greatly enhances the applicability of bright light interventions in the workplace , in phototherapy routines and for personal use ( for example , in preventing jet lag ). for example , in industrial situations where the job may call for some duties in a dark or dimly lit environment , the use of bright light to produce adaptation to shift rotation need not be compromised . since the required duration of bright episodes is related to the activation rate , α , which is itself strongly dependent on light intensity , i , the prescription for temporal light patterning changes with the brightness of available light . the mathematical representation of the photic transducer permits an optimal accommodation to any imposed limitations of brightness or work schedule . based on prior modelling work , it is known that for extended durations of light exposure ( e . g ., 3 to 5 hours ) the penalties to be paid by lowering light intensity from about 10 , 000 lux to 3 , 000 lux were modest . the relationship b = ci 1 / 3 predicts only a 33 % decrease in drive to the pacemaker for this more than threefold reduction of light intensity . recent data at 1250 lux imply the decrease in pacemaker drive is even smaller than this prediction . seemingly , there is little profit in pursuing very large i . however , transducer models shows that when intermittent bright light patterning is considered , 10 , 000 lux actually has a very special advantage over 3 , 000 lux , by allowing a much lower fraction of rime during which the light need be applied to provide a desired effect ( known as a shorter &# 34 ; duty cycle &# 34 ;). one simple consequence that can be deduced from the model is that if all light and dark episodes are brief ( i . e ., less than about 1 minute ) the her effect is equivalent to a steady intensity whose αvalue is that of the actual reduced by the fraction of time that the light episodes represent . for example , if 10 , 000 lux is viewed for 50 % of the rime ( and darkness for the other 50 % ), the equivalent steady intensity is that for which α1 / 2 times α ( 10 , 000 ). using the exponent p = 0 . 85 gives an equivalent steady intensity of 4 , 400 lux . put another way , the availability of 10 , 000 lux allows a duty cycle of 0 . 5 ( for rapid intermittence ) with the equivalent of 4400 lux . with our current estimate of photic transducer parameters , equations ( 2 ) and ( 3 ) predict that the loss in drive to the pacemaker will be less than 5 %. a similar calculation for a duty cycle of 0 . 2 ( 20 % of at 10 , 000 lux and 80 % of the time at 0 lux ) gives an equivalent steady i of 1 , 505 lux and a reduction of pacemaker drive of 16 %. the use of intermittent light schedules offers a special opportunity for devices by means of which a person can monitor the status of his / her photic transducer . in particular , by monitoring light exposure with a tiny ambulatory lux meter and feeding such data to a special purpose microcomputer that integrates equation ( 1 ), the user can obtain on - line an output portraying both the correct level of &# 34 ; ready &# 34 ; and &# 34 ; spent &# 34 ; elements and also the cumulative drive delivered to the circadian pacemaker from any chosen start time . if the user has remained away from suitably bright light for too long a time , a warning reminder can be sounded . in this way , the user can achieve desired objectives for manipulating the circadian pacemaker ( both type 1 and type 0 ) resetting ) without personal attention to minute - by - minute light exposure . moreover , it is seldom that intermittent light patterns will be a simple mixture of bright episodes and totally dark episodes . rather , a continuous pattern of variations from quite bright to quite dim light will be more common , and online computation is almost essential to avoid serious stimulus lapses which could strongly reduce cumulative drive . this is especially important where light in evening hours is called for , since normal environmental light is not strong and serious effort is required to access bright light . at a higher level , the measured pacemaker drive can be applied to a computer replica of the pacemaker itself and the overall phase and amplitude status of the pacemaker displayed . those capabilities are especially important if the user is planning to achieve maximum phase shifting effects by type 0 resetting ( i . e ., suppression of circadian amplitude en route to the final desired state ). it should be remembered that efficient resetting of the circadian pacemaker requires avoidance of light drive at certain times as well as strong delivery of light at other times . if a computer replica of the pacemaker is available and the resetting objectives are read in , an output indicating when light is to be avoided can be easily generated . when combined with the aforementioned photosensor , warning signals can be produced . this can be important since the photic transducer model implies that relatively brief ( e . g . a few minutes ) exposure to unwanted light can produce significant adverse drive to the pacemaker . the computation that monitors the ready / spent status of the photic transducer operates on a time scale of minutes to a few hours . the computation that estimates the status of the circadian pacemaker itself is necessarily operating on the circadian time scale . the improved method described herein may be applied to other settings or devices to efficiently effect modification of the circadian phase . for example , a lounge used by shift workers could be equipped with bright lights and a timing device which has been programmed in accordance with the improved model of the present invention . another example of an application of an intermittent light stimulus would involve a pair of eyeglasses with means for exposing the wearer to light of selected intensity at selected times . such eyeglasses could be used , for example , by those travelling across time zones or by shift workers . because the light source would be close to the eyes of the wearer , and because the light stimulus would be intermittent , very little power would be required for such a device . a similar light emitting device could be similarly incorporated into a visor or hat . yet another example of an application of the method of the present invention would be to mount a light source and a control mechanism onto the headboard of a bed , or other lounging location where the user is likely to be when the light stimulus is to be applied . it is envisioned that such a device could be small enough to be carried by a traveler , for example . the method of the present invention may be further applied to any of the devices disclosed in the parent patents described at the beginning of this application , the disclosures of which being incorporated in their entirety herein by reference . the endogenous ( deep ) circadian pacemaker , hereafter designated as &# 34 ; the x oscillator ,&# 34 ; or simply &# 34 ; x ,&# 34 ; may be modelled mathematically by a second - order differential equation of the van der pol type , specifically : ## equ13 ## in the absence of any forcing function , f x , x will have an approximately sinusoidal waveform with an amplitude of 1 ( that is , the full excursion of x from a maximum of + 1 to a minimum of - 1 will be 2 ). the forcing function , f x , consists of two effects . the dominant effect is that of the light to which the retina is exposed . the secondary effect is due to endogenous internal influences of the activity - rest pattern . in the form given above , time t is measured in clock hours . the parameter m x is the &# 34 ; stiffness &# 34 ; of the x oscillator and for normal humans is expected to be in the range 0 . 05 ≦ m x ≦ 0 . 15 with 0 . 1 as the representative value . the estimate of 0 . 1 for m x was originally chosen as a trial value by analogy with the value of m y ( the internal &# 34 ; stiffness &# 34 ; of the y oscillator ) of our dual oscillator model of the human circadian timing system which had been validated by earlier experimentation characterizing a phenomenon called phase trapping . our experimental success in manipulating the amplitude of the oscillatory output implies that m x is very unlikely to be larger than 0 . 15 , and certainly not larger than 0 . 2 . an oscillator with an internal stiffness coefficient less than 0 . 03 would be unreasonably susceptible to external influences and therefore physiologically incompatible with the observed robustness of the endogenous circadian (&# 34 ; x &# 34 ;) oscillator sensitive in this context . the parameter τ x represents the intrinsic period of the x oscillator and for normal humans is expected to be in the range 23 . 6 & lt ; τ x ≦ 25 . 6 with 24 . 6 as the representative value . for most people in the age range 5 to 55 years , sleep occurs in a single consolidated episode each 24 hour day . in the laboratory paradigm of &# 34 ; free run &# 34 ; ( self - selected sleep and wake ) the sleep / wake cycle time for young adults is typically in the 25 to 26 h range . about 30 % of free run experiments lead spontaneously to internal desynchrony in which the sleep / wake cycle time exceeds 30 hours ( ranging up to 50 hrs ) while the core body temperature rhythm proceeds at about 24 . 5 h . we ascribe these separate rhythms to distinct rhythm generators : y for the labile sleep / wake process and x for the &# 34 ; deep circadian pacemaker &# 34 ;. in synchronized free run the interactions between y and x produce mutual entrainment , and since the compromise cycle time , τ , is biased strongly toward τ x , it follows that the action of y on x is only about 25 % of the action of x on y . in its simplest form , the model is ## equ14 ## in which the drive of light on the circadian system is only in the x equation . the sensitivity function , b , includes the cube - root relationship for physical light intensity and the term - mx is included to provide a circadian modulation of the sensitivity based on the known modulation of visual sensitivity ( hence m = 1 / 3 was chosen ). in a recent modification , the light was also permitted to act on the x c equation ## equ15 ## where q = 1 was indicated at that time . it now appears that a reduced value q = 0 . 3 or 0 . 4 is preferred . a much more thorough appraisal of data has indicated two additions to the sensitivity function : with k = 1 / 3 and h = 1 / 2 as preferred values . the term k x c ( when combined with the original m x term ) serves to advance the circadian phase at which maximum sensitivity of the circadian system to light occurs , by approximately three hours . it also increases the amount of sensitivity modulation which occurs over the circadian cycle . the term hx c 2 acts to reduce sensitivity to light at circadian phases which are about ± 6 hours from the nadir of the circadian cycle ( which nadir is typically about 5 am for normally entrained persons ). overall , this circadian sensitivity function is considerably different from human visual sensitivity measured throughout the day and night and reflects a current appraisal of the acute action of light on the circadian pacemaker , when it has a rhythm amplitude close to nominal ( an amplitude of 1 in the mathematical model ). finally , the action of light in the x c equation is altered by two additional terms , ( a - bx ) ## equ16 ## where a = 0 . 1 and b = 0 . 1 . these terms are included so that , with the corrections in the b - function just described , the phase shift observed when light is applied near the phase of the nadir of x is properly reproduced . put another way , the original simple model did a good job when light was applied at the nadir of x but had other deficiencies . when the b - function was modified to address these deficiencies , we end up with errors for light applied at the nadir and the a - bx terms correct these . thus , the enhanced model is expressed by ## equ17 ## where : τ x = 24 . 2 μ = 0 . 13 c = 0 . 18 while the method of the present invention has been disclosed in connection with the preferred embodiment thereof , it should be understood that there are alternative realizations of the model which fall within the spirit and scope of the invention as defined by the following claims .

the present invention is a method for modifying the circadian cycle of a human subject to a desired state including the steps of determining the characteristics of the desired circadian cycle , selecting an appropriate time during which to apply a light stimulus to effect a desired modification of the present circadian cycle , and applying the stimulus at the selected time to achieve the desired circadian cycle for the subject . the light stimulus of the present invention includes an episode of intermittent light consisting of at least two pulses of enhanced light separated by at least one pulse of reduced light .

the invention exploits the considerable advantages of “ rolled architecture ” in neural regeneration conduit . in rolled architecture , axial channels are replaced by a single spiraling axial space . this provides several advantages , including one or more of the following : ( 1 ) increased surface area for adherence of neural regeneration - supporting cells inside the conduit and to guide regeneration of an injured nerve ; ( 2 ) a polymer hydrogel layer that provides an aqueous milieu for cell migration and neurotrophic agent diffusion ; and ( 3 ) neurotrophic agents loaded into microspheres lining the inside of the conduit ; ( 4 ) non - uniform geographic arrangement of microspheres to create axial or radial concentration gradient ( s ) of a single neurotrophic agent or multiple neurotrophic agents ; ( 5 ) creation of a spatial gap ( to accommodate regenerating nerves ) by a hydrogel / microsphere layer acting as a spacer , or spacers joined or contiguous with the support , along the inside of the conduit ; ( 6 ) choice of conduit materials ; and ( 7 ) ease of manufacturing . [ 0020 ] fig1 a is a cross sectional view of a partially - rolled nerve regeneration conduit 10 . a porous support 12 has an outer surface 13 and an inner surface 15 . an approximately spiral lumen 14 is created by rolling the support 12 . formation of a uniform space 14 between rolled layers of the support 12 is facilitated by a semi rigid hydrogel / microsphere layer ( shown in fig1 b ) adhered to the inner surface 15 of the support . the outer surface 13 faces outward with respect to the origin 16 of the spiral 17 , and the inner surface 15 faces inward with respect to the origin 16 of the spiral 17 . for ease of depiction , the schematic representation shows a partially - rolled conduit , whose spiral 17 lumen contains only approximately 3½ rotations . in preferred embodiments of the invention the spiral 17 contains from 8 to 40 rotations . the number of rotations will depend on various factors , including thickness of the support , thickness of the gap between support layers , and the desired outside diameter of the fully - rolled , cylindrical conduit . the conduit can be designed to have an outside diameter approximately matching the diameter of the nerve in which a gap is being bridged . [ 0021 ] fig1 b is a schematic , cross sectional view of a portion of a multilayered sheet 20 used to form the nerve regeneration conduit 10 . a layer of schwann cells 26 is adhered to the inner surface 15 of the porous support 12 . neurotrophin - laden microspheres 24 are embedded in a hydrogel layer 22 . referring to fig2 a - 2 c , an alternative embodiment of a conduit is shown . fig2 a is a top view of an unrolled sheet 120 , showing inside surface 115 . instead of a hydrogel layer providing spacing between layers of a roll , sheet 120 includes continuous spacers 130 and discontinuous spacers 132 ( fig2 c ). of course , in other embodiments , a sheet can include either continuous or discontinuous spacers only . these spacers 130 and 132 and the rest of the sheet 120 can be formed from any castable foam material that is suitable for implantation , produced using microfabrication techniques , or formed using ink jet technology as described herein . schwann cells 126 are adhered on inside surface 115 . to form a rolled conduit 110 , sheet 120 is rolled in direction b shown in fig2 a and 2b . rolled conduit 110 has outside surface 113 . conduit 110 also includes an axial gradient of neurotrophin molecules 134 which are loaded into spacers 130 and 132 . such a gradient can be provided when the spacers and / or sheet is fabricated by ink jet technology . alternatively , conduit 110 can be used in conjunction with microspheres and / or a hydrogel ( not shown ) that contain one or more neurotrophins , the microspheres being positioned between spacers 130 and 132 . there is considerable latitude in material used to form the conduit support 12 . the material must be porous and biocompatible . in addition , it must have suppleness or ductility sufficient to permit rolling of the support into a compact , cylindrical structure , e . g ., having a diameter approximately 0 . 5 to 3 . 0 mm , suitable for surgical implantation in the repair of transected or crushed nerves . preferably , the support can be cut readily with surgical instruments , yet strong enough to anchor surgical sutures . in embodiments incorporating a layer of cells , the support should allow for adherence of cells . it is , however , important to note that cell adherence is not necessary for the operation of the invention . the thickness of the support 12 ( single layer ) can vary . preferably it is from 5 to 200 μm , and more preferably , it is from 10 to 150 μm . optimal thickness will depend on the material used to form the support 12 , the size and anatomical location of the nerve to be repaired , and the length of the nerve gap ( if any ) to be bridged in the repair . after being formed by rolling , the cylindrical nerve conduit preferably displays at least some flexibility . in some embodiments of the invention , the support 12 is formed partly or completely from a naturally occurring biological material . a suitable naturally occurring biological material is small intestinal submucosa ( sis ). sis is an a cellular collagen matrix that contains endogenous growth factors and other extracellular matrix components . techniques for harvesting and handling sis are known in the art . see , e . g ., lantz et al ., j . invest . surg . 6 : 297 - 310 ( 1993 ). other potentially useful natural , biological materials are vein tissue and a cellular material . in many embodiments of the invention , the support contains only non - immunogenic components . for example , sis in not immunogenic . if immunogenic components are used , suitable immuno - suppressive therapy may be necessary . such immunotherapy is known to those of skill in the art . see , e . g ., evans et al ., progress in neurobiology 43 : 187 - 233 , 1994 . in some embodiments of the invention , the support 12 is a thin sheet of synthetic polymer . suitable synthetic polymers include polyhydroxyalkanoates , e . g ., polyhydroxybutyric acid ; polyesters , e . g ., polyglycolic acid ( pga ); copolymers of glycolic acid and lactic acid ( plga ); copolymers of lactic acid and ε - aminocaproic acid ; polycaprolactones ; polydesoxazon ( pds ); copolymers of hydroxybutyric acid and hydroxyvaleric acid ; polyesters of succinic acid ; polylactic acid ( pla ); cross - linked hyaluronic acid ; poly ( organo ) phosphazenes ; biodegradable polyurethanes ; and pga cross - linked to collagen . poly ( organo ) phosphazene supports are described in langone et al ., biomaterials 16 : 347 - 353 , 1995 . polyurethane supports are described in robinson et al ., microsurgery 12 : 412 - 419 , 1991 . the support can be bioresorbable , e . g ., plga , or nonbioresorbable , e . g ., sis . in addition , the inclusion of an electrically conducting polymer ( e . g ., oxidized polypyrrole ) in the conduit , in conjunction with electrical stimulation , can augment nerve repair . such a strategy is described in schmidt et al ., proc . natl . acad . sci . usa 94 : 8948 - 8953 , 1997 . the support and any structures contiguous with it ( e . g ., spacers ) can be fabricated using any method known in the art . for example , the use of foam casting for generating prosthetic sheets with varying porosity can be adapted from processes described in nam et al ., biomaterials 20 : 1783 - 1790 , 1999 ; nam et al ., j . biomed . mat . res . 47 : 8 - 17 , 1999 ; and schugens et al ., j . biomed . mat . res . 30 : 449 - 461 , 1996 . the porosity of biomaterials formed from casting can be controlled using differential concentrations of salts or sugars , co 2 gas pressure , and other means known in the art . see , e . g ., lu et al ., biomaterials 21 : 1595 - 1605 , 2000 ; harris et al ., j . biomed . mat . res . 42 : 396 - 402 , 1998 ; and wake et al ., cell transplantation 5 : 465 473 , 1996 . the pores in the foam should be large enough for exchange of gases and nutrients as necessary for cell maintenance , but small enough so that the surface of the support is impermeable to cells . a typical range suitable for a support of the invention is about 10 - 100 μm . as an alternative to foam casting , microfabrication is a process that includes casting a polymer on top of a silicon wafer that has been etched . most common polymers used in this process include polydimethylsiloxane ( pdms ), which is non - biodegradable . however , microfabrication techniques can be adapted for biodegradable plga and the like , using a modification of the procedure described in becker , electrophoresis 21 : 12 - 26 , 2000 . in some embodiments of the invention , it is desirable to deposit or impregnate the support with neurotrophins ( e . g ., a gradient of one or more neurotrophins ) for facilitating axon migration and nerve regeneration in general . one means of accomplishing this task is to incorporate three - dimensional printing ( 3dp ) ink jet printing technology into the manufacture of the support to produce a gradient of neurotrophins . general 3dp techniques as applied to medical devices is described in u . s . pat . nos . 5 , 490 , 962 and 5 , 869 , 170 . if a gradient is not desired , a number of art - recognized methods can be used evenly distribute neurotropins throughout a support . in some embodiments of the invention , a monolayer of adherent cells 26 is cultured on the support 12 before it is rolled into a cylinder . preferably , the cells 26 remain adhered to the support after the support is rolled into a cylinder for implantation . the cells 26 are employed for their ability to promote axonal extension of neurons in nerves . schwann cells are particularly suitable , but any other adherent cell that promotes axonal extension can be employed . alternatively , even if the schwann cells do not adhere to the support , the cells can be encapsulated in the hydrogel described herein . schwann cells encapsulated in hydrogels are described in plant et al ., cell transplantation 7 : 381 - 391 , 1998 ; and guenard et al ., j . neurosci . 12 : 3310 - 3320 , 1992 . it is envisioned that a variety of cells can be included in the conduit to facilitate nerve regeneration . for example , the harvesting and use of olfactory ensheathing glial cells in nerve regeneration is described in verdu et al ., neuroreport 10 : 1097 - 1101 , 1999 ; and ramon - cueto et al ., j . neurosci . 18 : 3803 - 3815 , 1998 . in addition , neural stem cells , neural crest stem cells , or neuroepithelial cells can be harvested and optionally differentiated into neural support cells , such as described in mujtaba et al ., dev . biol . 200 : 1 - 15 , 2000 ; pardo et al ., j . neurosci . res . 59 : 504 - 512 , 2000 ; mytilineou et al ., neurosci . lett . 135 : 62 - 66 , 1992 ; and murphy et al ., j . neurosci . res . 25 : 463 - 475 , 1990 . alternatively , autologous bone marrow stromal cells can be differentiated into neural stem cells for use in a conduit . this conduit can then be grafted into the donor for nerve repair without the concern for graft rejection arising from implantation of allogenic or xenogenic cells . isolation and differentiation of bone marrow stromal cells are described in woodbury et al ., j . neurosci . res . 61 : 364 - 370 , 2000 ; and sanchez - ramos et al ., exp . neurol . 164 : 247 - 256 , 2000 . optionally , the cells employed in the monolayer 26 are genetically engineered for one or more desirable traits , e . g ., overexpression of a neurotrophic factor or axonal extension - promoting protein . such cells need not be of glial cell origin , since the recombinant expression of neurotrophic factor in non - glial cells renders them suitable for use in the invention . in other words , recombinant expression converts originally non - nerve support cells into nerve support cells . fibroblasts that express neurotrophins and are suitable for implantation are described in nakahara et al ., cell transplantation 5 : 191 - 204 , 1996 examples of axonal extension - promoting proteins include ngf ( kaechi et al ., j . pharm . exp . ther . 272 : 1300 - 1304 , 1995 ), fgf ( laird et al ., neuroscience 65 : 209 216 , 1995 ), and gdnf ( frostic et al ., microsurgery 18 : 397 - 405 , 1998 ). other neurotrophins include fk506 , 4 - methylcatechol , bdnf , cntf , mngf , nt - 3 , nt - 4 / 5 , cm101 , inosine , spermine , spermidine , hsp - 27 , igf - i , igf - ii , pdgf ( including pdgf - bb and pdgf - ab ), il - 1 , aria , lif , vip , ggf , and ms - 430 . production of a confluent layer of cells 26 on the support 12 can be accomplished readily through cell culture , using a mitogenic medium , and conventional animal cell culture techniques and equipment . conventional cell culture techniques are known in the art and can found in standard references . see , e . g ., casella et al ., glia 17 : 327 - 338 ( 1996 ); morrissey et al ., j . neuroscience 11 : 2433 - 2442 ( 1991 ). in other embodiments , the cells can be grown on both the inside and outside surfaces of a support . some embodiments of the invention include a polymer hydrogel layer 22 adhered to the support 12 or to a layer of cells 26 adhered to the support 12 . the polymer hydrogel layer 22 can be any biocompatible , bioresorbable polymer gel that provides an aqueous milieu for cell migration and neurotrophic agent diffusion . the hydrogel can be natural or synthetic . the hydrogel layer 22 can have a thickness from 5 to 120 μm , preferably from 10 to 50 μm , e . g ., approximately 20 , 25 or 30 μm . optimal hydrogel thickness depends on factors such as the diameter of the nerve being repaired and the number and diameter of microspheres 24 ( if any ) to be accommodated in the hydrogel layer 22 . exemplary materials for use in a polymer hydrogel layer 22 are fibrin glues , pluronics ®, polyethylene glycol ( peg ) hydrogels , agarose gels , polyhema ( poly 2 - hydroxyethylmethacrylate ) hydrogels , phpma ( poly n -( 2 - hydroxypropyl ) methacrylamide ) hydrogels , collagen gels , matrigel ®, chitosan gels , gel mixtures ( e . g ., of collagen , laminin , fibronectin ), alginate gels , and collagen - glycosaminoglycan gels . the hydrogel layer 22 can contain one or more neurotrophic agents or axon extension - promoting proteins . such neurotrophic agents can be loaded directly into the hydrogel 22 , loaded into microspheres 24 , or incorporated into the support or spacers as described herein . some embodiments of the invention include microspheres between the rolled layers of the support . the microspheres can be held in place by any suitable means . for example , the microspheres can be immobilized in the hydrogel layer . the microspheres can be “ blank ,” i . e ., containing no active ingredient . blank microspheres are can serve as spacers to aid in producing a desired and constant spacing between laminations of the support in the spiral . microspheres 24 useful in the invention can have diameters of approximately 1 μm to 150 μm . preferably , the microspheres are made of a semi rigid , biocompatible , bioresorbable polymeric material . a suitable polymeric material is a high molecular weight ( approx . 130 kd ) copolymer of lactic acid and glycolic acid ( plga ). plga is well tolerated in vivo , and its degradation time can be adjusted by altering the ratio of the two co - monomers . besides serving as spacers , microspheres can be loaded with one or more neurotrophic agents , or any other active ingredient , so that they serve as drug delivery vehicles . effective use of plga as a drug delivery vehicle is known in the art . see , e . g ., langer , ann . of biomed . eng . 23 : 101 , 1995 ; and lewis , “ controlled release of bioactive agents from lactide / glycolide polymers ,” in chasin and langer ( eds . ), biodegradable polymers as drug delivery systems , marcel dekker , new york ( 1995 ). a particularly advantageous feature of the invention is that microspheres loaded with a neurotrophic agent can be arranged in a pattern so as to result in an axial or radial concentration gradient in the lumen of the nerve regeneration conduit . moreover , when two or more neurotrophic agents are employed , the agents can be loaded into separate batches of microspheres , which can then be differently arranged to produce independent concentration gradients for each of the different neurotrophic agents . effects of neurotrophin concentration gradients are known in the art . see , e . g ., goodman et al ., cell 72 : 77 - 98 , 1993 ; and zheng et al ., j . neurobiol . 42 : 212 - 219 , 2000 . utilization of such concentration gradient effects is within ordinary skill in the art . in some embodiments of the invention designed to create a neurotrophic agent concentration gradient , the two ends of the conduit differ from each other with respect to one or more neurotrophic agents . such conduits may require implantation across a nerve gap in only one of two possible orientations . to ensure implantation in the proper orientation , the two ends of the conduit can be rendered visually distinguishable by any suitable means , e . g ., a non - toxic dye marking on the conduit itself , or markings on a sterile wrapper or container . surgical procedures known in the art can be employed when using a nerve regeneration conduit of the invention to repair transected peripheral nerves . suitable surgical procedures are described , for example , in hadlock et al ., archives of otolaryngology — head & amp ; neck surgery 124 : 1081 - 1086 , 1998 ; wo 99 / 11181 ; u . s . pat . no . 5 , 925 , 053 ; wo 88 / 06871 ; wang et al ., microsurgery 14 : 608 - 618 , 1993 ; and mackinnon et al ., plast . reconst . surg . 85 : 419 - 424 , 1990 . schwann cells were isolated from neonatal fisher rats . small intestinal submucosa ( sis ) was harvested from adult fisher rats for use as a support material in a nerve regeneration conduit . the sis was cut into 7 mm by 8 cm pieces and pinned out . schwann cells were plated onto the sis sheets and cultured until they reached confluence . the strips were then rolled into a laminar structure and implanted across a 7 mm gap in the rat sciatic nerve ( n = 12 ). control animals received sis conduits without schwann cells ( n = 11 ) or an autograft repair ( n = 12 ). at both 6 and 10½ weeks , functional recovery through the schwann cell - laden sis conduits , measured by sciatic function index , exceeded that through the cell - free conduits , but compared favorably with autografts . a number of embodiments of the invention have been described . nevertheless , it will be understood that various modifications may be made without departing from the spirit and scope of the invention . accordingly , other embodiments are within the scope of the following claims .

a neural regeneration conduit employing spiral geometry is disclosed . the spiral geometry is produced by rolling a flat sheet into a cylinder . the conduit can contain a multiplicity of functional layers lining the lumen of the conduit , including a confluent layer of adherent schwann cells . the conduit can produce a neurotrophic agent concentration gradient by virtue of neurotrophic agent - laden microspheres arranged in a nonuniform pattern and embedded in a polymer hydrogen layer lining the lumen of the conduit .

although a specific embodiment of the invention will now be described with reference to the drawings , it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the invention . various changes and modifications , apparent to one skilled in the art to which the invention pertains , are deemed to be within the spirit , scope and contemplation of the invention as further defined in the appended claims . referring to fig1 with greater particularity , the timed automatic pet food and water dispenser is denoted generally by the numeral 10 . the top of the feed storage bin ( fig2 ), is identified by the numeral 14 . electric power for timing and operating the device is supplied by means of electric supply cable 16 . top or lid 14 has a lift handle knob 92 that works in cooperation with a latch mechanism 32 attached to feed loading door 28 . feed loading door 28 is connected to feed storage bin 12 by means of front hinge 86 . it is one of the convenience features of the invention that a large bag of dry pet feed may be leveraged into the storage bin 12 by first releasing latch mechanism 32 then opening the top 14 of the feed storage bin and then lowering the feed loading door 28 by means of hinge 86 . the large bag of dry pet feed may then be opened and placed on the feed loading door 28 with the open end toward and into the storage bin . lifting the loading door thus provides a mechanical advantage through the lever action of the hinge 86 until the door is in the vertical position at which time the bag may be emptied and removed after which the top 14 may be closed and latched by means of latch mechanism 32 . a feed level indicator 18 may be merely a glass insert through which a visual indication of the amount of feed left in the bin may be determined . a control mechanism access door 30 permits access to the timing and controlling mechanisms to be discussed infra . a feed chute 20 is provided to dispense feed into feed dish 22 shown in phantom . the water level control 26 , to be explained later , is shown in place above float chamber 36 situated so as to control the water level of water supplied by main water supply 34 into water container 24 . referring now to fig2 a view provided by the sight lines 2 -- 2 of fig1 may be examined . as noted the feed storage bin is denoted by the numeral 12 , the top or lid of the storage bin is identified by the numeral 14 , while the feed loading door is denoted by the numeral 28 . the lift handle knob for lid 14 is identified by the numeral 92 while the feed level indicator is called - out by numeral 18 . a feed auger 60 having multiple flights , is shown situated near the contoured bottom 88 of bin 12 . feed auger 60 has a forward auger reduced shaft 98 by means of which it is supported at one end by front bearing support 100 . feed auger 60 is supported at its other end by included wall and auger support member 102 . dry feed from storage bin 12 will be supplied to feed chute 20 in a volume amount determined by the number of rotations permitted to auger 60 by means of the controlling mechanism to be explained in greater detail subsequently . feed chute 20 incorporates a chute open - and - close butterfly valve 64 having a pivoting extension arm activator 65 itself activated by control member 66 . control member 66 is operated under the influences of solenoid activating means 70 and resilient member 68 shown in the figure as a spring situated about the shaft of control member 66 . an electric motor drive 76 , secured by motor bolts , 90 drives auger 60 through the cooperation of a chain drive or the like 78 driven by means of drive sprocket 80 attached to the shaft of electric motor 76 whereby auger sprocket 82 is also driven by drive 76 . the numeral 74 denotes a timer , battery charger and ac to dc converter , operated in well known and conventional manner to power and time the operation of the pet feeding device . numeral 72 denotes a backup power pack to be brought on line whenever a domestic power failure occurs so that power cannot be supplied to the unit by means of electric supply cable 16 ( fig1 ). a food - mixing water supply 62 furnishes water to be mixed with the dry feed in the bin 12 so as to make gravy for the pets greater enjoyment of its food . water is furnished for this purpose under the action of another solenoid valve 63 ( fig6 ). fig3 affords an end view defined by the sight lines 3 -- 3 of fig2 . numeral 84 shows a rear hinge which constrains and operates the top or lid 14 . the water diverting manifold 35 comprises water supply pipe 48 , water supply pipe solenoid valve 49 , food mixing water supply pipe 62 , food mixing water supply solenoid valve 63 and input provision for receiving water from main water supply means 34 . the numerals 94 and 96 denote sprocket teeth on drive sprocket 80 and auger sprocket 82 respectively . referring now to fig4 means to supply and control drinking water for the pet may be examined . within the water container 24 there is situated a float chamber 36 having an interior float 38 . float chamber 36 is connected to water level control mechanism 26 by means of threaded float chamber connection means 58 . water level control mechanism 26 is secured to the wall of the storage bin by means of securing bolts 52 . water is brought into float chamber 36 by means of water supply pipe 48 and connected thereto by water pipe connector 54 . the water thus brought in is dispensed to water container 24 through slots 56 in the float chamber and the open bottom of the float chamber . the switching mechanism , powered by means of electric cables 50 , is operated off by cut off switch actuator 44 . when float 38 is driven upward by a rising water level in water container 24 and thus also in float chamber 36 , horizontal float stem member 42 on vertical float stem 40 will press upward against cut off switch actuator 44 thus acting to cut off the flow of water into water container 24 . conversely when float 38 is allowed to travel downward under the action of gravity and a lowering water level , horizontal float stem member 42 will press downward against cut on switch actuator 46 which is connected so as to permit the flow of water into water container 24 . thus the water level in water container 24 will be maintained within limits specified by limit switches 44 and 46 , said limits comprising an upper water level limit and a lower water level limit . fig5 shows the chute open and close means 64 in its activated position in phantom along with the food mixing water supply 62 . the line schematic drawing of fig6 shows the main water supply means 34 being supplied into the water diverting manifold 35 wherein it is split into two supply legs . one leg , controlled by the food mixing water supply solenoid valve 63 , furnishes water along the feed chute 20 by means of food mixing water supply 62 . the other leg , controlled by water supply pipe solenoid valve 49 , furnishes water to water level control mechanism 26 by means of water supply pipe 48 . thus there has been described a timed automatic pet food and water dispener that will allow the controlled feeding of pets without the owner &# 39 ; s being in personal attendance . great improvements in flexibility , personal freedom , ease of operation , reliability and economy have been provided through the novel advantages of the invention . it is pointed out that although the present invention has been shown and described with reference to a particular embodiment , nevertheless various changes and modifications , apparent to one skilled in the art to which the invention pertains , are deemed to lie within the purview of the invention .

a timed , automatic pet food and water dispenser which incorporates a leveraged loading storage bin for receiving a supply of particulate pet feed and having means for mixing water with said particulate feed therewith to produce a gravy and a softening of said particulate feed . a feed dispensing auger measures a predetermined amount of said particulate feed and furnishes said feed to a feed dish at predetermined time intervals controlled by a timer system . a water container comprising level control means provides water for drinking purposes independently of said timer system .

one aspect provides a composition for promoting bone formation to stabilize an orthopedic implant , the composition comprising an effective amount of a biological factor embedded in a carrier slurry . the carrier slurry includes a biocompatible fluid , a biodegradable polymer and a calcium phosphate compound . a biological factor refers to an osteoinductive substance that stimulates or induces bone growth , or an osteopromotive substance that facilitates bone growth . the term “ osteoinductive substance ” means a substance with the ability to stimulate the proliferation and differentiation of pluripotent mesenchymal stem cells ( mscs ). osteoinduction can be stimulated by osteogenic growth factors , although some ecm proteins can also drive progenitor cells toward the osteogenic phenotype . the term “ osteopromotive substance ” means a substance with the ability to stimulate the biochemical process of bone formation . example biological factors include , but are not limited to , bone morphogenetic proteins ( bmps ), including bmp - 2 , bmp - 3 , bmp - 4 , bmp - 5 , bmp - 6 , bmp - 7 , bmp - 8 , bmp - 9 , bmp - 10 , bmp - 11 , bmp - 12 , bmp - 13 , bmp - 14 , bmp - 15 , bmp - 16 , bmp - 17 , and bmp - 18 ; osteogenic proteins ; vascular endothelial growth factors ( vegfs ), including vegf - a , vegf - b , vegf - c , vegf - d and vegf - e ; connective tissue growth factors ( ctgfs ), including ctgf - 1 , ctgf - 2 , and ctgf - 3 ; osteoprotegerin transforming growth factor betas ( tgf - βs ), including tgf - β - 1 , tgf - β - 2 , and tgf - β - 3 , and inhibitors for tumor necrosis factor ( e . g ., enbrel ®). biological factors may also include platelet derived growth factors ( pdgfs ), including pdgf - a , pdgf - b , pdgf - c , pdgf - d , and gdf - 5 ; rhgdf - 5 ; nell - 1 protein , lim mineralization protein and peptides ; insulin - related growth factor - i ( igf - i ), insulin - related growth factor - ii ( igf - ii ); fibroblast growth factor ( fgf ) and beta - 2 - microglobulin ( bdgf ii ), as disclosed in the u . s . pat . no . 6 , 630 , 153 , which is incorporated herein by reference . the polynucleotides encoding the same may also be administered as gene therapy agents . the biological factor may also include statins , such as lovastatin , mavastatin , pravastatin , simvastatin , compactin ( mevastatin ), atorvastatin , fluvastatin , simvastatin and cerivastatin . simvastatin , mavastatin , fluvastatin and lovastatin were found to activate the promoter for bmp - 2 in rodents . the preferred biological factors are the recombinant human bone morphogenetic proteins ( rhbmps ) because they are available in relatively unlimited supply and do not transmit infectious diseases . most preferably , the bone morphogenetic protein is rhbmp - 2 , rhbmp - 4 , rhbmp - 7 , or heterodimers thereof . the concentration of the biological factor in the carrier slurry may range between about 0 . 01 to 10 mg / cc , i . e weight of the biological factor per volume of the carrier slurry . preferably , the concentration of the biological factor is between approximately 0 . 05 to 2 mg / cc , and more preferably between approximately 0 . 1 to 1 . 0 mg / cc . in certain embodiments , a relatively low dosage of the biological factor may be utilized . this low dosage may induce bone formation without any local transient bone resorption . alternatively , a higher dosage of the biological factor may be required when slow bone growth is expected , for example , in patients with known co - morbidities such as smokers , diabetics , and those on steroids . biological factors such as bmps are water - soluble , relatively low - molecular weight proteins that diffuse very easily in bodily fluids . it has been shown that a bmp delivered without a carrier does not endure more than a few hours at the deposited site . accordingly , a carrier slurry is provided to enclose the biological factor . the term “ carrier slurry ” refers to a flowable biomaterial used to ensure even distribution of the biological factor over the bone or implant surface and to keep the biological factor at the injury site for the desired period of time . it may be preferable that the biological factor is released over approximately a 1 to 30 day period , and more preferably over approximately a 7 to 21 day period . the term “ flowable ” in this context applies to compositions whose consistencies range from those that are deformable , e . g ., those that behave like putty , to those which are runny . the viscosity of slurry in the present invention ranges from about 100 to about 1 × 10 8 centipoises . the lower viscosity compositions are especially suitable when adhesion and entry of the composition into a cancellous bone surface or an open porous textured metal implant surface is desired . alternatively , higher viscosity compositions may be desirable where the composition is to be packed or filled , for example , into a void , defect , interbody fusion device or disc space , as such a composition may be flowable , but may also be cohesive and compression - resistant . the carrier slurry may be formed by hydrating a dry carrier with a biocompatible fluid . the dry carrier may comprise a biodegradable polymer and a calcium phosphate compound in dry form . in preferred embodiments , the ratio of the biodegradable polymer to the calcium phosphate compound is between about 80 : 20 to 40 : 60 by weight , preferably between approximately 75 : 25 and 50 : 50 . the slurry may include more than one type of biodegradable polymer or calcium phosphate . it can also include other additives such as , for example , crosslinking agents . preferably , the volume ratio of the biocompatible fluid to the dry carrier is between about 1 : 1 to 1 : 4 . the biological factor is preferably delivered over a period of approximately 1 to 30 days , and most preferably between approximately 7 to 21 days . accordingly , the amounts of the biodegradable polymer and the calcium phosphate compound should be sufficient so the slurry has a residence time in the body of approximately 1 to 30 days and most preferably approximately 7 to 21 days . the amount of dry carrier may also be selected based on the injury or the size of the implant to provide enough material to sufficiently cover all bone or implant surfaces , or , when applicable , to fill voids or defects in the target site . the term “ biodegradable polymer ” means a synthetic or a naturally derived biodegradable , biocompatible polymer that may be absorbed ( resorbed ) once implanted in a living mammalian body . it may be preferable to use a natural polymer when practicing the present invention . example natural biodegradable polymers include , but are not limited to , collagen , hyaluronic acid , fibrin glue , bone marrow , chitosan , alginate , cellulose , starches , silk , elastin , and other animal - or plant - derived polysaccharides . collagen is the most commonly used carrier . for example , a type i bovine collagen may be used in the present invention . a highly purified resorbable bovine type i collagen may preferably be composed of two formulations of collagen , that is , an insoluble fibrous collagen and a soluble collagen . the weight ratio of insoluble collagen to soluble collagen may be between approximately 30 : 70 and 70 : 30 . the ratio of soluble collagen and insoluble collagen effects the viscosity of the slurry ; using a higher percentage of insoluble collagen results in a thicker slurry . preferably , the collagen in the carrier slurry is a mixture of insoluble collagen fibers and acid - soluble collagen that are prepared from bovine hides , and contain telopeptides and 10 . 5 % to 17 % nitrogen and 10 . 5 % to 14 % hydroxyproline ( average percentage by mass of the collagen portion .) example synthetic polymers include , but are not limited to , polyethylene glycol ( peg ), polyvinyl alcohol ( pva ), polyorthoester ( poe ), polylactic acid ( pla ), polyglycolic acid ( pga ), polyactic - glycolic acid ( plga ) and combinations thereof . examples of calcium phosphate compounds include , but are not limited to , amorphous calcium phosphate , biphasic calcium phosphate , calcium phosphate , dicalcium phosphate , dicalcium phosphate dihydrate , calcium hydroxyapatite ( ha ), carbonated calcium hydroxyapatite , monocalcium phosphate , monocalcium phosphate monohydrate , octacalcium phosphate , tricalcium phosphate , alpha - tricalcium phosphate , beta - tricalcium phosphate ( beta - tcp ), tetracalcium phosphate , and combinations thereof . by way of a non - limiting example , the calcium phosphate compound may be a combination of 15 % ha and 85 % beta - tcp granules . a scaffold is formed where the 15 % ha is uniformly distributed through the 85 % beta - tcp . ha is a slow resorbing mineral that allows time for the remodeling to occur , while the beta - tcp is a quicker resorbing material . the combination is thus optimized to balance bony in - growth and resorption of the scaffold structure . the physical structure of the resulting scaffold emulates the highly osteoconductive porous structure of human cancellous bone , allowing for long - term stability and complete resorption . preferably , the average pore size within the granules is approximately 0 . 1 to 25 microns . the granules are preferably about 0 . 1 to 1 . 6 millimeters in diameter ( 100 to 1600 microns ), and contain a 100 % mineral content . to form a slurry , a biocompatible fluid may be added to the dry carrier , that is , to a dry mixture of a biodegradable polymer and calcium phosphate compound . examples of biocompatible fluids include , but are not limited to , water , saline solution , buffered solutions , blood , blood with thrombin , bone marrow aspirate , glycerol , or other fluids designed to allow the material to set up in situ . in preferred embodiments , the biocompatible fluid comprises buffered solutions , or blood with thrombin . preferably , the volume ratio of the biocompatible fluid to the dry carrier is between 1 : 1 , i . e . slurries with lower viscosities , to 1 : 4 , i . e thick slurries . a 1 : 1 ratio of biocompatible fluid to dry carrier indicates that 1 ml of biocompatible fluid is used for 1 cc of dry carrier . by way of a non - limiting example , in one specific embodiment about 4 to 6 cc of the carrier slurry is provided with the “ bulk ” concentration of the biological factor after mixing with the carrier slurry of between approximately 0 . 10 to 0 . 3 mg / cc . the slurry is formed by hydrating the dry carrier with between approximately 2 ml and 4 ml of the biocompatible fluid . in another embodiment , approximately 7 to 12 cc of the carrier slurry , with a “ bulk ” concentration of the biological factor after mixing with the carrier slurry of between approximately 0 . 5 to 1 . 0 mg / cc , is formed using between approximately 4 and 8 ml of a biocompatible fluid . in some embodiments , where faster resorption is desired , the composition is substantially or completely not cross - linked . in other embodiments , the compositions may be cross - linked . cross - linked compositions may last longer after implantation and may deliver the growth factor over longer periods of time , which may be beneficial for treating defects where the bone growth is slow , or for treating patients with conditions affecting bone healing rates , such as smokers or diabetics . cross - linking is well known in the art . for example , the composition may be crosslinked chemically with a carbodiimide , glutaraldehyde or formaldehyde among others . alternatively , the composition may be crosslinked using e - beam or gamma irradiation or ultraviolet light . cross - linking may also be accomplished by heat via thermal crosslinking . the invention also provides a medical kit for preparation of the combinations described above . as described above , one of the shortcomings of the prior art when attempting to modify the surface of an orthopedic implant was that the coating was applied during the manufacturing of the implant . accordingly , a surgeon had to decide whether to buy a coated or uncoated implant before the surgery , and could not customize the amount of biological factor applied to the implant for a particular procedure . the kit of the present invention addresses these shortcomings by allowing the surgeon to apply the biological factor to the implant herself and to customize both the amount of biological factor used and where to place it on the implant . one embodiment of the kit is shown in fig1 . the kit 10 may comprise a biological factor 22 in a container 20 . container 20 may be any type of sterile container used in the art . preferably , the biological factor 22 is contained in a syringe . the amount of biological factor may range between approximately 0 . 01 mg and 20 mg . in different embodiments , the kit 10 may include different amounts of the biological factor 22 to better meet the requirements of a specific procedure . the amount of biological factor 22 required for a specific procedure may vary depending on the size of the implant , type of injury or health of the patient . the present invention allows a physician to choose a kit with the minimum amount of biological factor sufficient for a specific procedure . this may decrease the cost of the procedure by reducing the amount of unused biological factor that is discarded after the procedure . in some embodiments , as shown in fig1 , the kit may also include a biocompatible fluid 32 in a container 30 for hydration of the biological factor 22 . the volume of biocompatible fluid 32 required to form different compositions may range between approximately 1 ml and 60 ml , and more preferable between 1 ml and 20 ml . the container 30 may be any type of sterile container used in the art . for convenience of use , the biocompatible fluid 32 may also be contained in a syringe 30 that can be connected to the syringe containing the biological factor . to facilitate connection of the containers 20 and 30 , a connector 40 may also be provided in the kit 10 . in order to dissolve the biological factor 22 in the biocompatible fluid 32 , the syringe 20 and the syringe 30 may be connected using the connector 40 as shown in fig2 . then , the syringe 20 containing the biological factor 22 may be loaded with a suitable amount of the biocompatible fluid 32 , as shown in fig3 . alternatively , the kit 10 may provide a single container containing a biocompatible fluid with a pre - dissolved biological factor . the kit 10 may also include a biodegradable polymer 52 and calcium phosphate 54 . the biodegradable polymer 52 and calcium phosphate 54 may be provided either in separate containers or , alternatively , they may be pre - mixed and provided in the same container 50 , as shown in fig1 . in preferred embodiments , the ratio of the biodegradable polymer 52 to the calcium phosphate compound 54 is between about 80 : 20 to 40 : 60 by weight . preferably the volume ratio of the biocompatible fluid used to hydrate the dry carrier is between 1 : 1 and 1 : 4 and the amount of dry carrier is sufficient to form between about 4 and 12 cc of the carrier slurry . the kit 10 may include an applicator 60 that may be used for applying the slurry to bone or an implant . a spatula 70 for mixing the slurry may also be provided with the kit 10 . in addition , a set of instructions ( not shown ) may be provided . the set of instructions preferably includes information necessary for proper use of the kit 10 , such as dosage and timing of administration of the composition . optionally , the set of instructions may also provide secondary information concerning , for example , postoperative care and observations of the patients receiving orthopedic implants coated with the composition of the present invention . a person of ordinary skill in the art will appreciate that the set of instructions can be in any suitable medium , including , without limitation , printed , video - taped , digital , and audio - recorded . in addition to english language instructions , instructions in other languages may be provided . by way of a non - limiting example , in one specific embodiment , the kit comprises between about 0 . 8 and 1 . 2 mg of the biological factor , between about 2 and 4 ml of the biocompatible fluid , and a sufficient amount of the dry carrier to form about 4 to 6 cc of the carrier slurry . in another embodiment , the kit comprises about 3 and 6 mg of the biological factor , between about 4 and 8 ml of the biocompatible fluid , and a sufficient amount of dry carrier to form between approximately 7 and 12 cc of the carrier slurry . the kit provides the surgeon with many of the tools necessary to practice the methods of the present invention . the first step in these methods is preparing the composition comprising a biological factor and a carrier slurry . by the way of a non - limiting example , the slurry may be prepared by following the flowchart in fig4 . in step 91 , the biological factor is hydrated with a biocompatible fluid . one example of this step is presented in fig2 and fig3 , and is described in detail above . alternatively , the biological factor may be provided pre - mixed within a biocompatible fluid , as indicated by step 92 . next , as indicated by step 93 , the biodegradable polymer and calcium phosphate compound may be mixed to form a dry carrier if provided in separate containers . alternatively , as indicated by step 94 , the dry carrier may be provided pre - mixed . in step 95 , the hydrated biological factor is then added to the dry carrier to form carrier slurry . next , in step 96 , the slurry is mixed to ensure homogeneity of the slurry and an even distribution of the biological factor throughout the slurry . the slurry can be mixed manually using a spatula , or may be mixed using mechanical equipment such as blenders , homogenizers , dispersers , mixers or similar devices . with reference to fig5 , after the slurry has been prepared , as indicated by step 100 , the slurry can be applied to the site of the injury . in one embodiment , indicated in step 101 , the slurry can be applied directly to the injured bone . various application methods may be used to apply the slurry to the target site . for example , because certain embodiments of the composition are flowable but cohesive and compression resistant , the composition may be injected into the target site using a cannula or syringe of sufficient diameter and should thereafter remain at the target site , thus providing a minimally invasive treatment . in a subsequent step 102 , the bone is then stabilized . one example of stabilizing the injured bone using an orthopedic implant is indicated in steps 103 and 104 , and may include making a cavity in the bone and inserting the implant into the bone 104 . in a subsequent step 105 , the composition may then be applied to the implant if desired . in addition to using the orthopedic implant , other well known methods to stabilize the bone may be used , as indicated in step 106 . for example , a fractured limb may be immobilized with a plaster or fiberglass cast , which holds the bones in position and immobilizes the joints above and below the fracture . in another embodiment , indicated by step 107 , the slurry is applied to an orthopedic implant using the applicator or by dipping the implant into the slurry . in step 108 , the implant may then be placed in or around the injured area . alternatively , the implant may be first placed in or around the injured area and then the slurry may be applied . the composition may also be applied to the implant both before and after the insertion . in addition to applying the composition to the implant , the composition may be applied directly to the injured area , as indicated by step 109 . all publications cited in the specification , both patent publications and non - patent publications , are indicative of the level of skill of those reasonably skilled in the art to which this invention pertains . all these publications are herein fully incorporated by reference to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference . although the invention herein has been described with reference to particular embodiments , it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention . it is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the following claims .

a composition is provided for faster bone repair and early orthopedic implant fixation . the composition comprises an osteoinductive or osteopromotive biological factor embedded in a carrier slurry . the slurry is prepared by wetting a biodegradable polymer and calcium phosphate particles with a biocompatible fluid . the composition may be applied to the site of the bone fracture , to an orthopedic implant or to both during the surgical procedure . the composition utilizes low dosages of the biological factor and , therefore , is cost effective to be used routinely .

identical components are provided with identical reference numerals in all the figures . fig1 shows a first embodiment of a transport container 1 according to the present disclosure at an open position . the transport container 1 comprises a lower component 2 and an upper component 3 , each having a semicylindrical shape . the lower component 2 and the upper component 3 may consist e . g . of a high pressure - resistant plastic material . the lower component 2 and the upper component 3 are connected to one another on their longitudinal sides via a first hinge 4 . the first hinge 4 defines a first swivelling axis 5 about which the upper component 3 can be swivelled relative to the lower component 2 so as to close the transport container 1 . the lower component 2 as well as the upper component 3 are provided with approximately semicircular end faces 6 at both ends thereof , when seen in the longitudinal direction . the end face 6 is flat so that a slide ( not shown ) can act more easily on a closed transport container 1 so as to push the transport container into and out of a high - pressure plant . each of the flat end faces 6 has provided therein openings 7 through which high - pressure medium can enter the closed transport container 1 so that the products accommodated in the transport container 1 are subjected to high pressure . if necessary , the cylinder sides may be provided with openings 7 as well . via a second hinge 8 , the upper component 3 has secured thereto a retaining element 9 implemented as a grating . the second hinge 8 defines a second swivelling axis 10 about which the retaining element 9 can be swivelled relative to the upper component 3 . in particular , the retaining element 9 can be swivelled from the open position shown in fig1 by 180 ° counterclockwise so that the outer edge 11 of the retaining element 9 will abut on the first hinge 4 . in the area of the first hinge 4 and on the outer edge 11 of the retaining element 9 , a closure member ( not shown ) can be provided , by means of which the retaining element 9 can be fastened releasably in the position in which it closes the upper component . the meshes 12 of the grating - shaped retaining element 9 define openings through which the high - pressure medium can flow freely between the lower component 2 and the upper component 3 , so that pressure compensation is accomplished between the two components of the transport container 1 . fig2 shows the transport container 1 according to fig1 in a closed position . in the open condition , both the lower component 2 and the upper component 3 of the transport container 1 were first filled with products 13 . fig2 shows , exemplarily , three rectangular sectioned products 13 , such as packaged foods , accommodated in the upper component 3 . also the other areas of the lower component 2 and of the upper component 3 have been filled with products 13 — as far as the geometry of the products 13 allows such filling . subsequently , the retaining element 9 has been swivelled about the second swivelling axis 10 and moved to a closed position where it is secured in position by the closure member ( not shown ). finally , the upper component 3 has been swivelled about the swivelling axis 5 defined by the first hinge 4 . the transport container 1 is thus closed and assumes the cylindrical shape shown in fig2 . in the closed position , the upper component 3 can be secured in position on the lower component 2 by a fastener so as to prevent the transport container 1 from being opened unintentionally . fig3 shows a second embodiment of a transport container 1 according to the present disclosure . also in this embodiment the transport container 1 comprises a lower component 2 and an upper component 3 , each of said components being semicylindrical in shape . for the sake of clarity , the openings 7 through which the high - pressure medium flows are not shown . a first difference in comparison with the first embodiment is that , in the second embodiment , the lower component 2 and the upper component 3 are not permanently connected to one another , but they are adapted to be releasably interconnected . in fig3 , they are shown in a condition in which they are separated from one another and in which the two components 2 , 3 are freely accessible with their filling opening 14 facing upwards , so that products 13 can be filled into said components 2 , 3 or removed therefrom . in the closed position of the transport container shown in fig2 , the two components 2 , 3 are secured in position on one another by a fastener . a second difference in comparison with the first embodiment is that both the lower component 2 and the upper component 3 now have a retaining element 9 of their own , said retaining element 9 being again grating - shaped . finally , another difference is to be seen in that both the lower component 2 and the upper component 3 each have a rail 15 . the respective retaining element 9 can be inserted into the rail 15 of the associated component 2 , 3 of the transport container 1 in the direction of the arrow p so as to cover the filling opening 14 and secure thus the filled - in products 13 in position in the respective component 2 , 3 of the transport container 1 . in its closed position , the retaining element 9 can be held on the respective component 2 , 3 of the transport container 1 either by a closure member or only by gravitation . when the two individual components 2 , 3 of the transport container 1 have been closed , they are placed one on top of the other in such a way that the closed , cylindrical transport container 1 according to fig2 is obtained . fig4 shows a cross - section through the closed transport container 1 filled with products 13 . whereas the products 13 in the lower component 2 rest on the bottom of said lower component 2 , the products 13 in the upper component 3 of the transport container rest on the retaining element 9 . the retaining element 9 thus holds the products 13 in the upper component 3 . spaces 16 between the products allow the high - pressure medium to pass through and — in cooperation with the openings 12 in the retaining element 9 — they provide pressure compensation in the transport container 1 in its entirety . a comparison with fig5 shows clearly that the transport container 1 according to the present invention achieves , in the case of automated filling , a much higher degree of filling than the conventional transport container 100 . whereas the transport container 1 according to the present invention accommodates twenty two products , the conventional transport container 100 , which has the same external dimensions , is only able to accommodate seventeen products . due to the higher degree of filling , the transport container 1 according to the present invention provides a much higher efficiency and a much higher throughput in a high - pressure treatment plant . starting from the above - described embodiments , the transport container 1 according to the present invention can be modified in many ways . in particular , arbitrary combinations are imaginable between lower and upper components 2 , 3 which are secured to one another releasably or permanently , retaining elements 9 which are secured , releasably or permanently , to one of said lower and upper components 2 , 3 or to both of them , as well as retaining elements 9 which are movably supported on the respective component 2 , 3 via a hinge 8 or a rail 15 . in addition , variants are imaginable in the case of which additional subdivisions or possibly removable partitions for securing the products 13 in position are provided in the lower component 2 or in the upper component 3 , or in the case of which the retaining element 9 has a different structural design . for example , a net or a group of chain links may be provided as a retaining element 9 , or the retaining element 9 could be largely closed and could have provided therein only a small number of openings 12 through which the high - pressure medium can flow . instead of a hinge 4 , also other suitable systems , e . g . plug connections , may be used for interconnecting the lower component 2 and the upper component 3 of the transport container 1 permanently or releasably . in addition , it is also possible to provide spring - biased safety elements on the lower component 2 , on the upper component 3 and / or on the retaining element 9 so as to retain the products 13 more reliably in position when an only partially filled transport container 1 is being conveyed and / or during the high - pressure treatment itself . an only partially filled transport container 1 may occur e . g . during a change of batches , when the production line is run empty , or when the individual packages have a disadvantageous geometry as regards filling . the safety elements will then guarantee that the products 13 will neither shift nor tilt so that their position in the transport container 1 will not change between loading and unloading of the transport container 1 . this makes automated unloading of the transport container 1 much easier . such a safety element may e . g . be provided in the form of a board which rests on the retaining element 9 via one or a plurality of pressure springs and which thus forces the products 13 contained in the lower component 2 of the transport container downwards . the safety elements may , however , also be acted upon by a spring vertically upwards or in a lateral direction . while embodiments of the invention have been illustrated and described , it is not intended that these embodiments illustrate and describe all possible forms of the invention . rather , the words used in the specification are words of description rather than limitation , and it is understood that various changes may be made without departing from the spirit and scope of the invention .

the disclosure relates to a transport container for accommodating products during a high - pressure treatment of these products . by means of the transport container , the products can be transported into and out of a chamber in which they are high - pressure treated . the transport container comprises a lower component and an upper component which are adapted to be connected to one another , the lower component as well as the upper component being configured for accommodating at least one product .

the use of a negative pressure applied on the shaping elements in a method for producing a bone implant surprisingly led to a desired result . the shaping elements are filled loosely into a tool and are charged with or subjected to a defined negative pressure in a vacuum - sealed system and subsequently the frame - forming mass is added to the tool utilizing the suction and cured by applying the defined negative pressure to the shaping elements and frame forming mass at a defined temperature over a defined period of time . alternatively , the shaping elements are charged with or subjected to the defined negative pressure together with the frame forming material after the filling of the tool with the frame forming material and simultaneously cooled - down , e . g . by a metal setting plate of the tool . this arrangement led to further standardized results and comprises the following steps : the loose filling of shaping elements into the tool and the structure - forming framing material mass was added , and the closed tool or container , which was not vacuum - sealed , was subjected to a defined negative pressure at a defined temperature and over a defined period of time under vacuum , and the material and tool were simultaneously cooled - down through the setting or cooling plate of the tool . the simple handling of this process made the result highly reproducible . however , also this result could surprisingly be further enhanced in view of the adjustable porosity of the surface by utilizing a deformable silicone mould instead of a solid metallic tool . this resulted in the implant , dependent on the applied negative pressure , having a continuous porosity extending up to the surface , said porosity being controllable through the amount of negative pressure on the one side and the elastic modulus of the tool on the other side . this method enables one to achieve a continuous porosity even if the shaping elements were not expandable , e . g . not air - containing , but were e . g . sugar spheres . as the shaping elements in this method , preferably expandable polystyrene spheres ( eps ) are used , e . g . styrofoam ® f414 expanded polystyrene , which is foamed with pentane as an expanding agent . upon applying a negative pressure , these spheres expand very fast and increase in volume . in this way , the contact bridge between the spheres becomes wider and therewith determines the diameter of the interconnecting passages in the frame - forming material up to the surface . upon using of a silicone tool , the spheres squeeze into the silicone wall and , furthermore , the negative pressure draws the deformable wall over the sphere surfaces into the implant . foamed materials to be used as shaping elements are preferably employed , also those to which an expanding agent was added , which is activated at a specific temperature or under specific preconditions . an especially preferred material is styrofoam ® f414 expanded polystyrene , having a preferred volumetric weight of the foamed polystyrene between 17 g / l and 70 g / l , preferably approx . 20 g / l to 35 g / l . the grain size distribution of the foamed material lies between 200 μm and 15 mm , and one can also use sizes between 1000 μm and 3000 μm . in order to determine the expansion and the deformability of the individual shaping elements , experiments were performed to determine the parameters in a simple manner , said parameters being required for the standardization of the method . for this purpose , different shaping elements having different volumetric weights , e . g . differently foamed polystyrene spheres having different diameters , were filled into a cylinder with movable , vacuum - sealed abutting pistons up to a defined height of 84 . 3 mm and exposed to a defined vacuum . from the change of the original height in dependency of the applied negative pressure , quantities were determined which represent an initial reduction of volume by removal of air between the shaping elements , followed by an expansion of volume which was adjustable to the former initial length by applying a force f , measured in n , and which represented the expansion pressure of the air in the shaping elements . depending on the time period , the force slowly decreased , which could be explained by the bursting of the air bubbles in the plastics . based on this phenomenon , the defined time periods for the charging with negative pressure were determined . pressures between 150 mbar and 800 mbar , preferably approximately 300 mbar to 500 mbar , over a time period of 15 minutes , applied on a phosphate - agar mixture , at a temperature of the implant of 4 to 12 ° c ., showed especially advantageous results in view of the outside porosity and the inner interconnections . deformable moulds , in particular silicones having a shore hardness below 25 shore , preferably below 18 - 20 shore , that can be used in casting or injection die casting methods are suitable . however , all plastically or elastically deformable materials can be used , the elastic modulus of which lies clearly below that of the shaping elements . correspondingly , the tools can be cast , but also can be manufactured in mass production with injection moulding methods . examples for plastically deformable tools are tools made of styrofoam ® expanded polystyrene having different density , examples for elastically deformable tools are the aforementioned silicones , wherein foamed silicones can also be used . these materials expand under negative pressure , and the expansion pressure of said materials in vacuum adds to the above described effect of the expandable shaping elements . castable framing materials including a mixture of hydroxylapatite ( ha ) or tricalciumphosphate ( tcp ) and an agar solution in a ratio of 10 g powder / 7 ml to 25 ml solution , which corresponds to a ratio of 1 . 4 to 0 . 4 , are preferably used . ideal preparations include a mixing ratio powder / solution that corresponds to 0 . 45 to 0 . 48 , e . g . 1600 g ha for 3500 ml of solution . depending on the composition , the shrinking factor can already be calculated on the basis of the preparation and lies between 0 . 95 to 2 . 9 , preferably between 1 . 75 and 2 . 15 . for a ha - agar mixture capable of flowing , which is filled at a temperature of 60 ° c ., at a ratio of 16 g / 35 ml of a 1 . 7 % agar solution , the shrinking factor is exactly 1 . 91 . upon these preconditions , i . e ., expandable shaping elements , a deformable silicone mould and an exact preparation with defined shrinking , very precise implants could be sintered net shaped , without the necessity of a post - processing . the definite design multiplied with the shrinking factor leads , e . g ., to an implant body made of plastics or any other material being easily processable in a cad / cam process , which is re - cast with a castable silicone in an original mould up to the top edge . after curing of the silicone , the shaping body can be easily mechanically removed . the silicone mould is perforated several times at the bottom and is subsequently filled with polystyrene spheres of a desired size , then closed with a silicone lid having venting holes . the mould or tool is then filled with a ceramic material forming a ceramic mass . immediately after the filling , the tool or mould is subjected to a negative pressure in a vacuum and drying chamber and cooled down to 4 - 12 ° c ., e . g ., through a setting or cooling plate . after curing of the ceramic mass , the tool can be de - assembled and the body of ceramic material and expanded polystyrene spheres can be easily removed . in an acetone washing , the spheres of styrofoam ® expanded polystyrene are dissolved from the ceramic mass , which forms the implant body . the ceramic mass forming the implant body is dehydrated in a series of steps using 70 / 80 / 90 and 100 % acetone , respectively . after each wash step the implant body is dried in air while it cools ( cool drying ). the weight of the implant body is documented every hour by means of a precision scale ; if no further loss of weight in the air begins to show and the curve of the weight remains linearly unchanged , the implant body is dried for 24 hours in a vacuum and drying chamber by adding p 2 o 5 in a vacuum of 150 - 250 mbar absolute pressure . the implant body is subsequently sintered at 1300 ° c . in a sintering furnace . this results in an open pore implant body that is true to size , and which has a clearly higher strength compared to mechanically post - processed bone substitute material cylinders or cubes . said strength of the implant body can be further increased by an outside structuring , e . g . rings , contractions , massive edges etc . in fig1 , a simple vacuum and drying chamber ( 10 ) is described , comprising a venting valve ( 13 ) and a tap for attaching a pipe leading to the vacuum pump ( 12 ) and a metallic cooling plate ( 11 ) having a filling tool ( 1 ) arranged on the cooling plate ( 11 ) and having a deformable tool received in a flush manner . the deformable tool comprises three parts , a body ( 2 ) that contains spherical shaping elements ( 9 ), a lid ( 7 ) with perforations ( 4 ) and a bottom ( 8 ) with perforations ( 5 ) for filling of a material such as a ceramic mass into the deformable tool . in fig2 a and 2 b , ceramic implants ( 20 ) according to the invention are shown , in fig2 a in a plan view and in fig2 b as a sectional view upon breaking open . the plan view of the sphere shell shows the open pores ( 22 ) and the rough shell ( 21 ). in the sectional view , the interconnecting pore structure ( 23 ) is shown . in fig3 , an implant according to the invention is shown as a bone dowel ( 30 ), e . g . for re - fixing a ligament in case of a cruciate ligament substitute across the outside of the dowel . the dowel ( 30 ) comprises horizontal ( 31 ) contractions , which can preferably also be arranged helically , and the outer shell is interrupted by spaced pores ( 32 ) across the complete surface . in fig4 , a light ceramic implant ( 40 ) is shown , sintered in this shape , having open pores across the complete outer surface ( 43 ), and comprising crossing depressions or channels ( 41 , 42 ), in which the eye muscles can be sewed , and which is used as a part of an artificial eye . fig5 shows a sphere conglomerate ( 50 ) consisting of solid spheres or sphere elements ( 51 ), which may however also consist of the elements of fig2 . the sphere conglomerate ( 50 ) features wide bridges ( 52 ) between the sphere elements and regular sphere intervals ( 53 ) that form pores or cavities . in fig6 a cross - section of a porous implant 60 is illustrated . the diameter of the pore of the outer shell is smaller than the diameter of the cavity connected therewith , in ratios of between 1 : 5 as illustrated at 62 to 1 : 1 . 5 as illustrated at 64 , and more particularly with the preferred range of ratios of 1 : 2 as illustrated at 66 to 1 : 3 as illustrated at 68 . the implant body 60 may be configured such that the cavity system is optionally coated with a filler material 70 having dampening or reinforcing properties , in a manner that the filling is restricted to the inside of the implant body and selectively completely fills same . the filler material 70 may be an absorbable or non - absorbable organic or inorganic filler material . styrofoam ® expanded polystyrene spheres having a diameter of 12 mm are immersed and introduced into a forming tool that is filled with hot wax having a temperature of 90 ° c . and being taken from the heating furnace for this purpose , said forming tool being within a cylindrical container having a perforated bottom with boreholes of 10 - 11 mm in diameter and a fixable lid seated flush on the spheres and having the same size boreholes . the forming tool with the wax and styrofoam ® expanded polystyrene spheres , fits flush into a cylindrical mould which has a removable bottom . after curing of the wax at room temperature , the bottom of the cylindrical mould is removed and the forming tool containing the wax and styrofoam ® expanded polystyrene spheres is pressed out . the forming tool holding the wax and styrofoam ® expanded polystyrene spheres is also separated from its bottom and lid and the formed wax - styrofoam ® expanded polystyrene spheres cylinder is pressed out and the styrofoam ® expanded polystyrene spheres are removed in an acetone washing . after drying in air , the resulting continuous , interconnecting , porous wax framing is inserted into a filling container receiving the framing in a flush manner . the filling container has a filler neck with perforations at the bottom of the container and may also contain a screen which is required for suctioning smaller styrofoam ® expanded polystyrene spheres into the cavity system of the wax framing . furthermore , the filling container is provided with a lid having venting boreholes , e . g ., having a diameter of 1 . 5 to 2 . 5 mm . styrofoam ® expanded polystyrene spheres having a diameter of e . g . 600 - 1200 μm are suctioned into the cavities in the wax framing , wherein a screen having a mesh size of 400 μm is arranged upstream . the cavity system of the wax framing is completely filled with the smaller styrofoam ® expanded polystyrene spheres and is then closed with a lid . the filling container is now filled with a ceramic mass , wherein the ceramic material forming the ceramic mass is filled into the filling container through the filler neck and suctioned in through the venting holes or the ceramic material is filled into the filling container without pressure simply through the filler neck . if the ceramic mass protrudes through the venting holes of the lid , the mould is filled and is put into a vacuum and drying chamber together with the tool and charged with a negative pressure of 500 - 600 mbar for 15 minutes and cooled - down during this time period by the metallic setting or cooling plate shown at ( 11 ) in fig1 . the thus cured wax - ceramic - styrofoam ® expanded polystyrene spheres are subsequently washed in acetone to remove the styrofoam ® expanded polystyrene in the acetone washing , dried in air and sintered together with the wax in a furnace at 1300 ° c . this results in completely isolated , at the outside a continuously porous and at the inside interconnected porous spheres having a diameter of 6 mm . due to the shrinking of the matrix material , completely separated spheres are formed . instead of individual porous spheres , an interesting material may be produced , which corresponds to a negative print of the marrow combs , and a sphere conglomerate having gaps between the porous spheres for the ingrowing of bone trabeculae and wide connecting bridges , which correspond to the contact points of the spheres : the steps correspond to example 1 , however , the wax - styrofoam ® expanded polystyrene framing or body is exposed to a defined negative pressure of e . g . 600 mbar during the curing in the vacuum and drying chamber . the following expansion of the styrofoam ® expanded polystyrene spheres results in wider bridges and thicker connecting arms between the spheres . after curing of the wax - styrofoam ® expanded polystyrene sphere framing or body , the styrofoam ® expanded polystyrene spheres are removed . the following steps correspond to example 1 , with suctioning into the cavities of the ceramic framing of the smaller styrofoam ® expanded polystyrene spheres , filling with ceramic material forming a ceramic mass , post - evacuating by cooling and subsequent dissolving of the shaping elements in acetone . contrary to example 1 , the cool drying step follows in steps of 2 hours each , in 70 / 80 / 90 and 3 × 100 % acetone , cooling in air in steps in the freezer , at 4 - 12 ° c . increasingly in e . g . 4 steps of 3 hours each until room temperature is reached and subsequently dehydration in the vacuum and drying chamber by using p 2 o 5 and a vacuum of about 150 mbar absolute pressure during 24 hours . upon such a procedure , wide bridges between the porous spheres remain and the wax framing may be burnt at e . g . 1300 ° c . together with the ceramic inlet . the wax may also be melted off in the heat furnace at 90 ° c . ; a precondition is that the ceramic mass is already dried in air . the result is a perfect framing made of interrelated , in the inside perfectly interconnected porous spheres with a continuous porous surface and an astonishingly high compression strength , which lies between 4 - 12 mpa , depending on the size of the spheres . this example relates to the production of a cube true in size , having an edge length of 15 mm and an open porosity over all surfaces . upon a matrix mass of 16 / 35 ha / agar suspension of 1 . 7 %, a shrinking factor of 1 . 91 is calculated and in a cad / cam process , a cube made of pom having an edge length of 28 . 65 mm is produced . since the cube achieves a high strength of 4 - 6 mpa , the edges are not rounded . the cube is put into a moulding tool and poured with self - curing silicone up to its top edge . after 24 hours , the cube is removed mechanically and the silicone tool is inserted into a filling tool , the bottom of which consists inside of a perforated silicone bottom and is covered in a flush manner with a silicone lid having venting holes after having been filled with 1200 μm sized styrofoam ® expanded polystyrene spheres . after the tool was closed with a screw cap having venting holes , it is filled with a ceramic material forming a ceramic mass . subsequently , the charging with negative pressure of 500 mbar for 15 minutes upon simultaneous cooling occurs in the vacuum and drying chamber on a metallic and coolable setting plate . after that , the tool is de - assembled and the ceramic - styrofoam ® expanded polystyrene cube is carefully taken out mechanically and washed in acetone to remove the polystyrene spheres in the acetone washing , leaving a ceramic frame . for a crack - free drying , a cool dehydration follows , as described in examples 1 and 2 , and subsequently , the ceramic frame cube is sintered in a furnace at about 1300 ° c . the result is a cube true in size and having a very high compressive strength , with open porosity over all surfaces and a continuously interconnecting porosity of the inner structure and reinforced edges made of solid ceramics .

implants and methods for producing same are described , the implants featuring an adjustable porous shell , the inside being continuously interconnectingly adjustably porous and which can be sintered net shaped ; these implants exhibit a high compression stability and show , when being combined with filler materials with or without active agents , different chemical , physical - mechanical , biomechanical or also pharmacological properties . the essential features of the manufacturing process are described in fig . and comprise expandable shaping elements , deformable elastic tools , the application of defined negative pressures , temperatures during defined application periods in combination with combined materials , which can be separated from each other physically , chemically or mechanically and removed .

referring now specifically to the drawings , a power generation system and method according to a preferred embodiment of the present invention is illustrated in fig1 and is shown generally at reference numeral 10 . the power generation system 10 generally comprises a water inlet 12 , an inlet pipe 14 , energy generation station 16 , an outlet pipe 18 , and a water outlet 20 . the water inlet 12 may be any water inlet known to one of ordinary skill in the art , including a fire department connection ( s ) ( fdc ) point exterior of a building . fdcs are commonly utilized by the fire department to add water supply to the fire suppressant piping in a building that supplies water to the sprinklers . the present invention would not increase the water supply to the sprinklers , but would consist of a water inlet 12 located in close proximity to the standard fdc and utilizing a connection similar to that employed by an fdc . the inlet pipe 14 transports water , or other suitable liquid , from the water inlet 12 to the energy generation station 16 . the energy generation station 16 may produce electrical energy or mechanical power , depending upon the configuration of the energy generation station 16 as described in more detail below . the inlet pipe 14 consists of any material that is suitable to transport water , or other suitable liquid , from one location to another based upon the desires of the user . preferably , the inlet pipe 14 is composed of mild steel with an anticorrosive coating ; however , it should be noted that any material capable of transporting pressurized water may be utilized , including but not limited to , polyvinyl chloride ( pvc / upvc ), ductile iron , polyethylene , copper , concrete , stainless steel , and galvanized steel . the inlet pipe 14 transports water from the water inlet 12 to the energy generation station 16 . the energy generation station 16 consists of a water turbine and generator 28 . the water turbine contains blades , and the inlet pipe 14 deposits water onto the blades , creating a force on the blades . the shape of the turbine blades is determined by the pressure of the water entering the generation station 16 from the water inlet 14 . generally , the water exits the inlet pipe 14 and the blades of the turbine are impelled by the water flowing through the turbine . as is well known in the art , the generator converts the mechanical energy produced by the flowing water impelling the blades , converting the mechanical energy to electrical energy . as is well known in the art , the blades are engaged to a turbine - generator shaft . the rotational movement of the blades causes the turbine - generator shaft to rotate . the turbine - generator shaft is engaged to a rotor that also rotates when the turbine - generator shaft rotates . the rotor rotates around a stationary stator , thus producing an electrical current . the electrical current is then used to power a number of devices as set forth in more detail below . in another alternative embodiment , the energy generation station 16 consists of blades 28 within a housing for providing mechanical power . as the water exits the inlet pipe 14 , the blades 28 are impelled by the water , thus causing the blades 28 to rotate . the blades 28 are attached to a drive shaft 22 that rotates at the same rotational velocity as the blades 28 . in other words , as the blades 28 rotate , the rotational movement of the blades 28 drives the drive shaft 22 . a clutch 24 is disposed between the drive shaft 22 and power shaft 26 . the end of the power shaft 26 may be engaged to a device for supplying rotational movement . a flywheel ( not shown ) stores kinetic energy and aids in reducing speed variation caused by load variations . the flywheel stores the kinetic energy and aids in reducing speed variations caused by load variations . the type of flywheel utilized will be determined by the desires of the user . the clutch 24 is engaged and disengaged by a piston 40 . the piston 40 , may be powered by a solenoid control 48 , which drives the piston 40 , thus engaging and disengaging the clutch 24 . in one alternative embodiment , the piston is positioned within the water outlet pipe 18 . however , the piston 40 may be positioned in any arrangement suitable for engaging and disengaging the clutch 24 . the solenoid control 48 may be any device capable of moving the piston 40 in a vertical direction to engage and disengage the clutch 24 . after the water has impeded the blades , the water exits the energy generation station 16 through an outlet pipe 18 . the outlet pipe 18 consists of any material that is suitable to transport water , or other suitable liquid , from one location to another based upon the desires of the user . preferably , the outlet pipe 18 is composed of the same material as the inlet pipe 14 . the outlet pipe 18 may be composed of mild steel with an anticorrosive coating ; however , it should be noted that any material capable of transporting pressurized water may be utilized , including but not limited to polyvinyl chloride ( pvc / upvc ), ductile iron , polyethylene , copper , concrete , stainless steel , and galvanized steel . the outlet pipe 18 transports water from the energy generation station 16 . in another exemplary embodiment of the present invention as illustrated in fig2 , the power generation system 110 generally comprises a water inlet 112 , an inlet pipe 114 , energy generation station 116 , an outlet pipe 118 , and a water outlet 120 . the inlet pipe 114 transports water , or other suitable liquid , from the water inlet 112 to the energy generation station 116 . the energy generation station 116 consists of a water turbine and generator . the water turbine contains blades , and the inlet pipe 114 deposits water onto the blades , creating a force on the blades . the shape of the turbine blades is determined by the pressure of the water entering the generation station 116 from the water inlet 114 . generally , the water exits the inlet pipe 114 and the blades of the turbine are impelled by the water flowing through the turbine . as is well known in the art , the generator converts the mechanical energy produced by the flowing water impelling the blades , converting the mechanical energy to electrical energy . as is well known in the art , the blades are engaged to a turbine - generator shaft . the rotational movement of the blades causes the turbine - generator shaft to rotate . the turbine - generator shaft is engaged to a rotor that also rotates when the turbine - generator shaft rotates . the rotor rotates around a stationary stator , thus producing an electrical current . the electrical current is then used to provide power to drive the drive shaft 122 . in another alternative embodiment , the energy generation station 116 consists of blades within a housing for providing mechanical power . as the water exits the inlet pipe 114 , the blades are impelled by the water , thus causing the blades to rotate . the blades are attached to a drive shaft 122 that rotates at the same rotational velocity as the blades . in other words , as the blades rotate , the rotational movement of the blades drive the drive shaft 122 . a clutch 124 is disposed between the drive shaft 122 and power shaft 126 . a flywheel ( not shown ) which stores kinetic energy and aids in reducing speed variation caused by load variations may be engaged to the drive shaft 122 . the flywheel stores the kinetic energy and aids in reducing speed variations caused by load variations . the type of flywheel utilized will be determined by the desires of the user . the drive shaft 122 , as illustrated in fig2 , is engaged to a first gear 130 optionally positioned within a gear box 132 . the first gear 130 is engaged to a second gear 134 . the second gear 134 drives a second drive shaft 136 . the angle between the drive shaft 122 and second drive shaft 136 is about 90 °; therefore , the first gear 130 and second gear 134 may be helical gears or a wormset . the angles between the axes of the cones of the gears and the included angles of the cones can be any compatable value as long as the apices of the cones intersect . failure of the apices of the cones to intersect would cause a mismatch of velocity at the interface . the apex of each gear cone has a zero radius , thus zero velocity . all other points on the gear cone will have a nonzero velocity . if a bevel gear is utilized , the velocity ratio of the bevel gears is defined by the following equation : a straight bevel gear may be utilized , wherein the teeth are parallel to the axis of the gear . alternatively , a spiral bevel gear may be utilized , wherein the teeth are angled with respect to the axis of the gear . in any event , the cone axes must intersect in both cases . the first gear 130 drives the second gear 134 , which in return rotates the second drive shaft 136 . a clutch 124 is disposed between the drive shaft 122 and a power shaft 126 . the end of the power shaft 126 may be engaged to a device for supplying rotational movement . a flywheel ( not shown ) stores kinetic energy and aids in reducing speed variation caused by load variations . the type of flywheel utilized will be determined by the desires of the user . the clutch 124 is engaged and disengaged by a piston 140 . the piston 140 , may be powered by a solenoid control 148 , which drives the piston 140 , thus engaging and disengaging the clutch 124 . in one alternative embodiment , the piston is positioned within the water outlet pipe 118 . however , the piston 140 may be positioned in any arrangement suitable for engaging and disengaging the clutch 124 . after the water exits the energy generation station 116 through the outlet pipe 118 . the outlet pipe 118 consists of any material that is suitable to transport water , or other suitable liquid , from one location to another based upon the desires of the user . preferably , the outlet pipe 118 is composed of the same material as the inlet pipe 114 . the outlet pipe 118 may be composed of mild steel with an anticorrosive coating ; however , it should be noted that any material capable of transporting pressurized water may be utilized , including but not limited to polyvinyl chloride ( pvc / upvc ), ductile iron , polyethylene , copper , concrete , stainless steel , and galvanized steel . the outlet pipe 118 transports water from the energy generation station 116 . in another alternative embodiment , as illustrated in fig3 , the inlet pipe 214 transports water , or other suitable liquid , from the water inlet 212 to the energy generation station 216 . the inlet pipe 214 consists of any material that is suitable to transport water , or other suitable liquid , from one location to another based upon the desires of the user . preferably , the inlet pipe 214 is composed of mild steel with an anticorrosive coating ; however , it should be noted that any material capable of transporting pressurized water may be utilized , including but not limited to polyvinyl chloride ( pvc / upvc ), ductile iron , polyethylene , copper , concrete , stainless steel , and galvanized steel . the inlet pipe 214 transports water from the water inlet 212 to the energy generation station 216 . in another alternative embodiment , the energy generation station 216 consists of blades 228 within a housing . as the water exits the inlet pipe 214 , the blades 228 are impelled by the water , thus causing the blades 228 to rotate . the blades 228 are attached to a first drive shaft 222 that rotates at the same rotational velocity as the blades 228 . in other words , as the blades 228 rotate , the rotational movement of the blades 228 drives the drive shaft 222 . the first drive shaft 222 , as illustrated in fig3 , is engaged to a first gear 230 optionally positioned within a gear box 232 . the first gear 230 is engaged to a second gear 234 . the second gear 234 drives a second drive shaft 236 . the angle between the drive shaft 222 and second drive shaft 236 is about 90 °; therefore , the first gear 230 and second gear 234 may be helical gears or a wormset housed within a gear box 232 . the first gear 230 drives the second gear 234 , which in return rotates the second drive shaft 236 . a clutch 224 is disposed between the second drive shaft 234 and a power shaft 226 . the end of the power shaft 226 may be engaged to a device for supplying rotational movement . a flywheel ( not shown ) stores kinetic energy and aids in reducing speed variation caused by load variations . the type of flywheel utilized will be determined by the desires of the user . the clutch 224 is engaged and disengaged by a piston 240 . the piston 240 , may be powered by a solenoid control , which drives the piston 240 , thus engaging and disengaging the clutch 224 . in one alternative embodiment , the piston is positioned within the water outlet pipe 218 . however , the piston 240 may be positioned in any arrangement suitable for engaging and disengaging the clutch 224 . the water exits the energy generation station 216 through an outlet pipe 218 . the outlet pipe 218 consists of any material that is suitable to transport water , or other suitable liquid , from one location to another based upon the desires of the user . preferably , the outlet pipe 218 is composed of the same material as the inlet pipe 214 . the outlet pipe 218 may be composed of mild steel with an anticorrosive coating ; however , it should be noted that any material capable of transporting pressurized water may be utilized , including but not limited to polyvinyl chloride ( pvc / upvc ), ductile iron , polyethylene , copper , concrete , stainless steel , and galvanized steel . the outlet pipe 218 transports water from the energy generation station 216 that is discharged through the water outlet 220 . in yet another exemplary embodiment of the present invention , as illustrated in fig4 , water is pumped into a water inlet 312 and into a first water vane 342 . a motor 344 rotates the water vane 342 , which forces water through an inlet pipe 314 . a second water vane 346 is positioned on the exit end of the inlet pipe 314 . the force of the water engaging the second water vane 346 causes the water vane to rotate a drive shaft 322 . the rotational movement of the drive shaft 322 may drive a number of components as described below . after the water engages the second water vane 346 , the water enters an outlet pipe 318 . the inlet pipe 314 and outlet pipe 318 consists of any material that is suitable to transport water , or other suitable liquid , from one location to another based upon the desires of the user . preferably , the outlet pipe 318 is composed of the same material as the inlet pipe 314 . the outlet pipe 318 may be composed of mild steel with an anticorrosive coating ; however , it should be noted that any material capable of transporting pressurized water may be utilized , including but not limited to polyvinyl chloride ( pvc / upvc ), ductile iron , polyethylene , copper , concrete , stainless steel , and galvanized steel . during use , the systems and methods described above may be used in a number of applications . one application includes the operation of an elevator during a fire to aid firefighters and save the lives of occupants of the building . when a fire occurs , the elevators in a building are designed to cease operation . while firefighters may override this shutoff , it is potentially dangerous for firefighters to use the elevators during a fire because of the very possible risk of an electrical outage , causing the elevator to become inoperable . in lieu of using the elevator as transportation , the firefighters must climb the steps to reach the floors . this is both time consuming and physically exhausting . one use of the present invention is to provide power to an elevator so the elevator may be utilized during a fire - nothwithstanding the threat of an electrical outage . in this exemplary embodiment , a pumper truck 50 is utilized to pump water into the water inlet ( 12 , 112 , 212 , 312 ). the pumper truck 50 is connected to a fire hydrant and the pumper truck 50 forces the water into the water inlet ( 12 , 112 , 212 , 312 ) of the system ( 10 , 110 , 210 , 310 ). preferably , the water inlet ( 12 , 112 , 212 , 312 ) is located on the same panel as the fdc . preferably , the panel will read “ fdc reeps 450 psi .” “ reeps ” stands for rescue and emergency elevator power systems . the term reeps would convey to the firefighters arriving at the scene of the fire to understand that the building is equipped with a reeps system as disclosed herein and the elevator may be safely operated after the pumper truck 50 is engaged to the water inlet ( 12 , 112 , 212 , 312 ). the pressure of the reeps system would also be indicated on the sign to convey to the firefighters the pressure needed to run the reeps system . the reeps system may use a 2½ or 3 inch connection on the exterior of a building . the outlet pipe ( 18 , 118 , 218 , 318 ) may discharge the water onto the ground or into a drain external of the building . however , the outlet pipe ( 18 , 118 , 218 , 318 ) may return the water to the pumper truck 50 to be recirculated to the reeps system . the building would include a discharge connection or fitting for allowing a hose to connect the connection to the pumper truck 50 . the pumper truck utilizes a centrifugal pump or the like , which allows the water exiting the outlet pipe ( 18 , 118 , 218 , 318 ) to be recirculated . a gated y valve may be engaged to the outlet pipe ( 18 , 118 , 218 , 318 ), so that if the water overheats and is too hot it can be flushed from the system . the inlet pipe ( 12 , 112 , 212 , 312 ) and outlet pipe ( 18 , 118 , 218 , 318 ) may be located internal or external to a building . preferably , the inlet pipe ( 12 , 112 , 212 , 312 ) and outlet pipe ( 18 , 118 , 218 , 318 ) are located internal of the building for protecting the pipes from the elements . the inlet pipe ( 12 , 112 , 212 , 312 ) and outlet pipe ( 18 , 118 , 218 , 318 ) may be located anywhere in the building , including within the elevator shaft of the building . the generation station ( 16 , 116 , 216 ) may be located within the machine room . the power generated by the generation station ( 16 , 116 , 216 ) may be used to provide electrical power to the electrical motor of the elevator . alternatively , the rotational movement of the power shaft ( 26 , 126 , 226 ) may rotate the motor , sheave or like device to power the elevator . as is well known , the sheave is the pulley like device that receives the hoist ropes of the elevator and the rotational movement of the sheave raises and lowers the elevator car . the benefit of this system is that water is being utilized to power the elevator , which is not subject to the same limitations as electricity during a fire . the firefighters may utilize the elevator safely and efficiently without a concern of a power outage caused by the fire . the operation of the elevator based upon the flow of water through the inlet pipe ( 12 , 112 , 212 , 312 ), generation station ( 16 , 116 , 216 ), and outlet pipe ( 18 , 118 , 218 , 318 ) is not subject to the limitations of an electrical current flowing through the building . in fact , the user of water for the generation of electricity or power to run the elevator will provide continuous power and electricity and will not be affected by a fire . the reeps system allows a firefighter to reach a floor utilizing the elevator without having to expend effort climbing multiple steps . fire equipment may be transported to the fire and surrounding floors by use of the elevator . further , the elevator may be utilized to transport injured or handicapped occupants of the building to safety . instead of or in addition to providing power or electricity to activate the elevator , the power or energy may be utilized to include a fan that may be engaged to the ventilation system of the building to provide ventilation even though the power to the building has been compromised . the fan would be a direct drive to the energy generation station 16 without the need for electricity . in another embodiment , the power or electricity supplied by the generation station ( 16 , 116 , 216 ) may be engaged to a generator for supplying power . in yet another embodiment , the electricity may be utilized to supply power to a winch that is located on the top of a building . the winch would be operated to carry supplies ( hoses , axes , medical equipment , etc .) utilized by a firefighter to the top of the building . alternatively , the rotational power of the power shaft ( 26 , 126 , 226 ) may be used to drive the winch . in yet another embodiment , the electricity supplied may be made available for any such uses by an electrical connector . the electrical connector would allow a standard electrical cord having a male end to be inserted into the electrical connector for providing power to a myriad of devices . a solenoid control ( 48 , 148 , 248 ) may be positioned on the exterior of the building for operating the clutch ( 24 , 124 , 224 ). the solenoid control ( 48 , 148 , 248 ) may include an indicator , such as a light , to indicate a desired rpm has been achieved by the power shaft ( 26 , 126 , 226 ), allowing the operator to engage and disengage the clutch ( 24 , 124 , 224 ). preferably , the solenoid switch ( 48 , 148 , 248 ) consists of a horizontal chamber for receiving pressurized liquid . a piston chamber intersects the horizontal chamber allowing the pressurized liquid to enter the piston chamber . the piston chamber is configured to receive the piston ( 40 , 140 , 240 ). as the pressurized liquid enters the horizontal chamber , the pressurized liquid exerts pressure on the piston ( 40 , 140 , 240 ), thus forcing the piston upward ( allowing the pressurized liquid to fill the void left by the upward movement of the piston ) and operatively engaging the clutch ( 24 , 124 , 224 ). when the flow of pressurized liquid is ceased , the pressurized liquid exits the piston chamber , thus allowing the piston ( 40 , 140 , 240 ) to return to its original position within the piston chamber and as a result the clutch ( 24 , 124 , 224 ) is disengaged . although the present invention has been illustrated and described herein with reference to preferred embodiments and specific examples thereof , it will be readily apparent to those of ordinary skill in the art that other embodiments and examples may perform similar functions and / or achieve like results . all such equivalent embodiments and examples are within the spirit and scope of the present invention and are intended to be covered by the following claims .

the present invention provides methods and systems for a power generation system , including an inlet for introducing a liquid into the system , an inlet pipe for carrying the liquid introduced to the inlet , a generation station for converting the flow of liquid into energy , and an outlet pipe for removing the liquid from the generation station .

with reference to the perspective view of fig1 there is shown a golf club head 100 modified from the shape of more conventional golf club heads through the provision of a void space 102 behind a face plate 104 above a sole plate 106 of the club head 100 . also shown in fig1 is a golf club hostel 108 which enters the club head at a heel 110 of the club . located oppositely to heel 110 is club toe 112 . in fig2 is shown an orthonormal matrix 112 which surrounds the club 100 , and is defined by an x , y and z coordinate system corresponding to the three essential axes of the club , shown to the upper left of fig2 . said x , y and z axes of said orthonormal matrix 112 provide for a 3 × 3 × 3 system of 27 volumetric coordinates . therein , the position ( x 0 , y 0 , and z 3 ) defines the location at which hostel 108 enters club head 100 . the ( x 2 , y 2 , x 3 ) position , shown in shading in fig2 represent the center of gravity of the club and is consistent with a normal or standard flight of the golf ball . in other words , a golfer having a perfect golf swing would , in accordance with the present system , apply a weighting element to a club head , of the type of club head 100 , at position ( x 2 , y 2 , z 2 ) of the matrix shown therein . for ease of reference in the figures which follow , applicable coordinate nomenclature for various positions of said three 3 × 3 × 3 weighting system are also shown . in the charts of fig3 - 5 are shown the xy , xz and yz coordinate relationships which affect particular parameters of ball strike , path , trajectory and rotation which are of interest to golfers . more particularly , shown in fig3 is the effect of different types of weighting within the xy plane of orthonormal matrix 112 , that is , the horizontal plane thereof . therein , weighting in the + x or toe direction will increase the loft or ballooning of flight path of the golf ball , so that + x weighting direction of the club will provide for slice ( right curvature ) compensation of the golf ball . conversely , weighting toward the heel or in the − x direction will provide for hook ( left curvature ) compensation . fig3 also indicates that maximum backspin of the ball may be achieved by weighting at a low y position , that is , at the plane of the face plate , while minimum back spin may be accomplished through weighting toward the rear of the club , this corresponding to the y 3 position . with reference to fig4 one may note that hook or slice compensation , as in fig3 remains a function of the weighting along the x - axis . in the xz plane which is a vertical plane co - parallel with club hostel 108 , trajectory may be controlled as a function of position of weighting upon the z - axis , that is , the lowest z - axis position ( z 1 ) will afford the highest trajectory , whereas the highest z - axis position ( z 3 ) will produce the lowest trajectory of ball flight . backspin of the ball is also a function weighting along the z - axis . as may be noted by the line at the middle of fig4 the z 1 position will produce a maximum spin of the ball , while weighting at z 3 will produce a minimum backspin . accordingly , viewing fig3 and 4 in combination , it may be appreciated that a minimum backspin may be achieved by weighting at the ( x 2 , y 3 , z 3 ) coordinate , while maximum backspin may be achieved by weighting at the ( x 2 , y 1 , z 1 ) coordinate , as will also be illustrated in the figures which follow . with reference to fig5 this chart corresponds to the yz plane which is a vertical plane substantially parallel with toe face 110 of the club ( see fig2 and 6 ). from fig5 it may be noted that minimum penetration , that is , maximum apex of ball flight , is achieved at the ( y 1 , z 1 ) position , while maximum penetration is achieved at the ( y 3 , z 3 ) position . further , the highest trajectory may be seen to exist at the ( y 2 , z 1 ) position , while the lowest trajectory is achieved at the ( y 2 , z 3 ) position . minimum backspin is achieved at ( y 3 , z 3 ) and maximum backspin at ( y 1 , z 1 ). with the above in mind , the weighting coordinate ( x 2 , y 2 , z 3 ), which is shown in fig6 should be appreciated as one that does not provide for either hook or slice compensation but which provides for reduced trajectory ( flatter path of ball flight ) and some decrease in backspin due to the z 3 part of the coordinate shown . in fig7 are shown two different weighting coordinates , both within the y 1 axis which includes the plane of face plate 104 of the club head . more particularly , a weighting element a shown to the left of fig7 is the ( x 3 , y 1 , z 2 ) position and affords neutral ballooning , slice compensation , and some additional backspin . in distinction , weighting element b of coordinate ( x 2 , y 1 , z 1 ) provides for high trajectory , maximum backspin and minimum penetration . with reference to fig8 weighting element c ( coordinate x 2 , y 3 , z 3 ) provides for low trajectory , minimum backspin and maximum penetration , while element d of fig8 provides for neutral ballooning of ball flight , slice ( right curvature ) compensation and medium trajectory . with reference to the weighing element at ( x 1 , y 1 , z 2 ) shown in fig9 such an arrangement will provide for neutral ballooning , hook compensation , slightly additional backspin and medium trajectory . the weighting element ( x 2 , y 3 , z 1 ) shown in fig1 affords high trajectory , high backspin and high penetration , although not as high penetration as would exist were the weighting at the ( x 2 , y 3 , z 3 ) position . shown in fig1 is a weighting element at the ( x 2 , y 3 , z 2 ) position . thereby , there is achieved hook compensation , high penetration and , no change in the ball &# 39 ; s natural trajectory . in the weighting scheme shown in fig1 , that is , weighting at the ( x 3 , y 3 , z 3 ) coordinate position , one achieves slice compensation , decreased backspin , low trajectory and maximum penetration . three - dimensional relationships of the above - described parameters of backspin , penetration , trajectory and ballooning are illustrated in fig1 . it may be appreciated that ballooning control occurs primarily as a function of the x - axis , as does hook and slice compensation , while maximum backspin occurs as a function of weighting at the ( y 1 , z 1 ) position with minimum backspin occurring with weighting at the ( y 3 , z 3 ) position . penetration is also a function of the combined effect of two axes , that is , maximum penetration occurring with weighting at the ( y 3 , z 3 ) position and minimum penetration occurring with weighting at the ( y 1 , z 1 ) coordinate . in fig1 is shown the use of weights e and f in two different areas of the golf club 100 of fig1 . therein , a good player would move weight e to the back of the club to achieve as penetrating a shot as he could , and would also position weight f to reduce the spin , putting an additional weight in the x - axis center ( x 2 ) of the club . this makes the sweet spot smaller , that is , the player must strike the ball right in the center ( x 2 ). that is , an ideal strike which would result in a best transference of energy . however , it causes a largest margin of error . such a golfer therefore would have to be a rather good player to move to the center of the face where he wants to hit the ball . said weight e also maximizes penetration . in fig1 is shown the effect of a horse shoe - like structure g , symmetric about the yz plane at the x 2 position . this helps the basic or average player . such a player moves the weight toward the heel and the toe 112 to make his sweet spot as wide as possible . structure g also moves the weight down toward the back to get some height on the ball , and also to get more penetration to pick - up some distance . this would be a club for a basic , standard player who simply needs some help that is not interested in slice hook combination . it &# 39 ; s just addressing trajectory and spin rate . with reference to fig1 , there is shown the use of a propeller type weight h , having its center at ( x 2 , y 2 , z 2 ), which would be used if one were hitting the ball a bit to the left and low . to compensate for that , the weight is moved to the left , so that the ball will move to the right . to counteract the moving the weight to the left , one may place a projection of the weight h down toward the right hand corner to get the ball up into the air again , and to also move another projection to the rear for penetration and movement up in the air . with reference to fig1 , there is shown the use of a saddle - like weighting element i inserted along the sides and behind the face plate . the benefits of such a weighting geometry are that the weight is set to hit the ball a little higher because the weight is low . it also tends to give it a bit more of penetration , because the weight is moved back . by also moving it to the left , one pushes the ball out to the right , tending to give a shot slightly to the right and is penetrating , but yet will have some spin on it . so it starts out low , goes right and then slows down . the following charts relate to weighting coordinates to figures , by planes of the orthornomal matrix . chart 1 ( xy plane ) x1 ( heel ) x2 x3 ( toe ) y 1 fig . 7 ( b ), 14 ( f ) fig7 ( a ), 8 ( d ) y 2 fig2 , 16 y 3 fig1 , 14 ( e ) fig8 ( c ), 10 , 14 ( e ) fig1 , 14 ( e ) [ 0060 ] chart 2 ( xz plane ) x1 ( heel ) x2 x3 ( toe ) z1 ( heel ) fig7 ( b ), 10 , 16 z2 fig2 ( f ) fig7 ( a ), 8 ( d ) z3 fig6 ( c ) [ 0061 ] chart 3 ( yz plane ) y1 ( toe ) y2 y3 z1 fig7 ( b ) fig1 , 14 ( e ) z2 fig7 ( a ), 8 ( d ), 9 z3 fig8 ( c ), 12 in fig1 - 20 are shown the use of clip - on type weighting elements . more particularly , a weighting element j of fig1 moves weight to the rear of the club , thus increasing penetration , while lowering the enter of gravity of the club and increasing spin . in a weighting element k of fig1 , weight is not moved back as far , and is raised - up slightly higher than that of element j . this reduces penetration with slightly reduced backspin , the result being a more controllable ball strike . in fig2 , weighting element l provides an elevation of weight , thereby lowering trajectory which also widens the sweet spot , as in element g of fig1 . also , if element l is asymmetric to the right of a yz plane of symmetry thru location x 2 , slice compensation is also provided . it is noted that many of the above functions of the weighting elements may be achieved thru variation in weight and dimension of sole plate 106 ( see fig1 ). for example , if a change in weight is indicated at a ( x , y , z 1 ) coordinate , a change in weight or weight - distribution in the sole plate will affect the parameters shown in the chart of fig3 . also , as may be noted in fig4 addition or reduction of weight at z 1 will affect trajectory and backspin . while there has been shown and described the preferred embodiment of the instant invention it is to be appreciated that the invention may be embodied otherwise than is herein specifically shown and described and that , within said embodiment , certain changes may be made in the form and arrangement of the parts without departing from the underlying ideas or principles of this invention as set forth in the claims appended herewith .

the performance of a golf club may be enhanced through the provision of a void space behind a face plate and above the sole plate , to decrease club weight and provide single or combinations of selectable weighting elements within volumetric coordinates of an orthonormal matrix about the void space . the weighting coordinates are provided in response to ball strike , flight analysis and physiologic observation of the golf strike swing . ball backspin , trajectory , penetration and hook or slice may be modified through the use of a definable weighting strategy .

the accompanying colored photographs illustrate the overall appearance of the new and distinct variety of the ulmus l . plant , which is known as ‘ guanyin ’. the descriptions disclosed herein are based upon observations of the plant growth . ‘ guanyin ’ buds a week earlier than ulmus chinensis in spring . new leaves thereof are light yellow , and drop after about 20 days . reborn leaves are gray - green with white edges . after about 30 days , outer leaves grow light yellow spots . with sunlight becoming strong , the leaves are changed from light yellow to yellow - white . from summer to autumn , outer mature leaves have light white spots , new leaves have light yellow or yellow - white spots , and inner leaves are gray - green with white edges . the ‘ guanyin ’ has small leaves , which is ½ of a size of ulmus pumila l . leaves . an amount of the leaves are doubled to the one of ulmus pumila l . leaves . in winter , top buds of the ‘ guanyin ’ wither while many side buds grow . branches are slim and close to each other , and branch capability is strong . a crown is egg - shaped and compact . the ‘ guanyin ’ inherits characteristics of a female parent ulmus chinensis such as cold tolerance , drought tolerance and salt tolerance . after ten years of observation and 30000 strains of asexual reproduction , the variety has sufficient stability and consistency . the variety has cold tolerance , drought tolerance , salt tolerance and shade tolerance , and is able to grow in most parts of the northern hemisphere . the variety is suitable for rootstock asexual reproduction with ulmus chinensis , ulmus laevis and ulmus americana . the variety is suitable for grafting on ulmus chinensis var . pendula and ulmus laevis var . pendula , into a shape of a flower , without growth imbalance . the variety is able to be cultivated as foliage plants and bonsai . these features and other characteristics of the plant are apparent from the figures .

‘ guanyin ’ is a distinctive variety of ulmus l . plant , which is characterized by its appearance and color of the whole plant .

an ultrasound image based on tissue motion and tissue perfusion information may provide an indication of tissue viability . if perfusion is detected and no tissue motion is observed , the tissue region may be hibernating and may be salvageable via surgical intervention . if no perfusion and no motion are detected , the tissue region may be necrotic . if no perfusion is detected and the motion of the region is normal , the perfusion estimator likely did not correctly estimate perfusion . referring to fig1 a preferred embodiment of an ultrasound system for generating a tissue viability image is shown generally at 10 . the system 10 includes a transmit beamformer 12 , a transducer 14 , a receive beamformer 16 , and a demodulator and filter 18 as a beamformer path . a b - mode processing path is connected in parallel with a doppler processing path to the beamformer path . the b - mode processing path includes a detector and log compressor 20 and an acoustic buffer 22 , and the doppler processing path includes a quadrature demodulator 24 , digital to analog converter 26 and an autocovariance and moment calculator 28 . the b - mode processing path provides intensity information for perfusion estimation , and the doppler processing path provides velocity , variance or energy information as tissue motion information . a scan converter 30 also connects to the b - mode and doppler processing paths . a display 36 connects to the scan converter 36 . other processing paths including different , additional or fewer components may be used . during operation , the transmit beamformer 12 provides excitation signals to the transducer 14 , such that ultrasound beams are focused within a region . the ultrasonic energy is reflected from impedance mismatches within the body . some of the reflected energy impinges on the transducer 14 . signals associated with the reflected energy are amplified and provided to the receive beamformer 16 . the receive beamformer 16 sums the signals from the various elements of the transducer 14 after applying appropriate delays . the summation is performed such that a continuous focus is maintained . the summed signals are demodulated and filtered by the demodulation and filter block 18 . the demodulated and filtered signals are provided to the b - mode and doppler processing paths . for b - mode processing , the signals are detected and log compressed in the detector and log compressor 20 . the resulting information is stored in the acoustic buffer 22 . after an entire scan of a region or a frame of data is acquired , the data is output from the acoustic buffer 22 to the scan converter 30 . other processing paths and associated techniques for generating ultrasound intensity or b - mode information may be used . for tissue motion processing , the demodulated and filtered signal is provided to the quadrature demodulator 54 . the quadrature demodulator 54 demodulates and low pass filters the information . the digital to analog converter 26 converts the analog information to digital samples . the digital samples are filtered to obtain information associated with desired motion ( i . e . tissue motion ). for example , a user is able to select from different filters , each with different values of low velocity cut - off . signals from non - moving tissue and slowly moving blood are removed from the information . the autocovariance and moment calculator 28 determines the autocovariance coefficients r ( 0 ), r 0 ( 0 ), r 1 ( 0 ) of the filtered samples . from these coefficients , the mean velocity , variance and energy of the doppler information is found . other tissue motion processing paths may be used , such as fully digital , fully analog or cross - correlation ( i . e . one or two - dimensional displacement as a function of multiple target interrogations ) processing paths . furthermore , velocity may be estimated as disclosed in u . s . pat . no . 5 , 285 , 788 . the tissue motion and intensity information is provided to the scan converter 30 . the scan converter 30 combines the intensity information and tissue motion information to generate a tissue viability image as discussed below . preferably , the scan converter 30 preserves the spatial orientation of the information . a processor 32 controls the timing and transfer of data between and through the various processing paths discussed above . the control of the system is responsive to information from a user interface 34 . preferably , the user configures the system 10 for tissue viability imaging . the system 10 is capable of estimating perfusion , and estimation of tissue motion , b - mode or tissue viability images . for tissue viability imaging , the initial configuration may comprise the generation of a b - mode image , but a different mode of imaging or combination of modes of imaging may be used . based on the image or other information , the user selects a region or regions for measurement or tissue viability imaging . in alternative embodiments , the region or regions are selected using software algorithms or other processes . in the preferred embodiment , the user also selects an appropriate perfusion estimation technique , such as wash - in , wash - out , triggering , binary indication or combinations thereof . other perfusion techniques and configuration selections may be used . various embodiments may aid in tissue viability imaging . for example , using fundamental imaging , velocity of tissue , such as the myocardium , may be measured and using harmonic imaging , perfusion estimates may be obtained , provided that contrast agents with a good harmonic response were injected into the blood stream . in one embodiment , the user may configure the system 10 for harmonic or fundamental frequency imaging , such as obtaining the b - mode information from harmonic echo information and the doppler tissue motion information from fundamental echo information . any of the data associated with the various modes discussed herein may be associated with harmonic or fundamental based echo information . after configuring the system 10 and injecting any contrast agent , the system 10 transmits multiple ultrasound waves for a plurality of lines for tissue viability imaging . preferably , the effects of artifacts , such as rib shadow and lung artifacts , are minimized or accounted for by having the patient hold their breath , using a small transducer , selecting an appropriate image window or using a negative offset imaging format such as taught by u . s . pat . no . 4 , 550 , 607 . various transmission and receive techniques may be used , such as receiving multiple lines in a single operation based on one transmission . preferably , ultrasonic transmissions associated with b - mode imaging are interleaved with ultrasonic transmissions associated with tissue motion imaging , such as line or frame interleaving . referring to fig2 a , a timing diagram of one embodiment for interleaving doppler tissue motion information and b - mode information is shown . a trace 40 demonstrates a transmission and reception process for obtaining tissue motion information ( e . g . doppler velocity estimates ) along one scanning line . a trace 42 represents the transmit and receive processing for b - mode information . since multiple transmit and receive operations are not required for b - mode processing , the time required to obtain the b - mode information is less than the time required for the tissue motion information of trace 40 . for example , the solid portion of trace 42 represents the interleaving of b - mode transmissions and receptions and is less than the time used for obtaining the doppler information represented by trace 40 . by successively interleaving b - mode and doppler operations , the entire user selected region of interest is interrogated by scanning along multiple lines . by line inter - leaving , any high power transmissions for one imaging mode may not destroy contrast agent prior to transmissions for another imaging mode . other timing and interleaving of transmission events may be used . any of the various methods of transmission as discussed above may be performed at different power levels . for example , transmissions associated with tissue motion imaging may be low power transmissions . the power is selected so that the ultrasonic waves do not destroy any contrast agent . ultrasonic waves associated with b - mode harmonic imaging are also preferably associated with low power , so as not to destroy any contrast agent . in alternative embodiments , either one or both of doppler tissue motion or b - mode perfusion imaging are associated with higher power transmission ( e . g . contrast agent destructive power levels ). preferably , higher power transmissions are associated with triggering . referring to fig2 b , a timing diagram demonstrating the interleaved transmission for doppler tissue motion imaging and perfusion estimations using triggering is shown ( trace 44 ). for triggering , the system 10 ( fig1 ) initiates a scanning sequence for transmission and reception once a trigger is detected . preferably , an ekg module provides a heart cycle signal to the system 10 . based on the heart cycle signal and control software , the system 10 initiates transmission and reception . various triggers , including an r - wave or other portions of the heart cycle or other detected events , may be used . for heart cycle triggering of tissue motion imaging , the triggers are preferably set between peak systolic or diastolic portions of the heart cycle . at peak systole or diastole , the motion of the heart is minimal . alternatively , multiple triggers within a single heart cycle or a trigger that varies within the heart cycle over a plurality of heart cycles are used . in alternative embodiments , multiple triggers may occur before a scanning sequence is initiated , such as scanning every second or third r wave . furthermore , the scanning sequence may consist of acquiring one or more frames of b - mode data , doppler data , or combinations thereof after each trigger . preferably , interleaved frames of one each of harmonic b - mode and a fundamental doppler information associated with high power transmissions are obtained after each trigger . the system 10 may acquire additional data after each subsequent trigger . other combinations of power level and imaging mode may be used with various triggers . for example , acquisition of b - mode data associated with high powered transmission may be triggered , and acquisition of doppler data associated with lower power transmissions may be continuous . preferably , the tissue viability imaging is finished over a period of three or four heart cycles . if a larger interval of time is used , new areas of the heart may enter the user specified region of interest and may adversely affect perfusion estimation . preferably , the patient is held steady or holds their breath to avoid unnecessary movement . the system 10 may also operate without triggering regardless of transmission power levels . based on the transmission and reception of information for tissue motion imaging , motion or velocity values are estimated as discussed above . perfusion estimates are calculated from b - mode or intensity information instantaneously or as a function of time . various techniques may be used for estimating perfusion , including time intensity , triggering , absolute perfusion and binary indication . other techniques for estimating perfusion may be used . for the binary indication technique , contrast agents are preferably injected into the patient &# 39 ; s blood stream . the contrast agent travels to the region of interest , such as the myocardium . a greater amount of contrast agent is present in areas where perfusion is not hindered or is high , than in areas with low perfusion or blood flow . areas with greater amounts of contrast agent are associated with higher intensities . the intensity information may be averaged as a function of time for accuracy or instantaneous values may be used . high intensity b - mode information in a region indicates high perfusion , and low intensity b - mode information indicates low perfusion . based on the intensity level and one or more thresholds , perfusion is estimated to exist , exist at different levels or not exist . perfusion may also be estimated with time intensity methods , such as wash - in , wash - out or wash - in wash - out techniques . for example , contrast agents are injected . a region of interest is imaged over a time period . the change of intensity at the region of interest over the time period is measured . various functions , such as a summation or average of intensities for a region of interest , may be used , and any region of interest may be subdivided into one or more regions of interest for separate perfusion estimation . preferably , the system 10 accounts for any non - linear processing ( i . e ., a change in intensity is not equal to a change in the amount of contrast agent ). the intensity level increases as the contrast agent enters the region of interest , and the intensity decreases as the contrast agent leaves the organ . based on the intensity level or b - mode information , the transit time of the contrast agent through the organ is calculated and is inversely related to blood flow . the type of time intensity estimation is a function of the time period selected . referring to fig4 a , an example of a wash - in curve is represented . the curve represents an average or summed intensity as a function of the time from injection to the time to reach a peak intensity value . referring to fig4 b , an intensity curve representing a wash - out curve is shown . perfusion is estimated from the amount of time for the contrast agent to transit from a peak intensity value to a minimum value . referring to fig4 c , a wash - in wash - out intensity curve is represented . both wash - in and wash - out transit times of contrast agents are measured as discussed above . for the time intensity perfusion estimations discussed above , various time periods as a function of intensity may be measured , such as times from or to intensities at a percentage above or below the peak and minimum intensity values . preferably , any percentages are determined through experimentation , and may be about 10 to 20 percent of the peak and minimum intensity values . furthermore , either continuous or triggered imaging may be used for time intensity calculations . perfusion may be estimated using triggering . for example , a triggering rate is varied . preferably , high power ultrasonic waves are transmitted at each trigger and the intensity of the echoes is measured . based on the resulting destruction of the contrast agent , the triggering rate is adjusted to maintain a steady state intensity . if the triggering rate or time between triggers is low , intensity increases . if the triggering rate is too rapid , the intensity decreases due to contrast agent destruction . the rate of triggering ( i . e . the time period between triggered frames ) associated with a steady state intensity estimates perfusion . perfusion may be estimated using absolute perfusion calculations , such as described in u . s . application ser . no . 08 / 949 , 237 for an ultrasonic method and system for measuring perfusion , filed oct . 10 , 1997 , the disclosure of which is herein incorporated by reference . for absolute perfusion , contrast agent is constantly infused with an infusion pump . preferably , the doppler imaging is associated with lower power transmission . after a constant intensity at the region of interest is established , a high powered ultrasonic wave is transmitted to destroy the contrast agent . either triggers or the user activate transmission of the high power ultrasonic wave . the increase in intensity after transmission of the high power ultrasonic wave is used to estimate perfusion . in a preferred embodiment , the absolute measure of perfusion is determined from the equation : 1n [ c ( tα )- c ( t )]= 1n [ c ( tα )- c ( t0 )]-( flv ) t , where c ( tα ) is the concentration of contrast agent at infinity ( i . e . a steady state value ), c ( t ) is the concentration of contrast at time t , f is the true blood flow rate and v is the volume fraction of blood within the region of interest . preferably , the concentration is a measure of the intensity at a point in the processing paths where signals are linear . the fraction f / v is the absolute measure of flow per unit volume . other equations may be used . referring to fig1 the tissue motion information is provided to the scan converter 30 . perfusion is estimated in the b - mode processing path or the scan converter 30 . alternatively , the tissue motion information is provided to a processor for tissue viability determination prior to the scan converter 30 , and the processor estimates perfusion . referring to fig3 b , the tissue motion information and perfusion estimates are combined in a lookup table 50 in the scan converter 30 . in alternative embodiments , processors , hardware or software combine the tissue motion information with the perfusion estimates . in the preferred embodiment , the tissue motion data and the perfusion estimates address a two - dimensional memory map . based on the address selections , a color display value ( e . g ., rgb or yuv ) is output by the lookup table 50 . referring to fig3 a , a preferred two - dimensional memory map is graphically demonstrated . tissue motion is estimated from doppler velocity values , and perfusion is estimated from b - mode intensity information collected instantaneously or over time . for example , perfusion is estimated using the absolute or binary techniques discussed above . the velocity information is plotted on the y - axis with positive velocities increasing in the positive y direction and negative velocities increasing in the y - direction . positive velocities are encoded by red blending towards yellow as the velocity increases and negative velocities are encoded in blue blending towards green as the negative velocities increase . in alternative embodiments , different colors are used or the same colors may be used for both positive and negative velocities . intensities or perfusion estimate information is encoded along the x - axis , either by a separate color or a brightness of the colors associated with velocity . other encoding techniques may be used . preferably , the brightness of the color increases along the x - axis . in a preferred embodiment , strong signals from the contrast agent or high perfusion estimates are encoded by colors to the right of a primary memory map , such as represented by map 52 and weak signals or estimates are encoded by colors to the left of the map 52 . referring to fig5 a and 5b , a preferred embodiment of a lookup table 60 and corresponding memory map , such as represented by map 62 for use with time intensity estimation of perfusion is shown . in this embodiment , tissue motion is estimated from doppler velocity or energy by a doppler engine 64 . the doppler engine 64 preferably operates in the manner described above for the doppler processing path to provide tissue motion estimates to the lookup table 60 . the lookup table 60 also receives transit time information as an estimate of perfusion from the computer and memory 66 . the radio frequency ( rf ) information input into the computer and memory 66 and the doppler engine 64 is preferably coherently summed and , demodulated and filtered . the computer and memory 66 determines the line number and sample number of the polar coordinate rf information given the cartesian coordinates of the region of interest selected by the user . based on the intensity of the rf data , perfusion is estimated as discussed above for the region of interest or multiple regions of interest . since rf data is input , the absolute value or the magnitude of the echoes is preferably utilized as the intensity . based on a start of injection signal or an amount of time between selected minimum and maximum intensity values , the computer and memory 66 calculates the transmit time . in alternative embodiments , detected data is used to calculate time intensity curves . for this alternative embodiment , the computer and memory 66 is placed in the data path after the rf data is detected . preferably , the data is obtained before log compression or is linearized before processing . in alternative embodiments , log compressed or scan converted data is input to the computer and memory 66 . referring to the map 62 , the tissue motion and perfusion estimate information is provided as addresses for each point within a region . tissue motion , such as doppler velocity estimates , are plotted along the y - axis of the map 62 as discussed above for map 52 ( fig3 b ). the transit time is encoded along the x - axis of the map 62 in a manner similar to the intensity or perfusion data of map 52 ( fig3 b ). preferably , the maximum transit time is encoded as small x - axis values and small transit times are encoded as high x values of the map 62 . small transit times indicate high blood flow , and high blood flow indicates good perfusion . other mapping patterns may be used . referring to fig3 and 5 , the output signals are used to generate an image indicating tissue viability . for the preferred map patterns discussed above , regions encoded by colors at p1 and p2 of fig3 a and 5b indicate good perfusion and tissue motion ( i . e ., healthy , normal tissue ). regions encoded by a color associated with p3 or p4 indicate that perfusion was detected but no tissue motion was observed , such as associated with hibernating tissue . regions encoded with colors associated with p5 and p6 indicate tissue motion associated with little or no perfusion , such as erroneous imaging . regions encoded by colors associated with p7 and p8 may indicate no motion or perfusion , such as associated with necrosis of tissue . more or fewer colors than the eight ( p1 - p8 ) discussed above may be used . for example , only one dark or bright selection for perfusion and a range of three or more tissue motion colors are used for binary indication . three or more levels of brightness or color changes as a function of perfusion may be used for any of the various perfusion techniques . referring to fig1 the output signals are used to generate an image on the display 36 . preferably , a two - dimensional image is generated where perfusion is estimated for multiple spatial locations or pixels on the display . the perfusion estimate calculated for a region is used for each spatial location within that region . the tissue viability image may be combined with other images , such as overlaying a b - mode image . in alternative embodiments , the tissue viability image is generated by displaying an image responsive to the tissue motion estimates adjacent an image responsive to perfusion estimates . a perfusion estimation image may be overlaid on the tissue motion estimate image . in a preferred embodiment , a color key is displayed adjacent to the tissue viability image . for example , one of the maps 52 and 62 of fig3 a and 5a , respectively , is represented by the color key or legend display . the color key is preferably displayed adjacent to the tissue viability image . as discussed above , various modes of processing may be used to estimate tissue motion or perfusion . in one alternate embodiment , tissue motion is estimated with data generated in a strip doppler mode . strip doppler data is associated with a point or region within a patient and the display of a frequency spectrum along a y - axis and time along the x - axis . the strip display is preferably a gray scale display . the strength at a particular frequency modulates the brightness . for tissue viability imaging , the estimated perfusion associated with the region is represented by adding color to the strip display . in alternate embodiments , the perfusion estimation is associated with brightness and the energy or strength at a particular frequency is associated with color . based on the combination of tissue motion and perfusion estimation through adjacent , overlay or mapped information , the user assesses tissue viability . while the invention has been described above by reference to various embodiments it will be understood that many changes and modifications can be made without departing from the scope of the invention . for example , different memory maps and different types of information along the x - or y - axis may be used . different , including novel , perfusion or tissue motion estimating techniques may be used , such as techniques not using contrast agents . it is therefore intended that the foregoing detailed description be understood as an illustration of the presently preferred embodiments of the invention , and not as a definition of the invention . it is only the following claims , including all equivalents , that are intended to define the scope of this invention .

a method of imaging to aid tissue viability determinations is provided . tissue motion is detected for at least region of tissue . perfusion is estimated as a function of intensity data and time for the region of tissue . an image responsive to the detected tissue motion and the estimated perfusion is displayed . a combination of tissue motion imaging and perfusion estimation provides an assessment of tissue viability . if tissue exhibits perfusion and motion , then the tissue is likely normal . any other perfusion and motion characteristic combination indicates abnormal tissue viability .

biological samples were taken from 411 or 514 patients suffering from parkinson &# 39 ; s disease and from more than 300 healthy controls , and the dna was isolated therefrom by standard methods . the dna was amplified by pcr . the pcr primers used for this are listed in table i below . table i seq seq id id amplicon forward primer no . reverse primer no . exon 1 tgccgcctctgagtaggg 1 cggtctacccccaccatt 2 exon 1 ccggttgtctgttggggt 3 cggtctacccccaccatt 2 ca exon 2 tctgtgctttccctccat 4 tcatctgaagatgcgagc 5 tt aa exon 3 ggttggagctgcttattt 6 tcccccatcattgtcatt 7 gc t exon 4 cccagacttagaatcccc 8 gggattcttggaaggaag 9 aga ga exon 5 tagggaactgggggctgt 10 ccacattaaaggaacccg 11 at ttt exon 6 ggctcatttgtccctctg 12 ccccctctgattacactg 13 tc gt exon 7 gggtttggctaatagggt 14 ccatatcacactgcagcc 15 ga tct exon 8 tgtgtccttgaactaggc 16 ggagcctcatactcttgg 17 tttg tga a mutation screening was carried out with the amplicons . the mutation screening was carried using the dhplc mutation detection system supplied by transgenomic ( wave ). the dhplc utilizes the difference in melting behavior of homoduplex and heteroduplex dna . this entails double - stranded dna being bound by means of teaa ( triethylammonium acetate ) to an hplc column and detached from the column by an increasing acetonitrile gradient . the dna concentration of the acetonitrile buffer is detected by a laser after the column . the presence of heterozygous base exchanges on one strand with opposing bases in a double - stranded dna strand leads , due to the instability at this site , to early detachment from the hplc column , having the effect of shifting the detection peak on the wave system . the mutations can be detected through differences in the time of detachment of the dna . the employed dna is in the form of pcr amplicon from patients or healthy controls , with each exon being amplified separately . in order to detect possible mutations of an exon as heteroduplex , the pcr product is denatured , and renatured again with slow cooling , before use in the wave apparatus . it is possible thereby for wild - type and mutated dna strands to anneal and form heteroduplexes . since homozygous mutations cannot be detected in this case , having regard to the relative rareness of parkinson mutations the dnas from two patients in each case were pooled together and then measured by dhplc . since conspicuous detection peaks are therefore always the result of two patients &# 39 ; samples , the respective patients &# 39 ; samples were measured again with reference dnas ( purchased from the “ centre d &# 39 ; études des polymorphismes humaines ” ( ceph ), paris , france ). the samples which were still conspicuous were directly sequenced in a beckmann capillary sequencer . the optimized dhplc conditions for the developed pcr primer pairs are summarized in table ii below : table ii pcr annealing product wave primer pair temperature mgcl 2 length temperature wave gradient ( seq id no .) (° c .) ( mm ) ( bp ) (° c .) (% buffer b )* 1 + 2 58 1 573 64 . 2 60 - 72 3 + 2 58 1 350 64 . 2 59 - 71 4 + 5 58 1 289 61 . 2 57 - 73 59 . 8 57 - 67 6 + 7 58 1 298 61 . 5 55 - 65 58 . 0 58 - 68 8 + 9 58 1 116 60 . 0 46 - 60 10 + 11 58 1 174 61 . 0 51 - 63 12 + 13 58 1 147 60 . 8 50 - 63 61 . 0 51 - 61 14 + 15 58 1 159 59 . 5 51 - 61 50 - 66 16 + 17 58 1 251 60 . 5 56 - 66 * buffer b = 0 . 1 m triethylammonium acetate ( teaa ), 25 % acetonitrile it was possible by this method to identify two mutations in the omi / htra2 gene . the first mutation is a nucleotide exchange mutation in exon 1 of the gene , where a dgmp at position 421 of the open reading frame has been exchanged for a dtmp ( cf . fig1 ), leading at the protein level to an exchange of alanine for serine at position 141 . this mutation was found in 25 of a total of 414 patients with parkinson &# 39 ; s disease , and exclusively in the heterozygous state . it was further possible to find a second mutation in the omi / htra2 gene , where a dgmp at position 1195 of the open reading frame in exon 7 has been exchanged for a damp ( cf . in this connection fig4 ), resulting at the protein level in an exchange of glycine for serine at position 399 . this mutation was found in 4 of a total of 514 patients with parkinson &# 39 ; s disease , and likewise exclusively in the heterozygous stage . the presence of the mutation in exon 1 was verified by direct sequencing ( cf . fig2 ). it was further possible to confirm the presence of this mutation by pyrosequencing ( cf . fig3 ); in this case , biotinylated variants of the pcr primers listed in table i were employed . the nucleotide exchange mutation in exon 7 was likewise confirmed by direct sequencing ( cf . fig5 ) and also by restriction fragment length polymorphism ( rflp ) analysis after mvai digestion . with the wild - type sequence , restriction of the amplicon of exon 7 ( 163 base pairs ) with mvai results in three fragments : 113 bp , 44 bp and 6 bp . the g to a base exchange in position 1195 of the coding sequence leads to loss of a previously existing restriction cleavage site for the enzyme ( cf . fig6 ). in order to determine the relevance of the two mutations found in relation to parkinson &# 39 ; s disease , chromosomes from healthy age - correlated controls were screened for the two mutations using the aforementioned methods . in this procedure , not one exon 7 mutation was detectable in 740 chromosomes from healthy controls . it was possible to find the exon 1 mutation in only 10 cases among 662 chromosomes of healthy controls ( p = 0 . 05 ). the presence of one of the two found mutations accordingly correlates with a development of or predisposition to parkinson &# 39 ; s disease . both mutations are therefore valuable diagnostic markers for parkinson &# 39 ; s disease . in order to analyze the pathogenetic relevance of the two mutations found in the omi / htra2 gene , the cytotoxicity test was used to investigate whether cells which express the correspondingly genetically modified omi / htra2 protein are more sensitive to cytotoxins , i . e . undergo apoptosis more frequently with corresponding exposure . this test was carried out using the cytotoxicity detection kit ( ldh ) supplied by roche . the measure of apoptosis used in this case is the lactate dehydrogenase ( ldh ) released from the cytosol of the apoptotic cells into the surrounding medium after contact with the toxins . this ldh in turn is determined via conversion of a tetrazolium salt into formazan , which can be measured through a change in color from yellow ( tetrazolium salt ) to red ( formazan ) using an elisa reader at a wavelength of 490 nm . the absorption at 650 nm is measured as reference comparison . in these investigations , 70 000 hek293 cells ( cells which stably express the wild - type omi / htra2 protein or appropriately mutated omi / htra2 protein ; prepared by standard methods as described for example in sambrook and russell ( 2001 ), molecular cloning — a laboratory manual , cold spring harbor laboratory press , new york , the contents of which are included in the description by reference ) in each kit were seeded in a 24 - well plate . the cells were incubated under normal culturing conditions in dmem ( invitrogen ), 10 % inactivated fetal calf serum ( invitrogen ), 1 % penicillin / streptomycin ( invitrogen ) for 24 hours . the culture medium was then removed and replaced by ldh assay medium ( dmem ), 1 % inactivated fetal calf serum , penicillin / streptomycin , which contained as cytotoxin either 0 . 5 μm staurosporin or 3 . 0 μm mg132 or solvent as negative control . the test was carried out in this case as triplicate test ( in each case for toxin - exposed cell lines and controls ). the appropriate medium was transferred into an empty well and incubated with the cells as background value for the elisa reader . incubation on use of mg132 was for 24 hours , and incubation on use of staurosporin was for 6 hours . after these incubation times , 150 μl were removed from each well and centrifuged . the centrifugation step served to sediment detached cells which might have altered the real ldh concentration through a later apoptosis . after the centrifugation , 100 μl of the supernatant were transferred into a 96 - well plate . the remaining 50 μl were resuspended and returned to the corresponding wells of the 24 - well plate . in order to detect the total amount of ldh , which is related to the total number of cells per well , then 50 μl of 10 % triton x - 100 solution were pipetted into each well in order to lyse the cells which were still alive . after an incubation time of 20 minutes , 100 μl of the centrifuged supernatant were then in turn pipetted into the 96 - well plate . 100 μl of ldh assay medium were then put in each well to be measured of the 96 - well plate and incubated at room temperature for 20 minutes . after this incubation time had elapsed , the reaction was stopped by adding 50 μl of 1 n hcl ( sigma ) and measured using the elisa reader . the ldh value then results from the ratio of the absorption of the first and second supernatant of a well and can thus be used as value for the proportion of cells which have died . the average of three wells treated in the same way yields the proportion of dead cells for a measurement with standard deviation . the result of such an experiment is depicted in fig7 and 8 . these show that the hek293 cells which expressed the exon 7 , i . e . the g1195a , mutation ( g399s ) were more than five times more sensitive to staurosporin than the wild - type hek293 cells ; fig7 , cf . first bar with fifth bar from the left . it further emerges that the hek293 cells which expressed the exon 1 , i . e . g421t , mutation ( a141s ) were approximately 1 . 4 times more sensitive to mg132 than wild - type hek293 cells ; fig8 , cf . first bar with third bar from left . function test on mitochondria from cells which express genetically modified omi / htra2 protein because of the observed morphological changes in the mitochondria in cells with overexpression of mutated omi / htra2 , the mitochondrial function in these cells was investigated . the mitochondrial membrane potential was measured by facs analysis ( flow cytometer ) using jc - 1 , as marker of mitochondrial homeostasis in sh - sy5y cells which stably express the wild - type or mutated ( s141 or s399 ) omi / htra2 . jc - 1 is a green fluorescent dye which can be employed to measure the mitochondrial membrane potential . it has the property of diffusing through cellular membranes and is moreover in the form of a monomer which fluoresces green on excitation with a 488 nm laser . in intact mitochondria there is accumulation of the dye owing to the mitochondrial membrane potential , and thus jc - 1 aggregates form . the aggregate now re - emits in a red fluorescent wavelength the excitation light and can thus be clearly distinguished both under a microscope and in a flow cytometer from the green fluorescent monomers . it is thus possible with jc - 1 to measure the mitochondrial membrane potential of mitochondria very well and also make statements about the early onset of apoptosis in cells , because the membrane potential collapses at a very early time during apoptosis . staurosporin was used as model of cellular stress in order to provoke loss of the mitochondrial membrane potential . the jc - 1 assay was adapted according to the description of the dye by molecular probes . for this purpose , cells were seeded in 6 - well plates 24 hours before toxin exposure ( hek293 : 700 000 cells / well , sh - sy 5h : 1 000 000 cells / well ) and allowed to grow adherently for 24 hours . after this time , the cells were cultivated further with the appropriate toxins in their normal cell culture medium and , after various incubation times , used further for the analysis . the cells were then detached from the cell culture dish with trypsin , centrifuged ( 1200 rpm , 4 minutes ) and washed once in pbs . after washing , recentrifuged and then resuspended in 500 μl of a 5 μg / ml concentrated jc - 1 / pbs solution . the cells were then incubated at 37 ° c . for 30 minutes . the incubation with jc - 1 was followed by three washing steps with pbs , immediately followed by analysis in the flow cytometer . in order to differentiate the cell population between green and red fluorescence and to make the adjustment in the flow cytometer , cells without jc - 1 , with jc - 1 and cells with jc - 1 treated with cccp were used . cccp is a protonophore which reversibly abolishes the mitochondrial membrane potential . it was thus possible after the staining readily to excite only the green fluorescence of the jc - 1 monomers , owing to treatment with cccp . after adjustment of the assay in the flow cytometer , the samples were then measured and evaluated . the result of this experiment is depicted in fig9 . in this case , the various cells were treated with 0 . 5 μm staurosporin for 4 hours . the y axis indicates the decline in the membrane potential in percent ( δψm [ loss in percent ]). the x axis depicts on the left the result of the measurements on wild - type cells ( omi / htra2 wt ), in the middle on cells with the exon 1 mutation ( omi / htra2 s141 ), and on the right on cells with the exon 7 mutation ( omi / htra2 s399 ). the pale bar on the left in each case shows the result of the measurements on untreated or dimethyl sulfoxide - treated cells ( control ( dmso )), and the dark bar on the right in each case shows the result of the measurements on cells treated with 0 . 5 μm staurosporin ( staurosporin 0 . 5 μm ). analysis of the jc - 1 fluorescence in this case showed that there is a distinct decline in the mitochondrial membrane potential after treatment with staurosporin in cells which have the s141 and s399 mutations in the omi / htra2 protein compared with wild - type cells . the mutations found in the omi / htra2 protein therefore lead to impairment of mitochondrial functional . the two newly found mutations in the human omi / htra2 gene accordingly are genetic modifications which have considerable effects on the integrity of the cells . incubation of such genetically modified cells with cytotoxin leads to an increased onset of apoptosis thereof . the inventors have thus found for the first time genetic modifications associated with parkinson &# 39 ; s disease which are involved both in the disturbed protein degradation — the omi / htra2 protein is a constituent of pathognomonic protein aggregates , called lewy bodies , as the inventors were able to confirm by their own experiments — and in the regulation of apoptosis , as shown by the data discussed above . the provision of the teaching of the invention therefore not only provides a diagnostic tool for discovering the development of or predisposition to parkinson &# 39 ; s disease , but also creates the basis for the development of a model system by means of which for example novel therapeutically effective antiparkinson substances can be discovered , or the molecular - pathological bases of the development of parkinson &# 39 ; s disease can be understood better .

the present invention relates to a method for diagnosing parkinson &# 39 ; s disease in a human being ; nucleic acid molecules used in this method ; a nucleic acid molecule which encodes a human omi / htra2 protein which has a genetic modification at amino acid position 141 and / or 399 compared with the wild type , and for corresponding segments thereof ; a host , preferably a transgenic non - human mammal , into which such a nucleic acid molecule has been introduced ; a peptide which is encoded by such a nucleic acid molecule ; a method for finding substances which bind to omi / htra2 protein which is genetically modified compared with the wild type ; a substance found with the aid of this method , and a preferably pharmaceutical composition which comprises such a substance . this invention additionally relates to a kit which comprises at least one of the aforementioned nucleic acid molecules .

as used in this specification the term &# 34 ; casino card game &# 34 ; refers to a card game in which the casino or &# 34 ; house &# 34 ; acts as the banker , collecting all losing wagers and paying all winning wagers . the casino is the &# 34 ; dealer &# 34 ; of the game . there is no head - to - head competition between players , and instead each player attempts to obtain the &# 34 ; best &# 34 ; hand possible , in accordance with a pre - defined pay out table . additionally , although the play of the game will be illustrated by making reference to a specific game layout , it should be understood and appreciated that the player - option casino game system of the present invention can be played with a different layout , or without the use of a layout ( video poker machines , cd - rom home versions of the game , internet gaming , etc . ), and still be within the scope of the present invention . reference is now made to the drawings wherein like numerals refer to like parts throughout . referring to fig1 there is shown a gaming table constructed in accordance with the principles of the present invention and designated generally by reference numeral 10 . in one preferred embodiment , the gaming table 10 is generally semicircular in shape , and is preferably sized to have approximately the same dimensions as a conventional casino gaming table of the type normally used to play blackjack . a dealer position 12 is located at the center along the linear , rear edge of the gaming table 10 . an area is provided immediately adjacent the dealer position 12 for placement of a chip tray 14 . casino games are typically played using chips rather than actual currency , and the chip tray 14 is used by a dealer as a bank , holding chips to pay winning wagers and receiving chips from losing bets . a plurality of playing positions 18 , 19 , 20 , 21 , 22 , 23 are spaced around the arcuate portion of the gaming table 10 . immediately adjacent each of the playing positions 18 - 23 are located a respective player playing area 26 , 27 , 28 , 29 , 30 , 31 . each of the player playing areas 26 - 31 defines an area for placement of wagers by each player , enumerates the payoff odds for each specific winning hand , and defines the &# 34 ; bonus &# 34 ; hands as well as identifying the &# 34 ; bonus &# 34 ; payoffs . corresponding to this schedule of regular and bonus payoffs are a sequence of dealer &# 39 ; s pay tables 35 located in front of the dealer position 12 adjacent the chip tray 14 . the dealer &# 39 ; s pay tables 35 serve as a convenient reference for the dealer during play of the game . in addition to being provided the chip tray 14 , a money paddle 37 is provided the dealer for use as a cash drop . a multi - deck card holder 39 is located adjacent the chip tray 14 . in a preferred embodiment three separate playing card casino games are available options to the players , and in such instance , the multi - deck card holder 39 is known as a &# 34 ; triple decker ™&# 34 ;. a table extension 41 is provided adjacent the dealer position 12 . placing the multi - deck card holder 39 at least partially on the table extension 41 further distances it from the playing positions 18 - 23 , enhancing security . a plurality of indicator tokens 43 are located immediately adjacent the multi - deck card holder 39 . the indicator tokens 43 are utilized during play of the game to identify the card game in play during a particular hand , as well as to identify the player who made the game selection . identification of the types of playing card games available for selection by the players is preferably provided , and is located mid - table in an identification field 45 . finally , the gaming system of the present invention optionally provides a jackpot specific for each gaming table . preferably , this jackpot is a permanent jackpot , seeded by the casino . alternatively , it can be the result of a mandatory additional ante from all of the players , or it can accumulate as a result of a combination of these two types of funding . as originally contemplated , a physical &# 34 ; jackpot bank &# 34 ; ( not shown ) would be placed on each table , perhaps of transparent materials to visually display the amount of accumulating paper currency . security considerations suggest the appropriateness of utilizing a jackpot merchandiser 49 that is placed on a particular gaming table 10 , identifying that particular table as participating in a jackpot wagering event . additionally , as is depicted in fig1 the jackpot merchandiser 49 preferably also includes amount indicia 51 that identifies the dollar amount of the jackpot award for that particular gaming table . turning now to fig2 a presently preferred embodiment for the multi - deck card holder 39 is provided . where different decks of playing cards are required for the particular game options available to each of the players , the multi - deck card holder 39 is designed to retain and keep separate each of the required playing card decks , thereby permitting the dealer to be in a position to promptly deal a particular game once it has been selected by a player . the multi - deck card holder 39 is divided into a plurality of individual card deck compartments 52 ( three compartments 52a , 52b , 52c are shown in fig2 ). each of the individual card deck compartments 52 are preferably sized to receive a single deck of playing cards ( not shown in the figures ). in the preferred embodiment depicted in fig2 the multi - deck card holder 39 is generally constructed as a transparent , open - sided , rectangular box . with the card holder 39 placed on the gaming table 10 during play of the hands , an enlarged side panel 56 and an enlarged back panel 58 assist in restricting access to the cards by players at the table . an end panel 59 , a partial cover 60 , and a bottom panel 61 complete the outer structure defining the box - like outside of the card holder 39 . in a preferred embodiment , the bottom panel 61 is slightly enlarged , extending beyond the enlarged back panel 58 and the end panel 59 to provide a larger footprint for the card holder 39 , enhancing its stability . the individual card deck compartments 52 are defined upon the placement of a preselected number of divider panels 62 . where there will be three separate playing card game options for the players , the placement of two divider panels 62 will create the required three individual card deck compartments 52a , 52b , 52c . aesthetics suggest the spacing of the initial card deck compartment 52a from the enlarged side panel 56 , and a positioning panel 63 is provided . additionally , an angled support deck 64 is provided as the support surface for the playing cards ( not shown ). by slightly elevating the playing card decks from the gaming table 10 , the angled support deck 64 simplifies the task of removing the decks of playing cards from the card deck compartments 52 . the decks of playing cards are retained in place on this angled support deck 64 by a support panel 65 ( see fig3 ). for security purposes it is desirable that a covering be placed over the individual card deck compartments 52 of the multi - deck card holder 39 . however , to assure that the dealer will have prompt access to the selected deck of playing cards , it is preferred that a plurality of individual cover panels 66a , 66b , 66c be provided . to further assist the dealer in ease of access to the individual card deck compartments 52 , the individual cover panels 66 are attached to the back panel 58 by a hinge 68 . this manner of attachment permits the cover panels 66 to be raised , simplifying access to the deck of playing cards ( not shown ). fig3 depicts such a raised cover panel position , wherein the individual cover panel 66c is shown both lowered , restricting access to the card deck compartment , as well as in a raised position ( shown in phantom ). as so raised , easy access is provided to the interior portions of the individual card deck compartment 52c . additional details regarding the player playing areas are provided with reference to fig4 . the majority of poker card games require an initial bet as well as a table ante . each of the player playing areas 26 - 31 includes a bet field 82 and an ante field 84 . a discard field 86 is also preferably provided , and can be conveniently located between the bet and ante fields 82 , 84 . once the game has been completed , payoffs for the players still remaining in the game are made in accordance with the odds specified in a payoff field 88 . since different types of poker games are options for the players , the payoff field 88 sets forth the odds and payoff for each of the game options . finally , to add further excitement to the gaming system of the present invention , a bonus field 92 is preferably provided , wherein specified hands in each of the various poker or ( other ) card game options are accorded bonus dollar amounts . although it is to be understood and appreciated that non - poker card games could be available optional games for play at a gaming table , for purposes of illustration , and not of limitation , in the examples discussed below , the players will be making their selection from among those poker games identified in fig3 namely &# 34 ; joker wild &# 34 ;, &# 34 ; deuces wild &# 34 ;, and &# 34 ; draw poker &# 34 ;. the play of the casino card game system of the present invention preferably utilizes a shuffled , 52 -, 53 - ( or more ) - card deck for each of the poker ( or other ) game options that are to be available for the players . beginning with the player seated to the dealer &# 39 ; s left , the game begins by that player choosing which of the three games are to be played during that next hand . the dealer announces the game selection to all of the players at the table , and places the appropriate indicator token 43 in front of the player who made the game selection ( termed the &# 34 ; buttoned player &# 34 ;). all players will then place their required , table bets , and will be given the opportunity to place an additional , &# 34 ; ante &# 34 ; bet while the dealer shuffles the cards . the dealer collects the table bets and , beginning with &# 34 ; buttoned player &# 34 ; and moving to the dealer &# 39 ; s right , the dealer deals one card at a time to each player until all players have the required number of initial cards , in this case , five . under the rules of the poker games just identified , players are permitted to draw up to three additional cards after the deal , placing their discards in their respective discard fields 86 . a player may also surrender all five of the dealt cards , and forfeit one - half of the player &# 39 ; s bet . in any event , beginning once again with the &# 34 ; buttoned player &# 34 ;, the dealer removes the discards and replaces them with an equal number of new cards . the dealer will continue on a player - by - player basis , providing replacement cards for any cards discarded , until all of the players have received up to their three new cards , have decided to forfeit or have not accepted any new cards and have decided to &# 34 ; stand pat &# 34 ;. if a player chooses to &# 34 ; stand pat &# 34 ;, accepting no new cards , once all of the other players have completed drawing their cards , the player standing pat may declare a bonus hand if that player &# 39 ; s original five cards appear on the bonus field 92 . the payout prescribed thereunder will be paid to that player , provided that an ante bet had previously been placed , prior to the dealing of the cards . that bonus player also remains eligible for the normal payout set forth on the payoff field 88 . following payment of the bonus awards , each player &# 39 ; s hand is then compared to the payout schedule located in the payoff field 86 in each of the player playing areas 26 - 31 . the game concludes with the dealer paying and taking all bets , from right to left , according to the pay table appropriate for the particular game being played . all cards are discarded back into the proper card deck compartment 52 , and the indicator token 43 returned to its proper location . the cover panel 66 is lowered , and a new game selection is made by the next player , with play thereafter continuing in the manner just described , in accordance with the rules of the particular game chosen by the next succeeding player from among the three game options . the present playing card game invention also contemplates the possible use of a jackpot payout , with utilization of this feature to be at the casino &# 39 ; s option . should such a jackpot feature be chosen , funding is preferably by the casino . other funding is possible , such as through an additional , player ante , or by blending player sources with the casino . the present invention is not to be viewed as limited with respect to the manner in which the jackpot bet is funded . regardless of the source , the jackpot merchandiser 49 identifies those tables having a jackpot . these jackpot funds are restricted towards funding jackpot events occurring on only that specific gaming table . additionally , the present invention contemplates the distribution of these jackpot funds on a &# 34 ; community &# 34 ; basis . upon the occurrence of a specific , pre - defined , jackpot playing card event by one of the players at that table -- the jackpot funds are to be equally distributed to all of the players at that table . an example of such a &# 34 ; jackpot event &# 34 ; might include the dealing of a &# 34 ; natural &# 34 ; royal flush ( as originally dealt , with no draw cards ). again , upon the occurrence of such an event , the jackpot funds are then equally distributed to all of those players at that table that had previously placed an ante bet . the present invention is further demonstrated by the following examples of play : there are six players at the table . each round , one player will have the opportunity to decide which game will be played that round . in this example , player # 1 chooses to play deuces wild . the dealer places the deuces wild button in front of player # 1 , selects a deck of playing cards appropriate for deuces wild , and announces to all : &# 34 ; you are playing deuces wild &# 34 ;. all players place a bet and ante . the dealer collects the antes . starting from the &# 34 ; buttoned &# 34 ; player and moving to the dealer &# 39 ; s right , each player receives one card at a time until all players have five cards . all players look at their cards and then must decide whether to fold , ( not play original five cards ) draw or stand pat ( no draw ). the dealer starts with the &# 34 ; buttoned &# 34 ; player , which in this case , is player # 1 . player # 1 decides to stand pat . the dealer asks the player , &# 34 ; are you declaring a bonus hand ?&# 34 ; the player says , &# 34 ; yes &# 34 ;. the dealer then places this player &# 39 ; s cards and bet in the appropriate area . player # 2 decides to stand pat . the dealer then asks the player , &# 34 ; are you declaring a bonus hand ?&# 34 ;. the player responds by saying that they are not . player # 3 decides to discard three cards and the dealer then replaces them with an equal number of new cards . player # 4 decides to discard two cards and the dealer then replaces them with an equal number of new cards . player # 5 decides to discard one card , so the dealer then takes the discard and replaces it with a new card . player # 6 decides to fold ( does not play the original 5 cards ) and receives half of the bet back . the dealer now pays and takes in order ( dealer &# 39 ; s right to left ). player # 6 has already folded , therefore no action will be taken by the dealer . player # 5 does not have a hand that appears on the pay table ( loses ). the dealer takes the bet . player # 4 has three of a kind . the hand is declared a &# 34 ; push &# 34 ;. player # 3 has a flush . the dealer pays the bet the proper odds from the pay table . player # 2 has a straight flush . the dealer pays the bet the proper odds from the pay table . player # 1 has five of a kind . the dealer pays the bet the proper odds from the pay table and the bonus payout , because this is an original five card bonus hand and player # 1 had placed an additional ante bet . there are six players at the table . each round , one player will have the opportunity to decide which game will be played that round . in this example , the player # 1 chooses to play joker wild . the dealer places the joker wild button in front of player # 1 , selects a deck of playing cards appropriate for joker wild , and announces to all : &# 34 ; you are playing joker wild .&# 34 ; all players place a bet and ante . the dealer collects the antes . starting from the &# 34 ; buttoned &# 34 ; player and moving to the dealer &# 39 ; s right , each player receives one card at a time until all players have five cards . all players look at their cards and then must decide whether to fold , ( not play original five cards ) draw or stand pat ( no draw ). the dealer starts with the &# 34 ; buttoned &# 34 ; player , which in this case , is player # 1 . player # 1 decides to stand pat . the dealer asks the player , &# 34 ; are you declaring a bonus hand ?&# 34 ; the player says , &# 34 ; yes &# 34 ;. the dealer then places this player &# 39 ; s cards and bet in the appropriate area . player # 2 decides to stand pat . the dealer then asks the player , &# 34 ; are you declaring a bonus hand ?&# 34 ;. the player responds by saying that they are not . player # 3 decides to discard three cards and the dealer then replaces them with an equal number of new cards . player # 4 decides to discard two cards and the dealer then replaces them with an equal number of new cards . player # 5 decides to discard one card , so the dealer then takes the discard and replaces it with a new card . player # 6 decides to fold ( does not play original 5 cards ) and receives half of the bet back . the dealer now pays and takes in order ( right to left ). player # 6 has already folded , therefore no action will be taken by the dealer . player # 5 does not have a hand that appears on the pay table ( loses ). the dealer takes the bet . player # 4 has a pair of kings . the hand is declared a &# 34 ; push &# 34 ;. player # 3 has three of a kind . the dealer pays the bet the proper odds from the pay table . player # 2 has a straight . the dealer pays the bet the proper odds from the pay table . player # 1 has five of a kind . the dealer pays the bet , based upon the proper odds from the pay table , and the bonus payout , because this is an original five card bonus hand . there are six players at the table . each round , one player will have the opportunity to decide which game will be played that round . in this example , player # 1 chooses to play draw poker . the dealer places the draw poker button in front of player # 1 , selects a deck of playing cards appropriate for draw poker , and announces to all : &# 34 ; you are playing draw poker &# 34 ;. all players place a bet and ante . the dealer collects the antes . starting from the &# 34 ; buttoned &# 34 ; player and moving to the dealer &# 39 ; s right , each player receives one card at a time until all players have five cards . all players look at their cards and then must decide whether to fold , ( not play original five cards ) draw or stand pat ( no draw ). the dealer starts with the &# 34 ; buttoned &# 34 ; player , which in this case , is player # 1 . player # 1 decides to stand pat . the dealer asks the player , &# 34 ; are you declaring a bonus hand ?&# 34 ; the player says , &# 34 ; yes &# 34 ;. the dealer then places this player &# 39 ; s cards and bet in the appropriate area . player # 2 decides to stand pat . the dealer then asks the player , &# 34 ; are you declaring a bonus hand ?&# 34 ;. the player responds by saying that they are not . player # 3 decides to discard three cards and the dealer then replaces them with an equal number of new cards . player # 4 decides to discard two cards and the dealer then replaces them with an equal number of new cards . player # 5 decides to discard one card , so the dealer then takes the discard and replaces it with a new card . player # 6 decides to fold ( does not play original 5 cards ) and receives half of the bet back . the dealer now pays and takes in order ( right to left ). player # 6 has already folded , therefore no action will be taken by the dealer . player # 5 does not have a hand that appears on the pay table ( loses ). the dealer takes the bet . player # 4 has a pair of jacks . the hand is declared a &# 34 ; push &# 34 ;. player # 3 has two pair . the dealer pays the bet the proper odds from the pay table . player # 2 has a flush . the dealer pays the bet the proper odds from the pay table . player # 1 has four of a kind . the dealer pays the bet the proper odds from the pay table and the bonus payout , because this is an original five card bonus hand . if any of these players had been dealt a royal flush ( in the original five cards ), in addition to receiving the proper odds from the pay table and being awarded an additional bonus payout , all money in the jackpot bank at that table will be equally distributed to all players that received a hand ( after having placed an initial bet ) and placed an ante bet in that game round . based upon calculations using well - known techniques , it has been determined through statistical analysis that the house will have an edge of approximately 2 . 71 % with draw poker , 2 . 13 % with joker poker , and 3 . 49 % with deuces wild , for an overall average of 2 . 78 %. these percentages equate to approximately a 20 % to 30 % hold . of course , this calculated house advantage will increase when players do not use the optimal strategy . it has been reasonably calculated that approximately 3 , 600 hands per table will be dealt in a 24 - hour playing period . based upon a $ 1 ante bet , 3 , 600 hands will equal $ 3 , 600 per 24 hour period or $ 1 , 314 , 000 per year . based on 3 , 600 hands dealt per 24 - hour period , there is a statistical probability of approximate bonus payouts per table per year of $ 650 , 000 per year . there is an estimated profit of $ 650 , 000 per table , per game , per year . the basis for such estimates are set forth in the following tables 1 , 2 , and 3 for each of the games previously mentioned , joker poker , deuces wild , and draw poker . table 1______________________________________joker wild analysis______________________________________pay table odds times / cycle bonus award payout______________________________________royal flush 500 - 1 4 30 , 000 120 , 0005 of a kind 200 - 1 13 12 , 500 162 , 500wild royal 100 - 1 20 5 , 000 100 , 000strt . flush 40 - 1 180 1 , 500 270 , 0004 of a kind 15 - 1 3120 250 780 , 000full house 6 - 1 total 1 , 432 , 500flush 3 - 1 drop 2 , 869 , 685straight 2 - 1 win 1 , 437 , 1853 of a kind 1 - 1 vig on ante 50 . 1 % two pairs pushpair k &# 39 ; s pushpayback % 94 . 58 optional ante $ 1 . 00 bet______________________________________adjustments for forfeits : hand type quantity increase by : increase % ______________________________________draw 5 320 , 844 0 . 1772 1 . 98double ins strt flush 31 , 860 0 . 05 0 . 06ace or king 508 , 836 0 . 0541 0 . 96ace and king 13 , 032 0 . 0624 0 . 03two card royals 39 , 492 0 . 1748 0 . 27 total payback % 97 . 87______________________________________ table 2______________________________________deuces wild analysis______________________________________pay table odds times / cycle bonus ($) payout (%) ______________________________________royal flush 500 - 1 4 25 , 000 100 , 000four deuces 200 - 1 48 3 , 000 144 , 000wild royal 20 - 1 480 950 456 , 0005 of a kind 12 - 1 624 450 280 , 800strt . flush 8 - 1 2 , 136 150 320 , 4004 of a kind 3 - 1 total 1 , 301 , 200full house 2 - 1 drop 2 , 598 , 960flush 1 - 1 win 1 , 297 , 760straight 1 - 1 vig on ante 49 . 9 % 3 of a kind pushpayback % 92 . 34 optional ante $ 1 . 00 bet______________________________________adjustments for forfeits : hand type quantity increase by : increase % ______________________________________draw 5 502 , 308 0 . 195 3 . 77double ins strt flush 13 . 512 0 . 145 0 . 08inside straight 114 , 180 0 . 160 0 . 70inside strt . flush 13 , 032 0 . 062 0 . 03two card royals 53 , 340 0 . 183 0 . 38deuce ( solo ) 338 , 112 - 0 . 006 - 0 . 78 total payback % 96 . 51______________________________________ table 3______________________________________jacks or better analysis______________________________________pay table odds times / cycle bonus ($) payout (%) ______________________________________royal flush 500 - 1 4 25 , 000 100 , 000strt flush 100 - 1 36 3 , 500 126 , 0004 of a kind 25 - 1 624 350 218 , 400full house 6 - 1 3 , 744 125 468 , 000flush 4 - 1 5 , 108 75 383 , 100straight 3 - 1 total pay 1 , 295 , 5003 of a kind 2 - 1 drop 2 , 598 , 960two pairs 1 - 1 win 1 , 303 , 460pair jacks push vig on ante 50 . 2 % payback % 96 . 24 % optional ante $ 1 . 00 bet______________________________________adjustments for forfeits : hand type quantity increase by : increase % ______________________________________draw 5 84 , 360 0 . 1449 0 . 47dbl ins strt flu ( 0 hi cd ) 6 , 768 0 . 0504 0 . 01one high card 402 , 528 0 . 0275 0 . 43two high cards 386 , 148 0 . 00805 0 . 12two card royals 30 , 072 0 . 02 0 . 02 total payback % 97 . 29 % ______________________________________ it is also possible to utilize the present inventive bonus and / or jackpot even where the players are not permitted to select the game just prior to the deal . for example , if the table in example 1 were to be restricted to deuces wild , the play would be the same , and the bonuses and jackpot payments would be made as stated therein . the same also would be true if the table were restricted to any one of the other poker games . the only difference : pre - deal selection of the game to be played , by the players , would not occur . our invention has been disclosed in terms of a preferred embodiment thereof , which provides an improved player - option casino game system of great novelty and utility . various changes , modifications , and alterations in the teachings of the present invention may be contemplated by those skilled in the art without departing from the intended spirit and scope thereof . it is intended that the present invention encompass such changes and modifications .

a method and apparatus for playing card wagering games that enables players to select the playing card game to be played for a particular wagering round from among multiple playing card game options . where different decks of playing cards are required for certain of the optional playing card games , a multi - deck card holder is provided , permitting a dealer to make an immediate selection of the appropriate playing cards upon selection of the playing card game by a player at that table . upon the conclusion of one wagering round , selection of the next playing card game is made by the same or a different player , and the play continues with the selection of playing card games entirely at the option of the players .

fig1 is a sectional view of a portion of the digestive tract in a body . food to be digested enters the stomach 102 through the cardiac orifice 110 from the esophagus . chyme , a semi - fluid , homogeneous creamy or gruel - like material produced by gastric digestion in the stomach exits the stomach through the pyloric orifice ( pylorus ) 108 and enters the small intestine 112 . the pylorus 108 is a distal aperture of the stomach 102 surrounded by a strong band of circular muscle . the small intestine , about nine feet in length , is a convoluted tube , extending from the pylorus to the ileo - caecal valve where it terminates in the large intestine . the small intestine has three sections , the duodenum 104 , jejunum 106 and the ileum ( not shown ). the first eight to ten inch section of the small intestine , the duodenum , is the shortest , widest and most fixed part of the small intestine . the duodenum has four sections : superior , descending , transverse and ascending which typically form a u - shape . the superior section is about two inches long and ends at the neck of the gall bladder . the descending section is about three to four inches long and includes a nipple shaped structure ( papilla of vater ) 114 through which pancreatic juice from the pancreas and bile produced by the liver and stored by the gall bladder enter the duodenum from the pancreatic duct . the pancreatic juice contains enzymes essential to protein digestion and bile dissolves the products of fat digestion . the ascending section is about two inches long and forms the duodenal - jejunal flexure 116 where it joins the jejunum 106 , the next section of the small intestine . the duodenal - jejunal flexure 116 is fixed to the ligament of treitz 118 ( musculus supensionus duodeni ). the juices secreted in the duodenum break the partially digested food down into particles small enough to be absorbed by the body . the digestive system is described in gray &# 39 ; s anatomy (“ anatomy of the human body ”, by henry gray ) and “ human physiology ”, vander , 3 rd ed , mcgraw hill , 1980 , the contents of which are incorporated herein by reference in their entirety . fig2 is a perspective view of a gastrointestinal implant device 200 according to the principles of the present invention . the gastrointestinal implant device 200 includes an elongated open - ended flexible sleeve or tube 202 having a first proximal opening 204 and a second distal opening 206 . within the sleeve 202 is a passageway that extends from the first proximal opening 204 to the second distal opening 206 for transporting the chyme exiting the stomach 102 ( fig1 ). the surface of the passageway ( the interior surface of the implant device 200 ) is smooth to enable the chyme to easily pass through . the exterior surface of the implant device 200 is smooth to prevent tissue in - growth and to be non - irritating to the bowel . within the implant device 200 at the proximal end including the first proximal opening 204 is a collapsible self - expanding stent 208 . the stent 208 includes a plurality of opposed barbs 210 for anchoring the implant device 200 to the muscular pylorus in the stomach 102 . the diameter of the stent 208 is dependent on the diameter of the pyloric orifice 108 ( fig1 ) about 0 . 8 ″ to 1 . 1 ″ based on human anatomy variations . in one embodiment , the length 1 of the stent 208 is selected to extend through the pylorus 108 and keep the pylorus 108 permanently open to induce “ dumping syndrome .” in an alternate embodiment , a stent with a shorter length 1 allows the pylorus 108 to open and close normally . the sleeve material is thin and conformable so that it collapses in the intestine to a small volume to minimize bowel irritability . it has a low coefficient of friction (& lt ; 0 . 20 ) so that chyme slides easily through it and the bowel slides easily around it . it is of low permeability to fluids so that the chyme does not touch the bowel wall and the digestive enzymes do not significantly breakdown the chyme . it is biologically inert and non - irritating to the tissues . one such material is expanded polytetrafluoroethylene ( eptfe ), a fluoropolymer , with a wall thickness of about 0 . 006 ″ and an internodal distance of 20 microns . this material is hydrophobic but is slightly porous . however , these very small pores may plug over time . the porosity may be reduced by coating the material on the inside , outside or in the pores with dilute solutions of silicone or polyurethane . another material is polyethylene with a wall thickness of less than 0 . 001 ″. rubber - like materials typically have friction coefficients of 1 - 4 , significantly stickier than these materials . however , in alternate embodiments other materials having similar characteristics can be used . the sleeve 202 includes two layers of material at least at the proximal end . a first outer layer covers the exterior of the stent . the second inner layer covers the interior surface of the stent 208 . the barbs 210 protrude from the exterior surface of the stent 208 through the first outer layer of the sleeve 208 . the holes in the first outer layer through which the barbs 210 protrude are filled with an impervious material such as silicone or urethane to limit mixing of digestive juices with the chyme flowing through the passageway . the diameter of the sleeve 208 is selected such that the first outer layer of the sleeve 208 fits over the stent 208 . the sleeve length 212 ranges from about one foot to about five feet . the typical length of the sleeve 208 is about 1 . 5 feet from the anchor ( barbs 210 ) in the pyloric region of the stomach to below the ligament of treitz 118 ( fig1 ). the length 212 of the sleeve 202 is selected to bypass the duodenum 104 ( fig1 ) and a portion of the jejunum . the length is increased to further decrease absorption by bypassing a longer section of the jejunum 106 ( fig1 ). the length 212 of the sleeve 202 is variable and dependent on the patient &# 39 ; s body mass index ( bmi ). the procedure is a less invasive alternative to surgery for the treatment of obesity and morbid obesity and also provides a new treatment approach for type 2 diabetes . the covered stent 208 can be collapsed into a sheath having a diameter less than ¼ inches to enable endoscopic delivery . covering the exterior surface of the stent 208 with the first outer layer of the sleeve 202 permits endoscopic removal of the implant device 200 by preventing tissue in - growth on the exterior surface of the stent 208 . markings can be added to the exterior surface of the sleeve 202 to detect the position and orientation of the sleeve on a fluoroscopic image and whether the sleeve is twisted . for example , a stripe can be painted down the length of the device 200 using tantalum impregnated ink , or tantalum bands can be bonded to the exterior surface of the device . if the sleeve 202 is twisted , the sleeve 202 can be untwisted by inserting a balloon into the proximal end of the device thereby sealing it , and then injecting water into the sleeve at low pressure . fig3 a is a plan view of the proximal portion of the gastrointestinal implant device shown in fig2 . fig3 b is a cross - sectional view as taken along line aa of fig3 a showing the stent 208 and the first outer layer 300 and the second inner layer 302 of the sleeve 202 shown in fig2 . as described in conjunction with fig2 , the sleeve 202 includes a first outer layer 300 and a second inner layer 302 . the first outer layer 300 is bonded to the second inner layer 300 at positions 306 below the distal end of the stent 208 and at positions 308 , above the proximal end of the stent 208 . a passageway 304 inside the second inner layer 302 of the sleeve 202 allows passage of chyme through the sleeve 202 . the stent 208 is sandwiched between the first outer layer 300 and the second inner layer 302 at the proximal end of the sleeve 202 and is free to move at the distal end within the first outer layer 300 and the second inner layer 302 of the sleeve 202 . the covered exterior surface of the stent 208 prevents tissue growth to allow removal of the implant device 200 . the covered interior surface of the stent 208 provides a smooth passageway for chyme to bypass the duodenum 104 . fig4 is a perspective view of the gastrointestinal implant device 200 with the first outer layer 300 of the sleeve 202 removed . the interconnecting struts which form the mesh ( a network of struts ) with diamond spaced openings are sufficiently flexible to allow the stent to be collapsed inside a delivery catheter and have sufficient elasticity to hold the pylorus open once the catheter is withdrawn . the force needed to hold the pylorus open is about 1 - 2 lbs . of radial force outward when the stent is compressed from its full diameter by 25 %. fig5 a is a sectional view of a body showing one embodiment of the gastrointestinal implant device 200 implanted in the digestive system . the first proximal end 204 of the implant device 200 is anchored to muscle in the pyloric portion of the stomach 102 . the barbs 210 grip onto the muscle to anchor the implant device 200 in place so that the implant device 200 can not be dragged into the stomach or down into the intestines with movement of the stomach and the intestines . fig5 b is a sectional view of a body showing an alternative embodiment of the gastrointestinal implant device 200 ′ implanted distal to the pylorus 108 . the sleeve 202 extends over the ligament of treitz 118 beyond the proximal jejunum . extending the sleeve below the ligament of treitz reduces the likelihood that the sleeve will move back through the duodenum 104 toward the stomach 102 . after the gastrointestinal implant device 200 has been placed in the body and anchored in either the pyloric portion of the stomach or distal to the pylorus 108 , chyme leaving the stomach passes through passageway 304 ( fig3 b ) inside the sleeve 202 and bypasses the duodenum 104 and proximal jejunum 106 . by directing the chyme through the sleeve 202 the digestion and the absorption process in the duodenum 104 is interrupted . by interrupting mixing of the chyme with juices in the duodenum 104 , partially digested food material is not broken down into particles small enough to be absorbed by the body . further , there is no mixing of bile with the chyme until the chyme reaches the jejunum 106 . the absorption of fats and carbohydrates is reduced by delaying the mixing of bile with the chyme . the pyloric valve opens periodically to allow chyme to exit the stomach 102 to the duodenum 104 . in one embodiment of the invention the length of the stent 208 is selected to keep the pyloric valve permanently open to induce “ dumping syndrome .” by keeping the pylorus 108 open , the chyme empties rapidly into the sleeve 202 and passes down through the sleeve 202 and into the jejunum 106 with minimal digestion . this results in a “ dumping syndrome ” which is a reaction to excessive rapid dumping of chyme into the jejunum 106 causing the patient to feel ill , dizzy and nauseated . this syndrome is particularly enhanced when sugars and carbohydrates are eaten and passed directly into the jejunum 106 . to hold the pyloric valve open , the length of the stent 208 should be at least 1 . 5 inches so that the stent 208 extends from the anchoring position in the pyloric portion of the stomach through the pyloric orifice 108 ( the opening from the stomach while the pyloric valve is open ). the length of the stent is selected so that the distal end of the stent is above the papilla of vater 114 ( fig1 ). as shown , the stent 208 extends through the pyloric orifice 108 to hold the pyloric valve permanently open . in an alternative embodiment , the length of the stent 208 is selected such that the stent 208 ends at the stomach side of the pyloric orifice 108 allowing the pyloric valve to operate normally . the sleeve 202 provides weight loss mechanisms by providing negative feedback , reduced fat digestion and reduced desire for food . the reduced fat digestion occurs because the sleeve 202 delays the mixing of bile and pancreatic juices with chyme from the stomach until after the chyme leaves the sleeve . the reduced desire for food may occur because the sleeve 202 blocks hormonal release from the duodenum . after the chyme from the stomach has passed through the sleeve , the sleeve becomes extremely thin and floppy , permitting the sleeve to contour to the inner walls of the intestine . the sleeve is non - compliant and drapes away from the intestinal walls thereby permitting the pancreatic juice to flow unimpeded into the duodenum through the papilla of vater . the normal peristalsis of the bowel is used to propel the chyme through the intestines . fig6 is a perspective view of a collapsible self - expanding stent 600 in the gastrointestinal implant device 200 shown in fig2 when expanded . the stent 600 is non - woven , collapsible and self - expanding , allowing endoscopic insertion and removal of the implant device 200 . the stent 600 includes a plurality of flat struts 602 forming an open space pattern to ease collapsing while ensuring self - expansion . the open space pattern allows for collapsing into a catheter for endoscopic delivery and removal . the struts 602 may be manufactured from heat - treated spring steel , or from an alloy such as a nickel - titanium , a shape - memory alloy commonly referred to as nitinol . other alloys include nickel - cobalt - chromium - molybdenum alloys possessing a unique combination of ultrahigh tensile strength , such as mp35n , available from asahi intecc co ., ltd . of newport beach , calif . in the embodiment shown , the stent has a length l of about 1 . 5 inches and has a diameter d of about 1 inch . the struts 602 are flat , about 0 . 010 inches wide and about 0 . 004 to 0 . 010 inches thick . the stent can be formed from a tube of material by laser cutting followed by expansion and heat setting , or other methods well known to those skilled in the art . in an alternate embodiment , the struts 602 can be formed separately and the strut intersections can be welded or attached by other means well known to those skilled in the art . visually the struts form sections 604 around the circumference of the stent . each section has a series of triangles with each triangle defined by one distal strut connection 606 and two proximal strut connections 608 , 610 . the ratio of the collapsed diameter to the expanded diameter of the stent is roughly 1 : 4 . when expanded , the angle α between divergent strut sections is about 45 - 50 degrees and the diameter of the stent is about one inch . when compressed , the angle θ between divergent strut sections is about 5 - 6 degrees to reduce the diameter of the stent to about 0 . 21 inch for endoscopic delivery and removal . the elasticity of the struts permits this compression . when the radial compression is released , the elasticity of the struts causes the stent to expand to diameter d . the stent assumes its desired diameter as the elastic restoring forces seek their minimum stress . the ends of the struts at the proximal end of the stent 600 are elongated and shaped to provide barbs 612 to anchor to the muscle in the pyloric portion of the stomach 102 . fig7 is a perspective view of the stent 600 shown in fig6 when compressed . the stent 600 is compressed until the angle β between divergent strut sections is about 5 - 6 degrees to reduce the diameter d of the stent 600 to about 0 . 21 inch for endoscopic delivery and removal . the barbs 704 at the proximal end of the stent are elongated . the barbs 704 can be shaped to anchor the stent to the muscular pylorus . fig8 is a perspective view of another embodiment of a stent 800 when compressed . pairs of barbs 802 at the proximal end of the stent 800 are elongated and can be shaped to provide opposed barbs to anchor the stent 800 in the muscle of the pylorus . fig9 is a perspective view of the compressed stent 800 shown in fig8 with the strut ends 902 , 900 bent to provide opposed barbs 904 , 906 . the barbs 904 , 906 engage the muscle of the pylorus to anchor the gastrointestinal implant device in the pylorus portion of the stomach . as shown in fig2 , the strut ends 900 , 902 protrude outward from the outer surface of the stent 800 in opposite directions . they may be perpendicular to each other . the barbs 904 , 906 at the ends of the respective opposed strut ends 900 , 902 dig into the pylorus muscle to anchor the stent . the barbs 904 , 906 at the end of the protruding opposed strut ends 900 , 902 prevent movement of the stent 800 in either direction ; that is , they prevent movement of the stent 800 into the stomach and prevent movement of the stent 800 down through the duodenum . fig1 is a perspective view of the stent 800 shown in fig8 when expanded . as discussed in conjunction with fig9 , the barbs 904 , 906 engage the muscle of the pylorus while the stent 800 is expanded . in the engaged position , the barbs 904 , 906 spread radially outward from the longitudinal axis of the stent 800 such that the tips of the barbs come into contact and engage the tissue . fig1 illustrates the gastrointestinal device 1100 shown in fig1 including an anti - buckling mechanism 1102 . a flexible , anti - rotation , anti - buckling mechanism 1102 is attached to the sleeve 202 and extends from below the distal end of the stent along the length l of the sleeve to the distal end of the sleeve 202 . in the embodiment shown , the anti - buckling mechanism 1102 is a guidewire device attached to the exterior surface of the outer layer of the flexible sleeve . guidewire devices are well known to those skilled in the art . a first proximal end of the guidewire device 1104 is attached below the stent and a second distal end of the guidewire device 1106 is attached to the distal end of the flexible sleeve . the diameter of the guidewire ranges from about 0 . 010 ″ to about 0 . 016 ″. the length of the sleeve 202 can be sized to just pass over the ligament of treitz thereby bypassing only the duodenum and proximal jejunum 106 . by doing this , it may not be necessary to provide any anti - buckling mechanisms in the sleeve 202 since the duodenum 104 is not very mobile compared to the jejunum 106 . typically , an anti - buckling mechanism 1102 is added to the exterior surface of a sleeve 202 having a length exceeding the length of the duodenum 104 and proximal jejunum 106 . the gastrointestinal implant device 200 is designed for endoscopic placement . fig1 is a perspective view of a portion of a catheter system 1200 for delivery of the gastrointestinal implant device . the catheter system follows a guide wire 1212 through the esophagus and the stomach to the pylorus portion of the stomach . the guide wire 1212 enters a first inner lumen at the proximal end 1208 of the catheter system 1200 and exits the first inner lumen at the distal end 1222 of the catheter system 1200 . the catheter system 1200 includes an outer sheath 1202 for storing the stent 208 in collapsed form , a flange 1216 to pull back the outer sheath 1202 and a sleeve retention wire mechanism 1214 for releasing a sleeve retention wire 1210 from the proximal end of the flexible sleeve 202 after the stent has been released from the outer sheath 1202 . as described in conjunction with fig2 , the distal portion of the gastrointestinal implant device includes a flexible sleeve 202 which can negotiate the duodenum and the jejunum . a sleeve retention wire 1210 travels through a second inner lumen and exits the second inner lumen to secure the distal end of the sleeve 202 to an inner sheath 1226 . the sleeve retention wire 1210 is coupled to the sleeve retention wire release mechanism 1214 for releasing the sleeve retention wire 1210 after the gastrointestinal implant device has been positioned in the pyloric section of the stomach . the release mechanism 1214 will be described later in conjunction with fig1 b . the sleeve 202 is secured temporarily outside the inner sheath 1226 allowing for proper positioning of the gastrointestinal implant device and then for release . as shown , the sleeve 202 is secured by the sleeve retention wire 1210 using a dead - bolt mechanism 1206 . non - stick coatings such as teflon on the sleeve retention wire 1210 are preferred to make release easier to accommodate tortuous anatomical pathways . the sleeve retention wire 1210 extends through the second inner lumen from the release mechanism 1214 of the catheter system 1200 to the dead - bolt mechanism 1206 . the dead - bolt mechanism 1206 is described later in conjunction with fig1 a . the sleeve retention wire 1210 holds the sleeve in position . the distal end of the folded sleeve is released by the release mechanism 1214 by pulling the sleeve retention wire 1210 backward from the proximal end 1208 of the catheter . as described in conjunction with fig1 , the proximal portion of the gastrointestinal device includes a covered stent . the covered stent does not enter the duodenum and thus is stiffer than the sleeve because it remains in the pylorus of the stomach . the stent in the gastrointestinal implant device is collapsed and stored in the outer lumen within the outer sheath 1202 between the flange 1216 and the distal end of the outer sheath 1202 . the stent is supported in a collapsed form by the outer sheath 1202 . the catheter 1200 is inserted into the digestive system through the esophagus to the pyloric section of the stomach . the proximal end of the outer sheath 1202 is positioned in the stomach , in the pylorus through the use of positioning ring 1224 . after the outer sheath 1202 has been positioned , the stent is retracted from the outer lumen of the catheter by pulling flange 1216 toward the proximal end of the catheter system 1200 . upon release , the stent self - expands by its own elastic restoring force to engage the anchor portion with the stomach muscle at the pyloric section of the stomach . fig1 is a cross - sectional view of the inner shaft 1226 taken along line e - e of fig1 . the sleeve retention wire 1210 passes through a second inner lumen 1314 in the inner sheath 1226 . the sleeve retention wire 1210 exits the second inner lumen 1314 and is threaded through folds of the sleeve 202 at 1302 in fig1 a . the sleeve retention wire 1210 re - enters the second inner lumen 1314 at 1302 ( fig1 a ). the guidewire 1212 passes through the first inner lumen 1310 . fig1 a is an expanded perspective view of the dead - bolt mechanism 1206 shown in fig1 . the sleeve 202 has been folded for delivery . the sleeve is wrapped around the inner sheath 1226 and bunched above the inner sheath 1226 . the sleeve is held in folded position around the inner sheath 1226 by threading the sleeve retention wire 1210 through the folds of the sleeve 202 . the sleeve retention wire 1210 exits the second inner lumen 1314 through an opening 1306 and pierces through folds of the sleeve 202 at 1304 . threading the sleeve retention wire 1210 through the folds of the sleeve 202 results in a plurality of small holes at the distal end of the sleeve 202 . the holes are reinforced with silicone or urethane to avoid tears in the material . the sleeve retention wire 1210 re - enters the second inner lumen through a second hole 1302 and advances a sufficient distance within the second inner lumen toward the distal end of the second inner lumen to resist pulling out of the second inner lumen . fig1 b is a sectional view of the dead - bolt mechanism 1206 shown in fig1 a illustrating the sleeve retention wire 1210 threaded through the sleeve . the sleeve retention wire 1210 exits the second inner lumen 1314 at 1306 and pierces through folds in the sleeve 202 at 1304 . the sleeve retention wire 1210 re - enters the second inner lumen 1314 at 1302 . fig1 is a sectional view of a portion of the catheter system shown in fig1 illustrating the collapsed stent 208 stored inside the outer sheath 1202 . the stent 208 is pre - compressed and held in a collapsed form inside the outer sheath 1202 of the catheter . the outer sheath 1202 is pulled back by the flange 1216 toward the proximal end of the catheter system 1200 to release the self - expanding stent 208 . the stent radially expands under its own elastic restoring force . the guidewire 1212 is directed through the first inner lumen 1310 and the sleeve retention wire 1210 is directed through the second inner lumen in the inner sheath 1226 . the inner sheath includes a first lumen through which the guidewire passes and a second lumen through which the sleeve retention wire passes . fig1 a - c illustrate a method for delivery of the gastrointestinal implant device . fig1 a is a plan view of the catheter system illustrating the collapsed stent stored inside the outer sheath 1202 of the gastrointestinal implant device . as described in conjunction with fig1 , the stent 208 is stored inside the outer sheath and the distal end of the sleeve 202 is secured outside the inner sheath 1226 by a sleeve retention wire 1210 . fig1 b is a plan view of the catheter system 1200 illustrating the gastrointestinal implant device after release of the stent 208 from the outer sheath 1202 . the flange 1216 has been pulled back toward the proximal end of the catheter system 1200 to pull back the outer sheath 1202 from the stent and the stent 208 has self - expanded . the sleeve retention wire 1210 holds the distal end of the sleeve 202 . once in place , the sleeve retention wire 1210 can be removed . as described previously in conjunction with fig1 , the sleeve retention wire 1210 is coupled to locking mechanism 1224 . handle 1600 in the locking mechanism 1214 acts as a pivot device to pull the sleeve retention wire 1210 from the dead - bolt mechanism 1206 . the distal end of the gastrointestinal implant device is released by moving handle 1600 in a clockwise direction 1604 . as the handle 1600 is moved in direction 1604 , the sleeve retention wire 1210 threaded through the folds of the sleeve is pulled back through the second inner lumen 1314 and disengages from the sleeve at the distal end of the gastrointestinal implant device . the sleeve retention wire 1210 extends from the distal end of the gastrointestinal implant device through the second inner lumen 1314 . the wire is connected to the handle 1600 at the proximal end of the catheter . fig1 c is a plan view of the catheter system illustrating the expanded gastrointestinal implant device after the sleeve retention wire has been released . the handle 1600 has been moved in a clockwise direction and the sleeve retention wire 1210 has been pulled back through the second inner lumen 1314 to release the distal end of the sleeve 202 . fig1 is a perspective view of another embodiment of the catheter system shown in fig1 . the catheter includes a ball 1800 coupled to the distal end 1222 of the inner sheath 1226 for guiding the catheter through the alimentary canal ( e . g ., to the pyloric portion of the stomach ). the ball 1800 is small enough so that it can be pulled back through the gastrointestinal implant device after the gastrointestinal device has been delivered , the stent expanded and the sleeve retention wire 1210 has been released . the sleeve is shown uniformly folded 1204 . however , the sleeve may not necessarily be uniformly folded . fig1 is a cross - section of an everting catheter system 1900 for delivery of a longer flexible sleeve . the gastrointestinal implant device 200 is shown with the stent sleeve anchor 1901 and the attached sleeve 1902 shown as delivered into the anatomy . the delivery catheter previously described is then removed . a balloon catheter 1906 is introduced into the stent sleeve anchor 1901 and the balloon 1908 inflated to seal the lumen of the stent 1901 . the sleeve 1902 is folded inside itself and an elastic band 1912 is used to seal the end of the sleeve . fluid is then injected through the balloon catheter shaft 1906 into the sleeve lumen 1910 , filling the lumen and pressurizing it . the pressure of the fluid is used to push the inner sleeve distally towards 1904 . when the sleeve 1902 has fully deployed distally , the elastic band 1912 falls off of the closed end of the sleeve 1902 and passes distally in the intestine until it is excreted . this mechanism permits deployment of a sleeve that is double the length of the delivered device . this may be needed as it is difficult to access the distal parts of the intestine with guidewires . this everting catheter system enables delivery of longer sleeves than are possible using only the delivery catheter described in conjunction with fig1 . fig1 is a perspective view of a retrieval device 2000 for removing the gastrointestinal implant device 200 from the digestive tract . as already described , the exterior surface of the stent 208 is covered with a material that prevents cellular in - growth allowing the stent 208 to be easily removed . the retrieval device 2000 includes an inner sheath 2004 and an outer sheath 2006 . a plurality of fingers 2002 extend from the proximal end of the inner sheath 2004 . the fingers 2002 engage the exterior surface of the gastrointestinal device . as the inner sheath 2004 is moved down over the fingers , the fingers 2002 pull radially inward to reduce the proximal stent diameter and pull the collapsed device into the outer sheath 2006 . fig2 is a perspective view of the retrieval device 2000 engaged with the stent 208 . the fingers 2002 of the retrieval device are positioned around the stent 208 . as the inner sheath 2004 is pushed over the fingers 2002 , the fingers pull radially inward on the proximal end of the stent 208 and the proximal end of the stent 208 is collapsed . after the stent 208 has been collapsed sufficiently such that the proximal stent diameter is less than the diameter of the outer sheath 2006 , the stent is drawn into the outer sheath 2006 . the entire gastrointestinal implant device can then easily be removed from the patient by pulling retrieval device 2000 through the stomach and the esophagus . fig2 is a perspective view of another embodiment of a gastrointestinal implant device 2200 . the gastrointestinal implant device 2200 includes a sleeve 202 and an anchoring ring 2204 . the distal end of the anchoring ring 2204 is bonded to the proximal end of the sleeve 202 . a plurality of eyelets 2206 are distributed around the circumference of the proximal end of the ring for anchoring the device to the pyloric muscle using anchors shown in fig2 . the anchoring ring 2204 is made from a flexible material such as silicone allowing the ring 2204 to be collapsed for endoscopic insertion and removal . the anchoring ring 2204 does not hold the pylorus open . however , in an alternate embodiment , the anchoring ring 2204 can be bonded to a stent with sufficient length and diameter to hold the pylorus open as described in conjunction with fig2 . the anchoring ring 2204 anchors the device and the stent holds the pylorus open . fig2 is a perspective view of the anchoring ring 2204 shown in fig2 in the expanded position . the sleeve is bonded to the outer surface 2300 of the proximal end of the anchoring ring whose diameter is 0 . 8 ″ or about the same as the diameter of the sleeve . the anchoring ring 2204 includes at least four eyelets to anchor the device in place . the outer most diameter of the ring is about one inch . in an alternate embodiment there can be more than four eyelets . fig2 is a perspective view of the anchoring ring 2204 shown in fig2 in a collapsed position for insertion and removal . the circular ring 2204 shown in fig2 has been compressed to an oval shape allowing the anchoring ring to be inserted into the lumen of a catheter for delivery . fig2 is a perspective view of an anchor 2500 for anchoring the collapsible ring shown in fig2 to the muscular tissue of the pyloric orifice . the anchor 2500 includes an anchor pin 2504 coupled to a second pin 2506 by a flexible shaft 2502 . the anchor pin 2504 includes a shaped barb 2508 for locking the anchor 2500 into the tissue . the anchor 2500 is delivered after the collapsible ring has been positioned in the pyloric orifice . the anchor is guided so that the anchor pin 2504 is directed through a respective eyelet with the barbed portion of the anchor pin 2504 guided toward the tissue . after the barb 2508 has been locked into the tissue , the second pin 2506 sits inside the gastrointestinal implant device while the barbed portion 2508 of the anchor pin 2504 sits inside the pylorus muscle tissue . for removal of the gastrointestinal implant device from the body , the flexible shaft 2502 of the anchor 2500 is cut . fig2 a is a perspective view of a delivery system 2600 for delivering the anchor 2500 after the gastrointestinal implant device has been placed in the pyloric orifice . the anchor 2500 is loaded in the distal end of a catheter having a single lumen tube 2600 . the hollow , distal end of the delivery device is a sharp needle made to penetrate the pylorus muscle . in an alternate embodiment , the distal end of the delivery device can be formed in an arc to improve access to the eyelets 2206 through an endoscopic approach . the catheter 2600 includes a pusher 2604 for releasing the anchor 2500 . the pusher 2604 is moved in a longitudinal direction 2602 to release the anchor 2500 from the lumen . fig2 b is a plan view of the delivery system 2600 shown in fig2 a . fig2 c is a cross - sectional view of the distal end of the catheter 2600 as taken along line b - b of fig2 b . as described in conjunction with fig2 , the anchor 2500 includes pins 2504 , 2506 coupled by a flexible shaft 2502 . the anchor 2500 is loaded in the lumen at the distal end of the catheter 2600 . the anchor pin 2504 is placed in the distal end of the tube 2600 and the second pin 2506 in the proximal end . the barb 2508 on the anchor pin 2504 is pointed toward the proximal end of the tube 2506 to engage with the tissue upon release in the muscle tissue . the catheter is advanced to the center of the ring positioned in the pyloric orifice . the sharp end 2510 is then pushed through an eyelet and into the muscle tissue . the pusher 2506 is pushed in longitudinal direction 2602 to release the distal anchor 2506 . once the distal anchor is released , the delivery system is pulled back , dragging the proximal part of the anchor out of the delivery device with the flexible shaft going through the eyelet , and the proximal anchor portion resting on the inside of the device . in the embodiment of the ring shown in fig2 , four anchors 2506 are delivered to anchor the gastrointestinal implant device through the four eyelets . fig2 d is a perspective view illustrating the sharp end 2510 of the needle inserted through an eyelet 2206 for delivery of the anchor 2500 to the tissue 2512 . the distal end of the catheter is formed in an arc 2520 to improve access the eyelets 2206 . the sharp end 2510 of the catheter is inserted through the eyelet 2206 into the tissue 2516 . the anchor pin 2504 of the anchor has been pushed out from the lumen into the tissue 2512 . fig2 e is a perspective view illustrating the barb 2508 engaging the tissue 2512 after delivery . the catheter has been removed from the eyelet 2206 leaving the anchor pin 2504 engaging the tissue 2512 . fig2 a - e illustrate an alternative embodiment of a locking mechanism for holding the distal end of the sleeve 202 in position during delivery of the gastrointestinal implant device . a snare wire 2656 is passed through one of the lumens of a catheter 2650 to the distal end . at the distal end , the end of the snare wire 2650 is looped back and attached to or anchored inside the catheter 2650 . the folds of the sleeve 202 are advanced through this snare loop . the snare handle 2664 pulls and releases the snare wire 2656 to lock and release the distal end of the sleeve 202 . the delivery system includes a pull tap 2666 for releasing a drawstring holding the stent in a collapsed position . fig2 b is cross - sectional view taken along line c - c of fig2 a through the inner sheath 2650 . the inner sheath has two lumens 2654 , 2662 and has a diameter of about 0 . 078 inches . the first inner lumen 2564 is for passing a guidewire through the inner sheath and is about 0 . 04 inches in diameter . the second inner lumen 2662 is for passing the snare wire through the inner sheath and is about 0 . 02 inches in diameter . the end of the snare wire 2658 is anchored inside the inner sheath 2650 . fig2 c is a cross - sectional view taken along line dd of fig2 a through the outer sheath 2600 showing the inner sheath 2650 within the outer sheath 2600 . the outer sheath has an inner diameter of about 0 . 1 inches and an outer diameter of about 0 . 143 inches . the open space inside the outer sheath can be used for passing a drawstring through the outer sheath . fig2 d is a cross - sectional view through the distal portion of the catheter 2650 showing the snare capturing the distal end of the sleeve 202 . the distal end of the sleeve 202 is captured by the snare wire 2656 by pulling the distal end of the sleeve through a loop formed by the snare wire 2656 . fig2 e is a sectional view through the distal portion of the catheter showing the snare locking mechanism . the distal end of the sleeve is locked by pulling the snare wire 2656 in a longitudinal direction 2664 toward the proximal end of the delivery system to capture the sleeve folds against the inner shaft . after the gastrointestinal implant device is properly positioned in the body , the snare wire is advanced in a longitudinal direction 2662 toward the distal end of the delivery system . this opens the snare wire 2656 and releases the sleeve 202 . fig2 is a perspective view of the distal portion of the gastrointestinal implant device including texturing 2700 . texturing of the distal end of the sleeve can be added to ensure that the actions of peristalsis do not advance the sleeve proximally , towards the stomach , but keep the sleeve pulled taught in the intestine . at the distal end of the sleeve , texturing 2700 is added with a directional aspect to it . the texturing 2700 can be molded into the sleeve material or added by adhesive or thermal bonding methods . the texturing material contains includes fibril shapes that are directed proximally so that any peristaltic waves that travel proximally , will have less force on the sleeve than distal peristaltic waves . the gastrointestinal implant device offers a new alternative where other means of weight loss and efforts at behavior modification have failed . because the gastrointestinal implant device is endoscopically introduced , there is a reduced risk at insertion compared to surgery . the procedure is also completely reversible , making this approach an ideal solution for patients who are desperate to reverse behavioral patterns that have lead to weight gain . when inserted in the body , the gastrointestinal implant device mimics the duodenal bypass of the roux - en - y procedure . the implanted device reduces caloric absorption by delaying enzyme mixing with food and provides the feedback produced by the roux - en - y procedure by producing dumping syndrome when high sugar meals are ingested . rapid stomach emptying is encouraged by inserting a stent in the pylorus to hold the pylorus open and all food bypasses the duodenum and passes rapidly into the jejunum . the implant device is an improvement on the roux - en - y procedure because it is minimally invasive and reversible . in the treatment of the super - obese where aggressive weight loss is not achieved , the length of the implant device below the stent can be further increased to drive the patient close to the point of malabsorption . the gastrointestinal implant device can be used to reduce type 2 diabetes symptoms by bypassing the duodenum . following gastric bypass surgery , patients commonly experience complete reversal of type 2 diabetes . while the exact mechanism of this remarkable effect is not understood , the clinical result is reported in a high percentage of cases . reversal of type 2 diabetes after gastric bypass is described in “ potential of surgery for curing type 2 diabetes mellitus ” by rubino et al . incorporated herein by reference in its entirety . since the gastrointestinal implant device provides equivalent blockage of duodenal processes , a similar effect is elicited but without the trauma of surgery . in patients who are not obese but suffer type 2 diabetes , a modified gastrointestinal implant device is inserted . this gastrointestinal implant device provides the necessary effect to hinder pancreatic processes and receptors without blocking absorption . in the embodiment of the gastrointestinal implant device for treating diabetes , the length of the stent is selected to allow the pylorus to operate normally . the length of the sleeve is also reduced to mimic the duodenum bypass . the sleeve extends to just below the ligament of treitz but does not extend further into the jejunum , thus allowing absorption to occur in the jejunum . fig2 is a perspective view of a gastrointestinal implant device with another embodiment of a collapsible self - expanding anchoring device . the gastrointestinal implant device 2800 includes a sleeve 202 and an anchoring device , or sleeve anchor , for anchoring the gastrointestinal implant 2800 device within the gastrointestinal tract . in some embodiments , the implant device 2800 includes a wave anchor 2810 coupled to a proximal portion of the sleeve 202 . wave anchors are described in more detail in co - pending u . s . patent application ser . nos . 10 / 858 , 851 and 10 / 858 , 852 , both filed on jun . 1 , 2004 , both claiming priority to u . s . provisional application nos . 60 / 528 , 084 filed on dec . 9 , 2003 and 60 / 544 , 527 filed on dec . 13 , 2003 ; u . s . patent application ser . no . 11 / 229 , 352 , filed on sep . 16 , 2005 , which claims priority to u . s . provisional application no . 60 / 611 , 038 , filed on sep . 17 , 2004 ; and u . s . patent application ser . no . 11 / 147 , 992 , filed on jun . 8 , 2005 , all incorporated herein by reference in their entirety . the wave anchor 2810 includes a compliant , radial spring 2900 shaped into an annular oscillating pattern . for example , the pattern is a wave pattern , such as a sinusoidal pattern formed about a central axis . the anchor provides an outward radial force , while allowing substantial flexure about its perimeter . such flexure is advantageous as it allows for minimally - invasive delivery and ensures that the device will substantially conform to the surrounding anatomical structure when implanted . the annular wave element 2900 can be formed from one or more elongated resilient members radially - disposed about a longitudinal axis and joined together defining a lumen along its central axis formed between two open ends . when implanted , the central axis 2815 of the anchor is substantially aligned with the central axis of the lumen 2820 ( e . g ., duodenum 104 ), allowing chyme to pass through the interior of the device 2800 . additionally , the compliant wave anchor 2810 minimizes trauma to the tissue by providing sufficient flexibility and compliance , while minimizing the likelihood of tissue erosion and providing a solid anchoring point to the tissue . in some embodiments , the wave anchor is adapted for placement within a region of the proximal duodenum referred to as the duodenal bulb 500 ( fig5 b ). for these applications , the axial extent of the anchor is preferably less than the distance between the pyloric sphincter and the ampulla of vater . exemplary relaxed lengths can range from about 20 to 50 mm ( i . e ., from less than 1 to about 2 inches ). the diameter of the wave anchor 2900 can have an initial installed diameter within the range of about 20 - 40 millimeters ( i . e ., between about 1 and 1¾ inches ). the compliance of the anchor 2900 , allows it to flex radially over a wide range according to natural contractions and expansions of the duodenum 104 ( i . e ., between about 25 and 45 mm ). in some embodiments , the relaxed diameter of the wave anchor 2900 can be about 50 mm ( i . e ., about 2 inches ). in other embodiments , the relaxed diameter can exceed 50 mm , being up to 60 mm ( i . e ., 2 . 5 inches ) or even more . in either case , the wave anchor 2900 can be temporarily collapsed to about 12 mm ( i . e ., about 0 . 5 inches ) for endoscopic placement . in some embodiments , the implant device includes a retrieval / repositioning feature . for example , the implant device 2800 includes a drawstring 2825 . the drawstring 2825 can be selectively woven around the perimeter of the anchor 2900 through openings of opportunity in the anchor 2900 . alternatively or in addition , the drawstring 2825 can be selectively woven through dedicated openings , such as eyelets provided on the anchor 2900 or in the proximal sleeve 202 . in operation , the drawstring 2825 , when pulled , contracts about the perimeter of the anchor 2900 to reduce the diameter of the anchor 2900 . collapsing the anchor 2900 in this manner before removing or repositioning the anchor 2900 is advantageous in avoiding tissue damage , particularly when the implant device 2800 includes barbs . in some embodiments , the gastrointestinal implant device 2800 can be inserted endoscopically in combination with a delivery catheter , such as any of the delivery catheters described herein ( fig1 and 17 ) or any of the delivery catheters described in u . s . patent application ser . no . 10 / 999 , 846 , filed on nov . 30 , 2004 , which is a divisional of u . s . patent application ser . no . 10 / 339 , 786 , filed on jan . 9 , 2003 , which claims the benefit of u . s . provisional application no . 60 / 430 , 321 filed on dec . 2 , 2003 ; any of the delivery catheters described in u . s . patent application ser . no . 10 / 726 , 011 , filed on dec . 2 , 2003 , which claims the benefit of u . s . provisional application no . 60 / 512 , 145 , filed on oct . 17 , 2003 ; or any of the delivery catheters described in u . s . patent application ser . no . 11 / 057 , 861 , filed on feb . 14 , 2005 , which claims the benefit of u . s . provisional application nos . 60 / 586 , 521 , filed on jul . 9 , 2004 and 60 / 610 , 614 , filed on sep . 19 , 2004 , all incorporated herein by reference in their entirety . in some embodiments , the gastrointestinal implant device can be repositioned and / or removed endoscopically in combination with a repositioning / removal device , such as any of the repositioning / removal devices described herein ( fig1 ) or any of the repositioning / removal devices described in u . s . patent application ser . no . 11 / 001 , 812 , filed on nov . 30 , 2004 , which is a divisional of u . s . patent application ser . no . 10 / 339 , 786 , filed on jan . 9 , 2003 , which claims the benefit of u . s . provisional application no . 60 / 430 , 321 filed on dec . 2 , 2003 ; or any of the repositioning / removal devices described in u . s . provisional application no . 60 / 645 , 287 , filed on jan . 19 , 2005 , all incorporated herein by reference in their entirety . various embodiments of the gastrointestinal implant device have been described herein . these embodiments are given by way of example and are not intended to limit the scope of the present invention . it should be appreciated , moreover , that the various features of the embodiments that have been described may be combined in various ways to produce numerous additional embodiments . while this invention has been particularly shown and described with references to preferred embodiments thereof , it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims . the appended claims are of a scope that covers the embodiments disclosed in priority application u . s . patent application ser . no . 10 / 858 , 852 referenced herein , and thus have the benefit of priority of that filing date . the claims are also of a sufficient scope to cover more recent embodiments , including those described above and those disclosed in u . s . patent application ser . nos . 11 / 229 , 352 and 11 / 147 , 992 , also referenced herein .

method and apparatus for limiting absorption of food products in specific parts of the digestive system is presented . a gastrointestinal implant device is anchored in the stomach and extends beyond the ligament of treitz . all food exiting the stomach is funneled through the device . the gastrointestinal device includes an anchor for anchoring the device to the stomach and a flexible sleeve . when implanted within the intestine , the sleeve can limit the absorption of nutrients , delay the mixing of chyme with digestive enzymes , altering hormonal triggers , providing negative feedback , and combinations thereof . the anchor is collapsible for endoscopic delivery and removal .

fig1 depicts a glove in accordance with the present invention referred to by the general reference character 10 . the glove 10 includes a covering 12 that is fabricated from a supple material such as woven cloth , leather , a natural or synthetic sheet material , etc . the covering 12 is tailored so the glove 10 envelopes a human hand 14 , illustrated by dashed lines in fig1 including a back 16 of the hand 14 and a palm of the hand 14 , not illustrated in fig1 . the covering 12 of the glove 10 includes a plurality of separate sheaths 20 , 22 , 24 , 26 and 28 which respectively encircle a little finger 30 , a ring finger 32 , a middle finger 34 , an index finger 36 , and a thumb 38 of the hand 14 . an inner surface 42 of the covering 12 , illustrated in fig3 is juxtaposed with and contacts skin on the hand 14 . secured on the inner surface 42 of the covering 12 which contacts the back 16 of the hand 14 is a first set 52 of five elongated pressure pads 54 . as illustrated in fig2 each of the pressure pads 54 is formed as an elongated bar 56 having a surface 58 above which projects a plurality of peaks 62 . also projecting above the surface 58 of the bar 56 is a ridge 64 which encircles the peaks 62 . the pressure pad 54 is preferably 2 . 40 cm long by 0 . 50 cm wide , and is preferably made from aluminum . the peaks 62 project 0 . 15 cm above the surface 58 with the entire pressure pad 54 being 0 . 16 cm thick . the ridge 64 projects a lesser distance of 0 . 1 cm above the surface 58 of the bar 56 than the peaks 62 . the pressure pads 54 are secured on the inner surface 42 of the covering 12 to be urged into contact with an area on the back 16 of the hand 14 identified as a low back area 68 . as depicted in fig1 the low back area 68 extends from the middle of a wrist line 72 to a top 74 of a 1st knuckle 76 of the middle finger 34 . it has been found that applying a moderate amount of pressure to the low back area 68 on the back 16 of the hand 14 is effective for relieving all kinds of pain in the lumbar and sacrum of the lower back . while a single , wider pressure pad might be substituted for the plurality of pressure pads 54 , the several pressure pads 54 are to be preferred . by conforming more closely to any curvature of the back 16 of the hand 14 rather than concentrating all of the pressure over a small area , the several pressure pads 54 distribute pressure more uniformly over a larger area of the low back area 68 on the back 16 of the hand 14 . secured on the inner surface 42 of the covering 12 of the sheath 20 is a second pressure pad 78 . the second pressure pad 78 is formed identically to one of the pressure pads 54 except that the length of the second pressure pad 78 is 0 . 80 cm rather than the 2 . 40 cm length of the pressure pad 54 , and therefore the second pressure pad 78 includes only a single peak 62 . as illustrated in fig3 and 4 , enclosed within the covering 12 the second pressure pad 78 is secured to a layer 82 of fabric by contact cement , not illustrated in any of the figs . within the sheath 20 , the layer 82 of fabric extends from the second pressure pad 78 laterally toward both sides of the sheath 20 to a seam 84 where it is stitched together with an upper half 86 and a lower half 88 of the covering 12 . ends of the layer 82 extending along the sheath 20 parallel to the seam 84 beyond ends of the second pressure pad 78 are secured to the inner surface 42 of the covering 12 by contact cement , not illustrated in any of the figs . interposed between the inner surface 42 of the upper half 86 of the covering 12 and the layer 82 immediately adjacent to the second pressure pad 78 is a pyramidially - shaped block 92 of resilient material such as sponge rubber . the pyramidially - shaped block 92 of resilient material is 0 . 50 cm thick . a surface of the pyramidially - shaped block 92 contacting the layer 82 immediately adjacent to the second pressure pad 78 is the same size and shape as the second pressure pad 78 , i . e ., 0 . 50 cm wide by 0 . 80 cm long . a surface of the pyramidially - shaped block 92 which contacts the inner surface 42 of the covering 12 extends outward 0 . 50 cm along each side of the block 92 beyond edges of that surface of the block 92 contacting the layer 82 . the inner surface 42 of the covering 12 pressing against the block 92 of resilient material urges the peak 62 of the second pressure pad 78 into contact at an i38 meridian location 94 on skin 96 of the little finger 30 . as depicted in fig1 the i38 meridian location 94 is halfway between a center 102 of a third knuckle 104 and a bottom line 106 of a finger nail 108 of the little finger 30 . it has been found that applying a moderate amount of pressure to the i38 meridian location 94 on the little finger 30 of the hand 14 relieves mental irritation , insomnia , anxiety , headaches , and pain of the neck and shoulder . the same effect may be achieved by locating the second pressure pad 78 halfway between the center 102 of the third knuckle 104 and a center 110 of a second knuckle 111 of the little finger 30 . secured on the inner surface 42 of the covering 12 of the sheath 22 is a third pressure pad 112 which is formed identically to the second pressure pad 78 . the inner surface 42 of the covering 12 of the sheath 22 urges the third pressure pad 112 into contact with the skin 96 of the hand 14 at a h2 meridian location 114 on the ring finger 32 . the h2 meridian location 114 is halfway between a center 116 of a third knuckle 118 and a bottom line 122 of a finger nail 124 of the ring finger 32 . it has been found that applying a moderate amount of pressure to the h2 meridian location 114 on the ring finger 32 relieves stress , fatigue , anxiety , headache , and pain of the neck , shoulder and low back . the same effect may be achieved by locating the third pressure pad 112 halfway between the center 116 of the third knuckle 118 and a center 126 of a second knuckle 127 of the ring finger 32 . secured on the inner surface 42 of the covering 12 of the sheath 24 is a pair of fourth pressure pads 132 . each fourth pressure pad 132 is formed identically to one of the pressure pads 54 except that the length of the fourth pressure pad 132 is 1 . 50 cm rather than the 2 . 40 cm length of the pressure pad 54 . therefore , each fourth pressure pad 132 includes three peaks 62 . the inner surface 42 of the covering 12 of the sheath 24 urges both fourth pressure pads 132 into contact with the skin 96 of the hand 14 at a i9 - i12 meridian location 134 on the middle finger 34 . the i9 - i12 meridian location 134 is located between the top 74 of the 1st knuckle 76 and a center 142 of a second knuckle 144 of the middle finger 34 . the fourth pressure pads 132 are positioned halfway between the top 74 of the 1st knuckle 76 and the center 142 of the second knuckle 144 , and are respectively offset 0 . 1 inches on either side of a line joining the 1st knuckle 76 and the center 142 of the second knuckle 144 . it has been found that applying a moderate amount of pressure to the i9 - i12 meridian location 134 on the middle finger 34 alleviates ailments of the heart , lung , and pain of the upper back . the structure described above for securing the second pressure pad 78 to the layer 82 with contact cement and interposing a block 92 of resilient material between the inner surface 42 of the covering 12 and the layer 82 immediately adjacent to the second pressure pad 78 is also employed for securing all of the first set 52 of pressure pads 54 , third pressure pad 112 , and fourth pressure pads 132 to the inner surface 42 of the covering 12 . similar to the second pressure pad 78 , the layers 82 , to which the third pressure pad 112 and the fourth pressure pads 132 are respectively secured by contact cement , are themselves secured on the inner surface 42 of the covering 12 , respectively of the ring finger 32 and the middle finger 34 , both by stitching to the seam 84 and by contact cement . however , no contact cement is used in securing the layer 82 of fabric to which the first set 52 of pressure pads 54 are secured by contact cement . rather the layer of fabric to which the pressure pads 54 are secured is fastened to the inner surface 42 of the covering 12 by stitching which encircles the entire perimeter of the layer of resilient material interposed between the layer 82 and the inner surface 42 of the covering 12 , and which passes through both the covering 12 and the layer 82 . although the present invention has been described in terms of the presently preferred embodiment , it is to be understood that such disclosure is purely illustrative and is not to be interpreted as limiting . while the pressure pads 54 , 78 , 112 , and 132 are preferably made from a metallic material such as aluminum , they may also be made from a magnetic material , from stainless steel , or from a quartz stone found in korea and japan . since the application of pressure individually to the low back area 68 , i38 meridian location 94 , h2 meridian location 114 , or i9 - i12 meridian location 134 on the skin 96 of the hand 14 is effective for relieving the various symptoms described above , a therapeutic appliance in accordance with the present invention may be constructed which applies pressure at fewer than all of those locations . as is readily apparent , a therapeutic appliance which omits one or more of the pressure pads 54 , 78 , 112 , and 132 as suggested in the preceding sentence does not require the use of a full glove , and therefore such an appliance could omit one or more of the sheaths 20 , 22 , 24 , 26 and 28 of the glove 10 . however , it has been found that the simultaneous application of pressure to the low back area 68 , i38 meridian location 94 , h2 meridian location 114 , and i9 - i12 meridian location 134 on the skin 96 of the hand 14 is more effective for relieving symptoms than an application of pressure at a lesser number of locations . consequently , without departing from the spirit and scope of the invention , various alterations , modifications , and / or alternative applications of the invention will , no doubt , be suggested to those skilled in the art after having read the preceding disclosure . accordingly , it is intended that the following claims be interpreted as encompassing all alterations , modifications , or alternative applications as fall within the true spirit and scope of the invention .

this invention generally concerns therapeutic appliances for alleviating pain by applying a moderate amount of pressure to specific locations on an individual &# 39 ; s hand . the present invention includes a glove having a supple , fitted covering that envelopes at least a portion of a human hand . the glove &# 39 ; s covering has an inner surface that is juxtaposed with and contacts the skin of the hand , and to which one or more pressure pads are secured . the appliance &# 39 ; s covering urges each pressure pad into intimate contact with the skin of the hand at specific locations thereon for applying a moderate amount of pressure thereto .

fig1 is a representation of the nucleotide sequence and corresponding amino acid sequence of wild - type diphtheria toxin encoding dna ( seq id no : 1 ). fig2 is a schematic representation of the secondary structure within which glu - 148 resides . the drawing is based on the previously described x - ray crystallographic model of the dt dimer ( collier et al ., u . s . ser . no . 07 / 881 , 394 , herein incorporated by reference ; choe et al ., nature 357 : 216 - 222 , 1992 ). glu - 148 ( e148 ) is seen to lie on a β - strand , one residue removed from a loop connecting this strand with the adjacent , nh 2 - proximal β - strand . h - bonds between backbone n (- - -) and carbonyl o (--) atoms within these 2 strands are shown . a study was undertaken of possible second - site mutations in a glu - 148 deletion mutant construct ( termed dt delta - 148 ) which might cause reversion to toxicity . it was found that activity can be partially restored by either of two mutations : changing valine - 147 to glutamic acid ( a two - base change ), or deletion of five residues towards the amino - terminus ( a fifteen nucleotide deletion ), thereby positioning glu - 142 in the position adjacent to tyr - 149 . thus , simply deleting a crucial residue such as glu - 148 cannot insure that a second - site mutation would not restore partial activity to a recombinant toxoid . this spurred applicants to construct additional genetic aberrations in dt which would require more extensive mutations to restore toxicity , and thus would be less likely to occur naturally . first , a double amino acid deletion ( residues 147 , 148 ) was made at the active - site of dt . this mutation alone renders toxicity of the dt toxoid less than 10 - 4 that of wild - type dt with respect to levels of protein synthesis inhibition . moreover , the appropriate three base change would have to occur in order for residue 146 to mutate to a glutamic acid and restore any detectable activity . secondly , the isoleucine residue at position 364 was changed to a lysine . this residue is located in the translocation domain and plays an important role in dt &# 39 ; s translocation from the endocytic vesicle to the cytosol . independently , this mutation produces a toxoid that is 500 - fold deficient in protein synthesis inhibition compared to wild - type dt . the appropriate two base change would have to occur in order for lysine 364 to mutate to isoleucine and restore toxicity . deletions and substitutions can be generated by oligonucleotide - directed mutagenesis of the diphtheria toxin fragment a ( dta ) gene , as described below . the mutant genes can then be expressed in e . coli or any other standard expression system by standard methods , and extracts assayed for nad : ef - 2 adp - ribosyltransferase activity and for dt - specific protein by western blot analysis as described below . a plasmid encoding the f2 fragment of dt , pbrptacbamhiatgf2 , was constructed according to the method of greenfield et al . ( greenfield et al ., pnas . 80 : 6853 - 6857 , 1983 ). the f2 fragment of dt contains the naturally - occurring dt leader sequence , all of fragment a , and the n - terminal 189 amino acid residues of fragment b , so that the final construct includes amino acids 1 - 382 of seq id no : 1 . the plasmid f2 was digested with bamhi and clai . the resulting 949 base - pair fragment was ligated with bamhi - and acci - restricted m13mp19 , yielding m13mp19 - f2 . an ndei restriction site spanning the translational start codon of f2 , and a translational stop codon at arg - 192 of f2 were created by the site - directed mutagenesis procedure described by sayers et al . ( nucleic acids res . 16 : 791 , 1988 ), yielding m13mp19 - dta . the 968 base - pair ndei - hindiii fragment of m13mp19 - dta was ligated in ndei - and hindiii - restricted pt7 - 7 ( tabor , in current protocols in molecular biology , ausubel et al ., eds . ; greene , wiley - interscience , new york , 1991 , pages 16 . 2 . 1 - 16 . 2 . 11 ), and the resulting plasmid , pt7 - dta , was used as a cloning vector to prepare each of the site - directed mutagenesis constructs of dta listed in table 1 . all site - directed mutants were constructed with m13mp19 - dta template dna and the appropriate oligonucleotide . the 539 - base - pair apai - bali restricted fragment of m13mp19 - dta , which encompassed the appropriate active - site mutation , was ligated with apai - and bali - restricted pt7 - dta and used to transform competent e . coli bl21 ( de3 ) ( studier et al ., j . mol . biol . 189 : 113 , 1986 ). transformants were grown overnight in luria broth ( 100 μg / ml ampicillin ), diluted 1 / 50 in m9 minimal media ( 100 μg / ml ampicillin ), grown to od 1 . 0 , induced for 3 hours with 1 mm iptg , and harvested by centrifugation ( 3000 × g , 5 min ). cell pellets were resuspended in 1 / 30 volume 10 mm tris , 1 mm edta , ph 8 . 0 ( te )+ 5 mm cac1 2 , 5 mm mgc1 2 ; freeze - thaw cycled three times ; incubated for 15 min with 0 . 1 mg / ml lysozyme and 1 μg / ml dnasei ; clarified by centrifugation ( 10 , 000 × g , 10 min ) and desalted on g - 25 sephadex , as described earlier ( douglas et al ., j . bacteriol . 169 : 4967 , 1987 ). dta - protein was then measured by western blot analysis and adp - ribosyltransferase activity was assayed as described ( tweten et al ., j . biol . chem . 260 : 10392 , 1985 ). construction of full - length diphtheria toxin delta147 , 148 ; 364i & gt ; k and delta146 - 148 ; 364i & gt ; k . pt7 - dta delta147 , 148 and pt7 - dta delta146 - 148 were digested with apai , msci . the 539 bp apai - msci fragment spanning each active - site deletion was isolated from a 1 % agarose gel and ligated separately into apai , msci digested ptac dt ser148 ; 364i & gt ; k , yielding ptacdtdelta147 , 148 ; 364i & gt ; k and ptacdtdelta146 - 148 ; 364i & gt ; k . each plasmid was used to transform competent e . coli tg - 1 . transformants were grown overnight in luria broth + 100 μg / ml ampicillin ( l - amp ), diluted 1 / 50 in l - amp . grown to od 1 . 0 , induced for 3 h with iptg , and harvested by centrifugation ( 3000 × g , 5 min ). cell pellets were resuspended in 1 / 30 volume 10 mm tris , 1 mm edta , ph 8 . 0 ( te )+ 5 mm cac1 2 , 5 mm mgc1 2 ; freeze - thaw cycled three times ; incubated for 15 min with 0 . 1 mg / ml lysozyme and 1 μg / ml dnasei ; clarified by centrifugation ( 10 , 000 × g , 10 min ) and desalted on g - 50 sephadex , by the same method used to desalt with g - 25 sephadex , as cited above . after deletion of glu - 148 ( table 1 , mutation 1 ), the specific nad : ef - 2 adp - ribosyltransferase activity of the resulting mutant form of dta was undetectable ( less than 10 - 4 that of wild - type dta .) however , this deletion , when combined with the replacement of val - 147 by a glu residue , created a product with 6 % wild - type activity ( table 1 , mutation 7 ). in contrast , deletion of glu - 148 coupled with a tyr - 149 to glu mutation ( table 1 , mutation 12 ) yielded an inactive product . longer deletions extending from glu - 148 nh 2 - terminally as far as residue 144 ( table 1 , mutations 2 - 5 ) yielded products with no detectable adp - ribosylation activity . however , the next construct in this series ( table 1 , mutation 6 ), involving deletion of residues 143 - 148 inclusive , produced a protein with detectable ( 0 . 6 % of wild - type ) activity . in mutation 6 , unlike mutations 1 - 5 , the nh 2 - proximal residue flanking the deletion is a glutamic acid ( glu - 142 ). activity ranging between 0 . 6 % and 9 % that of wild - type dta was observed when each deletion ( mutations 1 - 5 ) was combined with substitution of the nh 2 - proximal flanking residue with glu ( table 1 , mutations 7 - 11 ). full - length diphtheria toxin constructs possessing specific active - site deletions plus the addition of a membrane translocation domain modification were also assessed for overall protein stability . western blot analysis of both full - length diphtheria toxin constructs ( delta147 , 148 ; 364i & gt ; k and delta146 - 148 ; 364i & gt ; k ) revealed a single full - length protein band with few degradation products suggesting that the structural integrity of the protein was preserved . these active - site mutation results are consistent with a model in which the local polypeptide on the nh 2 - proximal flank of glu - 148 is more flexible and less firmly anchored than the local peptide on the cooh - proximal flank . the x - ray crystallographic structure of the dt dimer ( collier et al ., u . s . ser . no . 07 / 881 , 394 ) provides support for this model . glu - 148 resides within an antiparallel β - sheet bounding the active - site cleft and is only one residue removed from a large , 10 - residue loop ( residues 137 - 146 ), which connects the glu - 148 β - strand to the adjacent , nh 2 - proximal β - strand ( fig2 ). the polypeptide backbone of the four residues immediately following glu - 148 ( residues 149 - 152 ) is involved in h - bonding typical of antiparallel β - sheet , and this bonding , together with other packing interactions , may firmly anchor this region of polypeptide within the protein . these results illustrate two discrete genetic changes , one involving a substitution and the other an additional deletion , each of which is capable of reverting an enzymatically inactive diphtheria toxin active - site deletion mutant to a partially toxic state . the levels of activity restored are in all cases less than 10 % of wild - type , but are clearly of concern if the protein is to be expressed in vivo by a live vaccine . the substitution of glu for val - 147 could occur by either of two possible two base - pair transversions of the val codon ( gtt ) to a glu codon ( gaa or gag ). in contrast , deletion of both the val - 147 codon and the glu - 148 codon leaves ser - 146 immediately adjacent to tyr - 149 ; since the ser agc codon cannot be converted into a glu codon without a change in all three nucleotides , the risk of reversion of this particular six - nucleotide deletion mutant to a mutant with some restored activity is substantially less ( a probability lower than 10 - 10 / cell / generation ) than the risk of reversion of the mutant lacking only the glu - 148 codon . moreover , the construction of a genetic diphtheria toxoid possessing both an active - site deletion and another , independent aberration ( membrane translocation dysfunction ) further reduces the risk of reversion to toxicity . either dt delta147 , 148 or delta146 - 148 coupled with 364i & gt ; k would require the appropriate five base change ( three at residue 146 or 145 and two at residue 364 ) to restore detectable toxicity . this recombinant toxoid , dt delta147 , 148 ; 364i & gt ; k was cloned , expressed in e . coli , and assessed for overall protein stability and adp - ribosyltransferase activity . western blot analysis revealed a single full - length protein with few degradation products suggesting that the stability and overall structural integrity of the protein was maintained . as anticipated , the recombinant toxoid was devoid of activity (& lt ; 10 - 4 that of wild - type toxin ). after confirming that the mutant protein so produced lacks detectable enzymatic activity , the mutants may then be analyzed for immunogenicity as follows : guinea pigs ( or another species which is naturally sensitive to the cell - killing effects of diphtheria toxin ) are immunized with the recombinant toxoid of the invention according to the following protocol : between 1 and 50 μg recombinant toxoid , suspended in 50 - 100 μl of freud &# 39 ; s complete adjuvant , is subcutaneously injected into a guinea pig on day 1 , day 12 , and day 24 . blood samples are then assayed for antitoxin antibodies by testing serial dilutions for reactivity to naturally occurring diphtheria toxin . those animals which received high enough doses of toxoid to induce antitoxoid formation can be challenged with wild type diphtheria toxin , in order to see whether the antibodies are protective . those toxoids of the invention which induce a positive response in the above assay are likely candidates for incorporation into live vaccines . appropriate live vaccine microorganisms ( cells or viruses ) genetically engineered to express a toxoid of the invention can be tested by injecting the candidate vaccine into a dt sensitive animal , and , after a 2 - 3 month incubation period , challenging the animal with either a ) a lethal dose of naturally occurring dt , or b ) multiple , serially administered doses of naturally occurring dt , so as to calibrate the range of acquired immunity . a dna sequence encoding the diphtheria toxoid of the invention can be expressed by standard methods in a prokaryotic host cell . dna encoding the diphtheria toxoid of the invention is carried on a vector operably linked to control signals capable of effecting expression in the prokaryotic host . if desired , the coding sequence can contain , at its 5 &# 39 ; end , a sequence encoding any of the known signal sequences capable of effecting secretion of the expressed protein into the periplasmic space of the host cell , thereby facilitating recovery of the protein . by way of example , a vector expressing the diphtheria toxoid of the invention , or a fusion protein including the polypeptide of the invention , can consist of ( i ) an origin of replication functional in e . coli derived from the plasmid pbr322 ; ( ii ) a selectable tetracycline resistance gene also derived from pbr322 ; ( iii ) a transcription termination region , e . g ., the termination of the e . coli trp operon ( placed at the end of the tetracycline resistance gene to prevent transcriptional read - through into the trp promoter region ); ( iv ) a transcription promoter , e . g ., the trp operon promoter , or the diphtheria toxin promoter ; ( v ) the protein coding sequence of the invention ; and ( vi ) a transcription terminator , e . g ., the t1t2 sequence from the ribosomal rna ( rrnb ) locus of e . coli . the sequences of carrier molecules , the methods used in the synthesis of the dna sequences , the construction of fusion genes , and the appropriate vectors and expression systems are all well known to those skilled in the art . similar expression systems can be designed for fusion or non - fusion polypeptides , i . e ., for expression of the polypeptide of the invention alone . these procedures are an example of , but are not limiting on , the methods of the invention . prokaryotes most frequently used are represented by various strains of e . coli ; however , other microbial strains can also be used , e . g ., c . diphtheriae . plasmid vectors are used which contain replication origins , selectable markers , and control sequences derived from a species compatible with the microbial host . for example , e . coli can be transformed using derivatives of pbr322 , a plasmid constructed by bolivar , et al . ( gene 2 : 95 , 1977 ) using fragments derived from three naturally - occurring plasmids , two isolated from species of salmonella , and one isolated from e . coli . pbr322 contains genes for ampicillin and tetracycline resistance , and thus provides multiple selectable markers which can be either retained or destroyed in constructing the desired expression vector . commonly used prokaryotic expression control sequences ( also referred to as &# 34 ; regulatory elements &# 34 ;) are defined herein to include promoters for transcription initiation , optionally with an operator , along with ribosome binding site sequences . promoters commonly used to direct protein expression include the beta - lactamase ( penicillinase ), the lactose ( lac ) ( chang et al ., nature 198 : 1056 , 1977 ) and the tryptophan ( trp ) promoter systems ( goeddel et al ., nucl . acids res . 8 : 4057 , 1980 ) as well as the lambda - derived p l promoter and n - gene ribosome binding site ( shimatake et al ., nature 292 : 128 , 1981 ). examples of microbial strains , vectors , and associated regulatory sequences are listed herein to illustrate , but not to limit , the invention . the mutant diphtheria toxoid of the invention can be expressed in any known protein expression system and then purified by standard means . for instance , diphtheria toxoids of the invention can be synthesized by organic chemical synthesis or produced as a biosynthesized polypeptide . organic chemical synthesis can be performed by conventional methods of automated peptide synthesis , or by classical organic chemical techniques . one schooled in the art can purify the diphtheria toxoid polypeptide of the invention using conventional methods of protein isolation , e . g ., methods including but not limited to precipitation , chromatography , immunoadsorption , or affinity techniques . the polypeptide can be purified from the cells , or medium of the cells , of a microbial strain genetically engineered to express the diphtheria toxoid of the invention . the purified polypeptide may be combined with a suitable carrier ( such as physiological saline ); with an adjuvant that increases the immunogenicity of the toxoid ( such as aluminum salts , bacterial endotoxins or attenuated bacterial strains ( e . g ., bcg or bordetella pertussis ), attenuated viruses , liposomes , microspheres , or freund &# 39 ; s complete or incomplete adjuvant )); and / or with additional toxoids or killed or attenuated vaccine organisms ( to form a multivalent vaccine ). such a vaccine may then be administered to a human subject by any acceptable method , including but not limited to oral , parenteral , transdermal and transmucosal delivery . administration can be in a sustained release formulation using a biodegradable biocompatible polymer , such as a microsphere , by on - site delivery using micelies , gels or liposomes , or by transgenic modes ( e . g ., by biolistic administration of the dna of the invention directly into the patient &# 39 ; s cells , as described by tang et al ., nature 356 : 152 - 154 , 1992 , herein incorporated by reference ). appropriate live carrier organisms include attenuated microorganisms such as bcg , salmonella sp ., vibrio cholerae , streptococci , listeriae , and yersiniae . the dna of the invention can be stably transfected into such a microbial strain by standard methods ( sambrook et al ., molecular cloning : a laboratory manual . cold spring harbor lab . press , new york , 1989 . ), and then would be introduced into a patient by , for example , oral or parenteral administration . once introduced into the patient , the bacterium would multiply and express the mutant form of diphtheria toxin within the patient , causing the patient to maintain a protective level of antibodies to the mutant toxin . in a similar manner , an attenuated animal virus such as adenovirus , herpes virus , vaccinia virus , polio , fowl pox , or even attenuated eukaryotic parasites such as leishmania may be employed as the carrier organism . the mutant dna of the invention can be incorporated by genetic engineering techniques into the genome of any appropriate virus , which is then introduced into a human vaccinee by standard methods . a live vaccine of the invention can be administered at , for example , about 10 4 - 10 8 organisms / dose , or a dose that is sufficient to stably induce protective levels of antitoxin . actual dosages of such a vaccine can be readily determined by one of ordinary skill in the field of vaccine technology . standard methods of assaying the toxicity of diphtheria toxin mutants employ a diphtheria toxin - sensitive tissue culture cell line , which is a line of cells bearing the diphtheria toxin receptor , e . g ., viro or bsc1 cells . the cells are treated with a known amount of the candidate mutant diphtheria toxin , with naturally occurring diphtheria toxin ( as a positive control ), or with bovine serum albumin ( as a negative control ). after incubation , a survival assay is performed by counting viable colonies ( yamaizumi , m . et al . cell 15 : 245 - 250 , 1978 ). alternatively , the extent of cell - killing can be determined by measuring the extent of inhibition of protein synthesis . after incubation with one of the diphtheria toxin samples described above , a radiolabelled amino acid ( e . g ., [ 14 c ] leu ) is added to the growth medium of the cell culture , and the decline in de novo protein synthesis is measured by scintillation counting of tca - precipitable protein . such methods are routine , and known to one skilled in the art . other embodiments are within the claims set forth below . for example , a mutant form of diphtheria toxin fragment a can be generated which lacks glu - 142 as well as val - 147 and glu - 148 , or which lacks all of the residues from glu - 142 to glu - 148 , inclusive . such deletion mutants can be generated by site directed mutagenesis ( sayers , et al ., supra ), and analyzed for enzymatic activity and immunogenicity as described above . other amino acid residues that have been shown to be essential for the biological activity of diphtheria toxin include residues his - 21 , glu - 22 , lys - 39 , gly - 52 , gly - 79 , gly - 128 , ala - 158 , and gly - 162 of the fragment a portion of diphtheria toxin , and residues glu - 349 , asp - 352 , and ile - 364 of the fragment b portion . mutants lacking any one or more of these residues , in addition to lacking both val - 147 and glu - 148 , may be generated by standard methods of site - directed mutagenesis known to one schooled in the art . table 1__________________________________________________________________________adp - ribosyltransferase activities of diphtheria toxina - fragment with active - site mutations residue #: 141 142 143 144 145 146 147 148 149 amino acid : mutation ala glu gly ser ser ser val glu tyr activity__________________________________________________________________________none 100 % 1 --* nd ** 2 -- -- nd 3 -- -- -- nd 4 -- -- -- -- nd 5 -- -- -- -- -- nd 6 -- -- -- -- -- -- 0 . 6 % 7 glu -- 6 % 8 glu -- -- 9 % 9 glu -- -- -- 6 % 10 glu -- -- -- -- 0 . 6 % 11 glu -- -- -- -- -- 4 % 12 -- glu nd__________________________________________________________________________ *-- indicates deleted residue ** nd indicates less than 10 . sup .- 4 wildtype activity __________________________________________________________________________sequence listing ( 1 ) general information :( iii ) number of sequences : 1 ( 2 ) information for seq id no : 1 :( i ) sequence characteristics :( a ) length : 1942 ( b ) type : nucleic acid ( c ) strandedness : double ( d ) topology : linear ( xi ) sequence description : seq id no : 1 : ccggcgttgcgtatccagtggctacactcaggttgtaatgattgggatgatgtacctgat60ctgagagcgattaaaaactcattgaggagtaggtcccgattggtttttgctagtgaagct120tagctagctttccccatgtaaccaatctatcaaaaaagggcattgatttcagagcaccct180tataattaggatagctttacctaattattttatgagtcctggtaaggggatacgttgtga240gcagaaaactgtttgcgtcaatcttaataggggcgctactggggataggggccccacctt300cagcccatgca311ggcgctgatgatgttgttgattcttctaaatcttttgtgatggaaaac359glyalaaspaspvalvalaspserserlysserphevalmetgluasn151015ttttcttcgtaccacgggactaaacctggttatgtagattccattcaa407phesersertyrhisglythrlysproglytyrvalaspserilegln202530aaaggtatacaaaagccaaaatctggtacacaaggaaattatgacgat455lysglyileglnlysprolysserglythrglnglyasntyraspasp354045gattggaaagggttttatagtaccgacaataaatacgacgctgcggga503asptrplysglyphetyrserthraspasnlystyraspalaalagly505560tactctgtagataatgaaaacccgctctctggaaaagctggaggcgtg551tyrservalaspasngluasnproleuserglylysalaglyglyval65707580gtcaaagtgacgtatccaggactgacgaaggttctcgcactaaaagtg599vallysvalthrtyrproglyleuthrlysvalleualaleulysval859095gataatgccgaaactattaagaaagagttaggtttaagtctcactgaa647aspasnalagluthrilelyslysgluleuglyleuserleuthrglu100105110ccgttgatggagcaagtcggaacggaagagtttatcaaaaggttcggt695proleumetgluglnvalglythrgluglupheilelysargphegly115120125gatggtgcttcgcgtgtagtgctcagccttcccttcgctgaggggagt743aspglyalaserargvalvalleuserleuprophealagluglyser130135140tctagcgttgaatatattaataactgggaacaggcgaaagcgttaagc791serservalglutyrileasnasntrpgluglnalalysalaleuser145150155160gtagaacttgagattaattttgaaacccgtggaaaacgtggccaagat839valgluleugluileasnphegluthrargglylysargglyglnasp165170175gcgatgtatgagtatatggctcaagcctgtgcaggaaatcgtgtcagg887alamettyrglutyrmetalaglnalacysalaglyasnargvalarg180185190cgatcagtaggtagctcattgtcatgcataaatcttgattgggatgtc935argservalglyserserleusercysileasnleuasptrpaspval195200205ataagggataaaactaagacaaagatagagtctttgaaagagcatggc983ileargasplysthrlysthrlysilegluserleulysgluhisgly210215220cctatcaaaaataaaatgagcgaaagtcccaataaaacagtatctgag1031proilelysasnlysmetsergluserproasnlysthrvalserglu225230235240gaaaaagctaaacaatacctagaagaatttcatcaaacggcattagag1079glulysalalysglntyrleuglugluphehisglnthralaleuglu245250255catcctgaattgtcagaacttaaaaccgttactgggaccaatcctgta1127hisprogluleusergluleulysthrvalthrglythrasnproval260265270ttcgctggggctaactatgcggcgtgggcagtaaacgttgcgcaagtt1175phealaglyalaasntyralaalatrpalavalasnvalalaglnval275280285atcgatagcgaaacagctgataatttggaaaagacaactgctgctctt1223ileaspsergluthralaaspasnleuglulysthrthralaalaleu290295300tcgatacttcctggtatcggtagcgtaatgggcattgcagacggtgcc1271serileleuproglyileglyservalmetglyilealaaspglyala305310315320gttcaccacaatacagaagagatagtggcacaatcaatagctttatcg1319valhishisasnthrglugluilevalalaglnserilealaleuser325330335tctttaatggttgctcaagctattccattggtaggagagctagttgat1367serleumetvalalaglnalaileproleuvalglygluleuvalasp340345350attggtttcgctgcatataattttgtagagagtattatcaatttattt1415ileglyphealaalatyrasnphevalgluserileileasnleuphe355360365caagtagttcataattcgtataatcgtcccgcgtattctccggggcat1463glnvalvalhisasnsertyrasnargproalatyrserproglyhis370375380aaaacgcaaccatttcttcatgacgggtatgctgtcagttggaacact1511lysthrglnpropheleuhisaspglytyralavalsertrpasnthr385390395400gttgaagattcgataatccgaactggttttcaaggggagagtgggcac1559valgluaspserileileargthrglypheglnglygluserglyhis405410415gacataaaaattactgctgaaaataccccgcttccaatcgcgggtgtc1607aspilelysilethralagluasnthrproleuproilealaglyval420425430ctactaccgactattcctggaaagctggacgttaataagtccaagact1655leuleuprothrileproglylysleuaspvalasnlysserlysthr435440445catatttccgtaaatggtcggaaaataaggatgcgttgcagagctata1703hisileservalasnglyarglysileargmetargcysargalaile450455460gacggtgatgtaactttttgtcgccctaaatctcctgtttatgttggt1751aspglyaspvalthrphecysargprolysserprovaltyrvalgly465470475480aatggtgtgcatgcgaatcttcacgtggcatttcacagaagcagctcg1799asnglyvalhisalaasnleuhisvalalaphehisargserserser485490495gagaaaattcattctaatgaaatttcgtcggattccataggcgttctt1847glulysilehisserasngluileserseraspserileglyvalleu500505510gggtaccagaaaacagtagatcacaccaaggttaattctaagctatcg1895glytyrglnlysthrvalasphisthrlysvalasnserlysleuser515520525ctattttttgaaatcaaaagctgaaaggtagtggggtcgtgtgccgg1942leuphephegluilelysser530535__________________________________________________________________________

a dna encoding an immunologically cross - reactive form of diphtheria toxin fragment a , wherein the codons corresponding to val - 147 and glu - 148 of naturally - occurring diphtheria toxin are deleted from the dna .

referring now to fig1 the exercising machine employing the biasing means of this invention is generally indicated by the reference numeral 40 . a base portion generally indicated by reference numeral 41 comprising base means 3 , lateral support means 4 and support foot means 2 is assembled using bolts 27 , washers 30 and nuts 34 . upright support means 1 is similarly attached to support foot means 2 while bench means 6 is fitted to support foot means 2 and brace means 5 with removable pins means 18 and 20 . an upper body exercise apparatus , generally indicated by reference numeral 42 , comprises upper head means 7 with biasing support means 8 and arm lever means 9 mounted thereto with mounting pins 21 and 22 respectively and handbar lever means 10 with handlebar means 11 attached thereto with bolts 27 , washers 31 and nuts 33 fitted to upper head means 7 using handlebar lever pivot means 19 inserted through hole means 25 in pivot tube means 26 or opposite pivot tube means 24 welded to upper head means 7 . upper body exercising apparatus 42 is slidably mounted upon upright support means 1 by inserting removable bolt means ( not shown ) through hole means 36 in upper head means 7 and through hole means 35 in upright support means 1 . handlebar grips 29 are fitted over the ends of handlebar means 11 and handles 32 on arm lever means 9 . foam grips 16 cover the ends of arm lever means 9 and foam pads 17 are fitted over fulcrum means 14 on leg lifting lever means 13 and lower head means 12 . lower head means 12 is slidably disposed in slot means 46 between bench rails 47 and secured thereto with bench brace mounting pin 20 through holes ( not shown ) in bench rails 47 and hole means 55 in lower head means 12 . bracket means 44 is disposed on the under side of lower head means 12 . bracket means 48 including fulcrum mounting means 49 is disposed on the end of lower head means 12 opposite the end thereof which is slidably disposed within slot means 46 . leg lifting lever means 13 is rotatably mounted upon lower head means 12 with bolt 28 inserted through hole means 50 in bracket means 48 and hole means 52 in leg lifting frame pivot tube 51 and secured thereto with nut 34 . foam pads 17 are disposed on fulcrum means 14 inserted through fulcrum mounting means 49 and fulcrum means 14 on both ends of leg lifting lever means 13 . biasing means 15 are mounted upon support pins 38 and lever pins 39 on either side of upper head means 7 wherein said biasing means 15 provide resistance to the movement of arm lever means 9 in a horizontal plane of motion indicated by reference arrow 37 . biasing means 15 may alternatively be fitted over handlebar lever means pins 43 and removable pin means 18 which has been inserted into pivot tube means 26 in upper head means 7 providing resistance to motion of handlebar lever means 10 in a vertical plane as indicated by the double ended reference arrow 53 . removable pin means 18 may also be placed in opposite pivot tube means 24 above handlebar lever pin means 43 with handlebar lever means 10 pivotably mounted in pivot tube 26 providing resistance to motion of handlebar lever means 10 in a downward vertical direction as well . similarly , biasing means 15 may alternatively be placed within bracket means 44 on lower head means 12 and bracket means 45 on leg lifting lever means 13 securing same with biasing means mounting pins 23 providing resistance to motion of leg lifting lever in a vertical plane as indicated by reference arrow 54 . referring now to fig2 through 5 , biasing means 15 comprises elastomeric band means 60 of fig3 end member 70 of fig4 and containing means 80 of fig5 . elastomeric band means 15 is taken transverse the longitudinal axis of each leg 68 and may be of any desired - cross - sectional - configuration as shown in fig1 - 15 , whereas in fig3 inside surface 61 opposes outside surface 62 and first side edge 63 opposes second side edge ( not shown ), defining thereby a generally rectangular - cross - section - elastomeric band means 60 . end member 70 comprises hub means 71 , an outer portion consisting of flange means 72 and 73 , pulley surface 74 , mounting hole means 75 , and web means 76 . containing means 80 comprises a tube of elastomeric material with inside surface 81 , outside surface 82 , first end 83 and second end 84 . containing means 80 may also be provided with labeling means 85 disposed on outside surface 82 in any manner known in the art . referring now to fig8 and fig9 biasing means 15 is assembled by placing one end member 70 within bight 65 of elastomeric means 60 wherein the portion of inside surface 61 disposed within bight 65 of elastomeric band means 60 abuts a portion of pulley surface 74 , and wherein first side edge 63 and second side edge ( not shown ) are contained between and contiguous with flange means 72 and 73 of end member 70 . the opposite bight 65 is then placed over an assembly pin 90 which has containing means 80 placed thereon , elastomeric band means 60 is elongated by pulling upon end member 70 while containing means 80 is slidably moved from the position on assembly pin 90 toward end member 70 such that first end 83 of containing means 80 is adjacent end member 70 . inside surface 81 of containing means 80 is therefore contiguous with outside surface 62 and side edges 63 thereby containing elastomeric band means 60 in an oval configuration as shown in fig1 when removed from assembly pin 90 . finally , a second end member 70 is placed within the open bight 65 of partially assembled biasing means 15 to produce the fully assembled biasing means 15 of fig2 . assembly pin 90 may be utilized as shown in fig1 to move containing means 80 toward the first end member 70 such that the second end member 70 may be more readily placed in bight 65 and to move containing means 80 to the final central position of biasing means 15 . alternately , each bight 65 of elastomeric band means 60 may be placed upon mounting pins 90 and elongated to facilitate placement of containing means 80 in the central portion between bights 65 and then end member 70 may be separately placed within each bight 65 to provide the fully assembled biasing means 15 . separate biasing means 15 of the instant invention may be constructed in a similar manner wherein the - cross - sectional - elastomeric band means 60 may be varied to provide a different amount of resistance to motion . for instance , the thickness of elastomeric band means 60 of fig3 between outside surface 62 and inside surface 61 may be approximately 0 . 184 inch to provide a biasing means 15 which produces a resistance to movement of approximately 30 pounds when extended to 150 % of the original distance from centerline 66 to centerline 67 which represents essentially the mid range of extension of any of the lever means of exercising means 40 . similarly , elastomeric band means 60 of fig3 with a thickness between outside surface 62 and inside surface 61 of 0 . 368 inch will provide resistance of approximately 60 pounds when biasing means 15 is extended to 150 % of the original distance between centerline 66 and 67 . therefore , biasing means 15 of fig2 may be constructed of differing resisting strengths by changing the thickness of elastomeric band means 60 to provide a complete set of biasing means 15 for exercise apparatus 40 of fig1 . similarly , biasing means 15 of differing resisting strengths may be provided by altering the - cross - sectional - shape where said elastomeric band means 60 is other than rectangular in cross - section . for instance , see fig1 - 15 wherein various - cross - sectional - configurations of elastomeric band means 60 are shown . end member 70 may then also be altered to conform to the peripheral surface contour of elastomeric band means 60 such that elastomeric band means 60 is contained within first and second flange means 72 and 73 respectively while inside surface 61 of elastomeric band means 60 is supported by pulley surface 74 of end member 70 . the resisting strengths of the various elastomeric band means 60 of the instant invention are determined from the modulus of elasticity of the material selected . a modulus of elasticity curve of the material to be used for the elastomeric band means is determined by subjecting a tensile slab of the material to extension while measuring the force required to extend the material as is well known in the art . for instance , the force required to extend the material of elastomeric band means 60 to a length which is 33 . 3 % greater than the original length was 1 . 089 pounds for a slab of material 0 . 250 inches wide by 0 . 040 inches thick . this yields a force per unit area of 108 . 9 pounds per square inch ( psi ). therefore , in order to develop thirty pounds of force in biasing means 15 at an extension of 50 % between the centerlines 66 and 67 which represents a 33 . 33 percent length extension of the entire length of elastomeric band means 60 , the total - cross - sectional - area of each leg 68 would be 0 . 1377 square inches . similarly , to develop ninety pounds of force in biasing means 15 , the total - cross - sectional - area would be 0 . 413 square inches . where elastomeric band means 60 is rectangular in - cross - section - and the width between flange means 72 and 73 of end member 70 is 0 . 750 inches , the thickness of elastomeric band means 60 would be the aforementioned 0 . 184 inches to develop thirty pounds whereas the thickness for elastomeric band means 60 would be 0 . 551 inches to develop ninety pounds . the biasing means 60 of the present invention overcomes the limitations of biasing means 92 of the prior art as shown in fig6 which can readily rupture by a quickly propagating crack developing from any of the discontinuities present in the molding operation of the flat slab . for instance , the biasing means 92 of fig6 is prone to such rupture at the recess shown by arrow 91 because the highest stress is concentrated at this location when the biasing means 92 of fig6 is extended . this high stress is created because then end section 93 of biasing means 92 does not extend and hence all the elongation of biasing means 92 must take place between the points 94 and 95 . in the instant invention , inside surface 61 of elastomeric band means 60 contained within the bights 65 of biasing means 15 contacts surface 74 of each end member 70 and therefore biasing means 15 is free to move thereon , hence the entire length of elastomeric band means 60 extends substantially equally since the - cross - sectional - area of each segment of elastomeric band means 60 is uniform throughout the entire length thereof . this unique combination of elastomeric band means 60 , end member 70 and containment means 80 provide biasing means 15 free of stress concentrations present in the prior art biasing means . the unique combination of elastomeric band means 60 , end member 70 and containment means 80 further provide the user with an early warning of any impending failure as elastomeric band means 60 moves about end member 70 during each extension thereof . since the - cross - sectional - area is constant throughout elastomeric band means 60 , no undue stress concentrations are present but any small crack which may occur on the outer surface thereof , where the highest stress during extension occurs , due to age of the elastomeric means 60 will be visible upon simple inspection prior to use . the user can then replace biasing means 15 or the elastomeric band means 60 at a convenient time without fear of sudden rupture of biasing means 15 during exercise . the biasing means 15 of the present invention further provides a margin of safety to the user as the full resisting force of the biasing means is developed near the mid point of extension of the biasing means 15 rather than at the lesser extension of the prior art biasing means . for instance , the biasing means 15 with a thickness of 0 . 184 inch develops approximately 13 . 5 kg at an extension of 150 % of the original distance between centerlines 66 and 67 while biasing means 110 of fig7 labeled 15 kg develops approximately 63 . 5 kg at the same extension . at full extension of the lever means of machine 40 , the biasing means of fig7 develops approximately 100 kg whereas the biasing means 15 develops only 30 kg . since the user will usually extend the biasing means to 80 to 100 % of the full extension of the lever means , the biasing means of the prior art could cause over exertion and possible injury to the user . the biasing means 15 of the instant invention is therefore a much safer biasing means for the casual user of the machine 40 . the biasing means 15 of the instant invention may be provided with reference characters disposed upon the outside surface 82 of containing means 80 indicating the relative strength of the biasing means 15 without units of measurement thereon as in the prior art biasing means of fig6 . the reference characters may be numeric , alphabetic , symbolic or a combination thereof . the user of the exercising device 40 can then select biasing means 15 as desired for the exercise to be performed based upon previous experience eliminating the transfer of heavy weights from a weight track . the containing means 80 may be constructed of a material selected from the group comprising metals , thermoplastic or thermoset elastomers , wovens or non - woven textile fabrics . the containing means 80 may be extruded , molded , woven , cast or formed by any means known in the art . the outer surface 82 of containing means 80 may be provided with labeling means 85 disposed thereon in a manner well known in the art . for instance , the containing means 80 may be provided with labeling means 85 labeling means 85 disposed on the outer surface 82 by pad printing . the labeling means 85 may further include safety information as desired by the customer or supplier or as required by governmental agencies . while the forms and methods of this invention now preferred have been illustrated and described as required by the patent statute , it is to be understood that other forms and method steps can be utilized and still fall within the scope of the appended claims wherein each claim sets forth what is believed to be known in each claim prior to this invention in the portion of each claim that is disposed before the terms &# 34 ; the improvement &# 34 ; and sets forth what is believed to be new in each claim according to this invention in the portion of each claim that is disposed after the terms &# 34 ; the improvement &# 34 ; whereby it is believed that each claim sets forth a novel , useful and unobvious invention within the purview of the patent statute .

a biasing element for an exercising machine is provided where one end of the biasing element is removably disposed on a lever arm of the exercising machine and the opposite end of the biasing element is disposed on a fixed support member of the exercising machine . the biasing element provides resistance to the movement of the lever arm in the plane of motion wherein the biasing element comprises at least one elastomeric band and a containing member to provide a bight on the ends of the biasing element for disposing on the respective portions of the machine . the biasing element may also have end members or support members placed within the bights . the biasing element , the containing member and the end members or support members may be initially separate and separable such that in the event of damage to any one of said members it may readily be replaced with another such elastomeric band element .

we have discovered that the combination of a tetra - substituted pyrimidopyrimidine with a corticosteroid substantially has substantial tnfα suppressing activity against stimulated white blood cells . the combinations of dipyridamole with fludrocortisone , and dipyridamole with prednisolone were particularly effective . thus , the combination of a tetra - substituted pyrimidopyrimidine with a corticosteroid is useful for the treatment of immunoinflammatory disorders . dipyridamole ( 2 , 6 - bis ( diethanolamino )- 4 , 8 - dipiperidinopyrimido ( 5 , 4 - d ) pyrimidine ) is a tetra - substituted pyrimidopyrimidine that is used as a platelet inhibitor , e . g ., to prevent blood clot formation following heart valve surgery and to reduced the moribundity associated with clotting disorders , including myocardial and cerebral infarction . typically , anticoagulation therapy ( prophylaxis or treatment ) is effected by administering dipyridamole at about 75 - 200 mg b . i . d , t . i . d ., or q . i . d . either alone or in combination with aspirin . in the invention , lower doses generally can be used , e . g ., 20 - 80 mg , administered by any of the prior art routes . tetra - substituted pyrimidopyrimidines are structural analogs that can replace dipyridamole in the methods and compositions of this invention . tetra - substituted pyrimidopyrimidines generally are of formula ( i ), above . combination therapy according to the invention may be performed alone or in conjunction with another therapy and may be provided at home , the doctor &# 39 ; s office , a clinic , a hospital &# 39 ; s outpatient department , or a hospital . treatment generally begins at a hospital so that the doctor can observe the therapy &# 39 ; s effects closely and make any adjustments that are needed . the duration of the combination therapy depends on the type of immunoinflammatory disorder being treated , the age and condition of the patient , the stage and type of the patient &# 39 ; s disease , and how the patient responds to the treatment . additionally , a person having a greater risk of developing an immunoinflammatory disorder ( e . g ., a person who is genetically predisposed or previously had an immunoinflammatory disorder ) may receive prophylactic treatment to inhibit or delay an inflammatory response . the dosage , frequency and mode of administration of each component of the combination can be controlled independently . for example , one compound may be administered orally three times per day , while the second compound may be administered intramuscularly once per day . combination therapy may be given in on - and - off cycles that include rest periods so that the patient &# 39 ; s body has a chance to recovery from any as yet unforeseen side - effects . the compounds may also be formulated together such that one administration delivers both compounds . the administration of each compound of the combination may be by any suitable means that results in a concentration of the compound that , combined with the other component , is antiinflammatory upon reaching the target region . the compound may be contained in any appropriate amount in any suitable carrier substance , and is generally present in an amount of 1 - 95 % by weight of the total weight of the composition . the composition may be provided in a dosage form that is suitable for the oral , parenteral ( e . g ., intravenously , intramuscularly ), rectal , cutaneous , nasal , vaginal , inhalant , skin ( patch ), or ocular administration route . thus , the composition may be in the form of , e . g ., tablets , capsules , pills , powders , granulates , suspensions , emulsions , solutions , gels including hydrogels , pastes , ointments , creams , plasters , drenches , osmotic delivery devices , suppositories , enemas , injectables , implants , sprays , or aerosols . the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice ( see , e . g ., remington : the science and practice of pharmacy ( 20th ed . ), ed . a . r . gennaro , lippincott williams & amp ; wilkins , 2000 and encyclopedia of pharmaceutical technology , eds . j . swarbrick and j . c . boylan , 1988 - 1999 , marcel dekker , new york ). pharmaceutical compositions according to the invention may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration . the latter types of compositions are generally known as controlled release formulations , which include ( i ) formulations that create a substantially constant concentration of the drug within the body over an extended period of time ; ( ii ) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time ; ( iii ) formulations that sustain drug action during a predetermined time period by maintaining a relatively , constant , effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance ( sawtooth kinetic pattern ); ( iv ) formulations that localize drug action by , e . g ., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ ; and ( v ) formulations that target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type . administration of compounds in the form of a controlled release formulation is especially preferred in cases in which the compound , either alone or in combination , has ( i ) a narrow therapeutic index ( i . e ., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small ; in general , the therapeutic index , ti , is defined as the ratio of median lethal dose ( ld50 ) to median effective dose ( ed50 )); ( ii ) a narrow absorption window in the gastro - intestinal tract ; or ( iii ) a very short biological half - life so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level . any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question . in one example , controlled release is obtained by appropriate selection of various formulation parameters and ingredients , including , e . g ., various types of controlled release compositions and coatings . thus , the drug is formulated with appropriate excipients into a pharmaceutical composition that , upon administration , releases the drug in a controlled manner . examples include single or multiple unit tablet or capsule compositions , oil solutions , suspensions , emulsions , microcapsules , microspheres , nanoparticles , patches , and liposomes . formulations for oral use include tablets containing the active ingredient ( s ) in a mixture with non - toxic pharmaceutically acceptable excipients . these excipients may be , for example , inert diluents or fillers ( e . g ., sucrose , sorbitol , sugar , mannitol , microcrystalline cellulose , starches including potato starch , calcium carbonate , sodium chloride , lactose , calcium phosphate , calcium sulfate , or sodium phosphate ); granulating and disintegrating agents ( e . g ., cellulose derivatives including microcrystalline cellulose , starches including potato starch , croscarmellose sodium , alginates , or alginic acid ); binding agents ( e . g ., sucrose , glucose , sorbitol , acacia , alginic acid , sodium alginate , gelatin , starch , pregelatinized starch , microcrystalline cellulose , magnesium aluminum silicate , carboxymethylcellulose sodium , methylcellulose , hydroxypropyl methylcellulose , ethylcellulose , polyvinylpyrrolidone , or polyethylene glycol ); and lubricating agents , glidants , and antiadhesives ( e . g ., magnesium stearate , zinc stearate , stearic acid , silicas , hydrogenated vegetable oils , or talc ). other pharmaceutically acceptable excipients can be colorants , flavoring agents , plasticizers , humectants , buffering agents , and the like . the tablets may be uncoated or they may be coated by known techniques , optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period . the coating may be adapted to release the active drug substance in a predetermined pattern ( e . g ., in order to achieve a controlled release formulation ) or it may be adapted not to release the active drug substance until after passage of the stomach ( enteric coating ). the coating may be a sugar coating , a film coating ( e . g ., based on hydroxypropyl methylcellulose , methylcellulose , methyl hydroxyethylcellulose , hydroxypropylcellulose , carboxymethylcellulose , acrylate copolymers , polyethylene glycols and / or polyvinylpyrrolidone ), or an enteric coating ( e . g ., based on methacrylic acid copolymer , cellulose acetate phthalate , hydroxypropyl methylcellulose phthalate , hydroxypropyl methylcellulose acetate succinate , polyvinyl acetate phthalate , shellac , and / or ethylcellulose ). furthermore , a time delay material such as , e . g ., glyceryl monostearate or glyceryl distearate may be employed . the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes , ( e . g ., chemical degradation prior to the release of the active drug substance ). the coating may be applied on the solid dosage form in a similar manner as that described in encyclopedia of pharmaceutical technology , supra . the two drugs may be mixed together in the tablet , or may be partitioned . in one example , the first drug is contained on the inside of the tablet , and the second drug is on the outside , such that a substantial portion of the second drug is released prior to the release of the first drug . formulations for oral use may also be presented as chewable tablets , or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent ( e . g ., potato starch , lactose , microcrystalline cellulose , calcium carbonate , calcium phosphate or kaolin ), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium , for example , peanut oil , liquid paraffin , or olive oil . powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using , e . g ., a mixer , a fluid bed apparatus or a spray drying equipment . controlled release compositions for oral use may , e . g ., be constructed to release the active drug by controlling the dissolution and / or the diffusion of the active drug substance . dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet , capsule , pellet , or granulate formulation of compounds , or by incorporating the compound into an appropriate matrix . a controlled release coating may include one or more of the coating substances mentioned above and / or , e . g ., shellac , beeswax , glycowax , castor wax , carnauba wax , stearyl alcohol , glyceryl monostearate , glyceryl distearate , glycerol palmitostearate , ethylcellulose , acrylic resins , dl - polylactic acid , cellulose acetate butyrate , polyvinyl chloride , polyvinyl acetate , vinyl pyrrolidone , polyethylene , polymethacrylate , methylmethacrylate , 2 - hydroxymethacrylate , methacrylate hydrogels , 1 , 3 butylene glycol , ethylene glycol methacrylate , and / or polyethylene glycols . in a controlled release matrix formulation , the matrix material may also include , e . g ., hydrated metylcellulose , carnauba wax and stearyl alcohol , carbopol 934 , silicone , glyceryl tristearate , methyl acrylate - methyl methacrylate , polyvinyl chloride , polyethylene , and / or halogenated fluorocarbon . a controlled release composition containing one or more of the compounds of the claimed combinations may also be in the form of a buoyant tablet or capsule ( i . e ., a tablet or capsule that , upon oral administration , floats on top of the gastric content for a certain period of time ). a buoyant tablet formulation of the compound ( s ) can be prepared by granulating a mixture of the drug ( s ) with excipients and 20 - 75 % w / w of hydrocolloids , such as hydroxyethylcellulose , hydroxypropylcellulose , or hydroxypropylmethylcellulose . the obtained granules can then be compressed into tablets . on contact with the gastric juice , the tablet forms a substantially water - impermeable gel barrier around its surface . this gel barrier takes part in maintaining a density of less than one , thereby allowing the tablet to remain buoyant in the gastric juice . powders , dispersible powders , or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration . formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent , suspending agent , and one or more preservatives . suitable dispersing or wetting agents are , for example , naturally - occurring phosphatides ( e . g ., lecithin or condensation products of ethylene oxide with a fatty acid , a long chain aliphatic alcohol , or a partial ester derived from fatty acids ) and a hexitol or a hexitol anhydride ( e . g ., polyoxyethylene stearate , polyoxyethylene sorbitol monooleate , polyoxyethylene sorbitan monooleate , and the like ). suitable suspending agents are , for example , sodium carboxymethylcellulose , methylcellulose , sodium alginate , and the like . the pharmaceutical composition may also be administered parenterally by injection , infusion or implantation ( intravenous , intramuscular , subcutaneous , or the like ) in dosage forms , formulations , or via suitable delivery devices or implants containing conventional , non - toxic pharmaceutically acceptable carriers and adjuvants . the formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation . formulations can be found in remington : the science and practice of pharmacy , supra . compositions for parenteral use may be provided in unit dosage forms ( e . g ., in single - dose ampoules ), or in vials containing several doses and in which a suitable preservative may be added ( see below ). the composition may be in form of a solution , a suspension , an emulsion , an infusion device , or a delivery device for implantation , or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use . apart from the active drug ( s ), the composition may include suitable parenterally acceptable carriers and / or excipients . the active drug ( s ) may be incorporated into microspheres , microcapsules , nanoparticles , liposomes , or the like for controlled release . furthermore , the composition may include suspending , solubilizing , stabilizing , ph - adjusting agents , and / or dispersing agents . as indicated above , the pharmaceutical compositions according to the invention may be in the form suitable for sterile injection . to prepare such a composition , the suitable active drug ( s ) are dissolved or suspended in a parenterally acceptable liquid vehicle . among acceptable vehicles and solvents that may be employed are water , water adjusted to a suitable ph by addition of an appropriate amount of hydrochloric acid , sodium hydroxide or a suitable buffer , 1 , 3 - butanediol , ringer &# 39 ; s solution , and isotonic sodium chloride solution . the aqueous formulation may also contain one or more preservatives ( e . g ., methyl , ethyl or n - propyl p - hydroxybenzoate ). in cases where one of the compounds is only sparingly or slightly soluble in water , a dissolution enhancing or solubilizing agent can be added , or the solvent may include 10 - 60 % w / w of propylene glycol or the like . controlled release parenteral compositions may be in form of aqueous suspensions , microspheres , microcapsules , magnetic microspheres , oil solutions , oil suspensions , or emulsions . alternatively , the active drug ( s ) may be incorporated in biocompatible carriers , liposomes , nanoparticles , implants , or infusion devices . materials for use in the preparation of microspheres and / or microcapsules are , e . g ., biodegradable / bioerodible polymers such as polygalactin , poly -( isobutyl cyanoacrylate ), poly ( 2 - hydroxyethyl - l - glutamnine ) and , poly ( lactic acid ). biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates ( e . g ., dextrans ), proteins ( e . g ., albumin ), lipoproteins , or antibodies . materials for use in implants can be non - biodegradable ( e . g ., polydimethyl siloxane ) or biodegradable ( e . g ., poly ( caprolactone ), poly ( lactic acid ), poly ( glycolic acid ) or poly ( ortho esters )). for rectal application , suitable dosage forms for a composition include suppositories ( emulsion or suspension type ), and rectal gelatin capsules ( solutions or suspensions ). in a typical suppository formulation , the active drug ( s ) are combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter , esterified fatty acids , glycerinated gelatin , and various water - soluble or dispersible bases like polyethylene glycols and polvoxyethylene sorbitan fatty acid esters . various additives , enhancers , or surfactants may be incorporated . for administration by inhalation , typical dosage forms include nasal sprays and aerosols . in a typically nasal formulation , the active ingredient ( s ) are dissolved or dispersed in a suitable vehicle . the pharmaceutically acceptable vehicles and excipients ( as well as other pharmaceutically acceptable materials present in the composition such as diluents , enhancers , flavoring agents , and preservatives ) are selected in accordance with conventional pharmaceutical practice in a manner understood by the persons skilled in the art of formulating pharmaceuticals . the pharmaceutical compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non - toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes . the formulations include creams , ointments , lotions , liniments , gels , hydrogels , solutions , suspensions , sticks , sprays , pastes , plasters , and other kinds of transdermal drug delivery systems . the pharmaceutically acceptable carriers or excipients may include emulsifying agents , antioxidants , buffering agents , preservatives , humectants , penetration enhancers , chelating agents , gel - forming agents , ointment bases , perfumes , and skin protective agents . examples of emulsifying agents are naturally occurring gums ( e . g ., gum acacia or gum tragacanth ) and naturally occurring phosphatides ( e . g ., soybean lecithin and sorbitan monooleate derivatives ). examples of antioxidants are butylated hydroxy anisole ( bha ), ascorbic acid and derivatives thereof , tocopherol and derivatives thereof , butylated hydroxy anisole , and cysteine . examples of preservatives are parabens , such as methyl or propyl p - hydroxybenzoate , and benzalkonium chloride . examples of humectants are glycerin , propylene glycol , sorbitol , and urea . examples of penetration enhancers are propylene glycol , dmso , triethanolamine , n , n - dimethylacetamide , n , n - dimethylformamide , 2 - pyrrolidone and derivatives thereof , tetrahydrofurfuryl alcohol , and azone ™. examples of chelating agents are sodium edta , citric acid , and phosphoric acid . examples of gel forming agents are carbopol ™, cellulose derivatives , bentonite , alginates , gelatin and polyvinylpyrrolidone . examples of ointment bases are beeswax , paraffin , cetyl palmitate , vegetable oils , sorbitan esters of fatty acids ( span ), polyethylene glycols , and condensation products between sorbitan esters of fatty acids and ethylene oxide ( e . g ., polyoxyethylene sorbitan monooleate ( tween ™)). the pharmaceutical compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated . the compositions may be adapted for direct application or for introduction into relevant orifice ( s ) of the body ( e . g ., rectal , urethral , vaginal or oral orifices ). the composition may be applied by means of special drug delivery devices such as dressings or alternatively plasters , pads , sponges , strips , or other forms of suitable flexible material . there are several approaches for providing rate control over the release and transdermal permeation of a drug , including : membrane - moderated systems , adhesive diffusion - controlled systems , matrix dispersion - type systems , and microreservoir systems . a controlled release percutaneous and / or topical composition may be obtained by using a suitable mixture of the above - mentioned approaches . in a membrane - moderated system , the active drug is present in a reservoir which is totally encapsulated in a shallow compartment molded from a drug - impermeable laminate , such as a metallic plastic laminate , and a rate - controlling polymeric membrane such as a microporous or a non - porous polymeric membrane ( e . g ., ethylene - vinyl acetate copolymer ). the active compound is only released through the rate - controlling polymeric membrane . in the drug reservoir , the active drug substance may either be dispersed in a solid polymer matrix or suspended in a viscous liquid medium such as silicone fluid . on the external surface of the polymeric membrane , a thin layer of an adhesive polymer is applied to achieve an intimate contact of the transdermal system with the skin surface . the adhesive polymer is preferably a hypoallergenic polymer that is compatible with the active drug . in an adhesive diffusion - controlled system , a reservoir of the active drug is formed by directly dispersing the active drug in an adhesive polymer and then spreading the adhesive containing the active drug onto a flat sheet of substantially drug - impermeable metallic plastic backing to form a thin drug reservoir layer . a matrix dispersion - type system is characterized in that a reservoir of the active drug substance is formed by substantially homogeneously dispersing the active drug substance in a hydrophilic or lipophilic polymer matrix and then molding the drug - containing polymer into a disc with a substantially well - defined surface area and thickness . the adhesive polymer is spread along the circumference to form a strip of adhesive around the disc . in a microreservoir system , the reservoir of the active substance is formed by first suspending the drug solids in an aqueous solution of water - soluble polymer , and then dispersing the drug suspension in a lipophilic polymer to form a plurality of microscopic spheres of drug reservoirs . the dosage of each compound of the claimed combinations depends on several factors , including : the administration method , the condition to be treated , the severity of the condition , whether the condition is to be treated or prevented , and the age , weight , and health of the person to be treated . additionally , pharmacogenomic ( the effect of genotype on the pharmacokinetic , pharmacodynamic or efficacy profile of a therapeutic ) information about a particular patient may affect the dosage used . as described above , the compound in question may be administered orally in the form of tablets , capsules , elixirs or syrups , or rectally in the form of suppositories . parenteral administration of a compound is suitably performed , for example , in the form of saline solutions or with the compound incorporated into liposomes . in cases where the compound in itself is not sufficiently soluble to be dissolved , a solubilizer such as ethanol can be applied . below , for illustrative purposes , the dosages for dipyridamole and fludrocortisone are described . for oral , intramuscular , subcutaneous , topical , inhalation , rectal , vaginal and ophthalmic administration of the tetra - substituted pyrimidopyrimidine , the dosage used according to the invention is about 0 . 5 - 800 mg / day , preferably about 5 - 600 mg / day , 10 - 100 mg / day , and more preferably 0 . 5 - 50 mg / day . administration can be one to four times daily for one day to one year , and may even be for the life of the patient . chronic , long - term administration will be indicated in many cases . in some cases of serious illness , up to 1600 mg / day may be necessary . for intravenous administration of the tetra - substituted pyrimidopyrimidine , the dosage used is about 0 . 1 - 200 mg / day , preferably about 0 . 5 - 150 mg / day , 1 - 100 mg / day , and more preferably about 0 . 5 - 50 mg / day . administration can be one to four times daily . systemic dosing will result in steady - state plasma concentrations preferably of 0 . 1 - 7 . 0 μm , more preferably , 0 . 5 - 5 . 0 μm , and most preferably , 1 . 0 - 2 . 0 μm . the dosage of the corticosteroid for use in combination with the tetra - substituted pyrimidopyrimidine is about 0 . 1 - 1500 mg / day , preferably about 0 . 5 - 30 mg / day , and more preferably about 0 . 1 - 10 mg / day . administration can be one to four times daily for one day to one year , and may even be for the life of the patient . chronic , long - term administration will be indicated in many cases . in cases of serious illness , dosages up to 3000 mg / day may be necessary . the following examples are to illustrate the invention . they are not meant to limit the invention in any way . stock solutions at 16 mg / ml of dipyridamole , and 1 . 6 mg / ml of fludrocortisone acetate ( sigma - aldrich , st . louis , mo . ; catalog numbers d9766 and f6127 , respectively ) were made in dimethylsulfoxide ( dmso ). the dipyridamole master plates were made by adding 25 μl of the concentrated stock solution to columns 3 , 9 , and 15 ( rows c through n ) of a polypropylene 384 - well storage plate that had been pre - filled with 75 μl of anhydrous dmso . using a tomtec quadra plus liquid handler , the 25 μl of dipyridamole stock solution was serially diluted four times into the adjacent columns ( columns 4 - 7 , 10 - 13 , 16 - 19 ). the sixth column ( 8 , 14 , and 20 ) did not receive any compound and served as a vehicle control . the fludrocortisone master plates were made by adding 25 μl of the concentrated stock solution to the appropriate wells ( row c , columns 3 - 8 ; row c , columns 9 - 14 ; row c , columns 15 - 20 ; row i , columns 3 - 8 ; row i , columns 9 - 14 ; row i , columns 15 - 20 ) of the appropriate master polypropylene 384 - well storage plate . these master plates had been pre - filled with 75 μl of anhydrous dmso . using the tomtec quadra plus liquid handler , the 25 μl was serially diluted four times in the adjacent rows ( rows d - g , and j - m ). the sixth row ( h and n ) did not receive any compound to serve as a vehicle control . master plates were sealed and stored at − 20 c . until ready for use . the final dipyridamole / fludrocortisone combination plates were generated by transferring 1 μl from each of the dipyridamole and fludrocortisone master plates to a dilution plate containing 100 μl of media ( rpmi ; gibco brl , # 11875 - 085 ), 10 % fetal bovine serum ( gibco brl , # 25140 - 097 ), 2 % penicillin / streptomycin ( gibco brl , # 15140 - 122 )) using the tomtec quadra plus liquid handler . this dilution plate was then mixed and a 10 μl aliquot transferred to the final assay plate , which had been pre - filled with 40 μl / well rpmi media containing the appropriate stimulant to activate tnfα secretion ( see below ). assay for tnfα suppressing activity by the combination of dipyridamole and fludrocortisone the compound dilution matrix was assayed using a tnfα elisa method . briefly , a 100 μl suspension of diluted human white blood cells contained within each well of a polystyrene 384 - well plate ( nalgenunc ) was stimulated to secrete tnfα by treatment with a final concentration of 10 ng / ml phorbol 12 - myristate 13 - acetate ( sigma ) and 750 ng / μl ionomycin ( sigma ). various concentrations of each test compound were added at the time of stimulation . after 16 - 18 hours of incubation at 37 ° c . in a humidified incubator , the plate was centrifuged and the supernatant transferred to a white opaque polystyrene 384 well plate ( nalgenunc , maxisorb ) coated with an anti - tnf antibody ( pharmingen , # 18631d ). after a two - hour incubation , the plate was washed ( tecan powerwasher 384 ) with phosphate buffered saline ( pbs ) containing 0 . 1 % tween 20 ( polyoxyethylene sorbitan monolaurate ) and incubated for an additional one hour with another anti - tnf antibody that was biotin labeled ( pharmingen , 18642d ) and horseradish peroxidase ( hrp ) coupled to strepavidin ( pharmingen , # 13047e ). after the plate was washed with 0 . 1 % tween 20 / pbs , the hrp substrate ( which contains luminol , hydrogen peroxide , and an enhancer such as para - iodophenol ) was added to each well and light intensity measured using a ljl analyst luminometer . control wells contained a final concentration of 1 μg / ml cyclosporin a ( sigma ). together , dipyridamole and fludrocortisone were able to suppress tnfα secretion in blood stimulated with phorbol 12 - myristate 13 - acetate and ionomycin . as seen in tables 1 and 2 , dipyridamole was able to enhance the potency of fludrocortisone by 60 - fold . at a concentration of 947 nm , fludrocortisone alone inhibited tnfα secretion by 39 %. addition of 124 nm dipyridamole to a concentration of only 15 nm fludrocortisone resulted in the inhibition of tnfα secretion by 39 % ( table 1 ). efficacy was maintained while reducing the total drug species by over 80 %, from 947 nm to 163 nm . in the presence of 2 μm dipyridamole , 50 % tnfα inhibition is achieved by only 4 nm fludrocortisone . this level of inhibition is not possible with fludrocortisone alone at concentrations that would be expected to cause serious mineralocorticoid - induced side effects . dipyridamole enhancement of fludrocortisone activity was observed in a secondary screen ( table 2 ). again , a low dose of 495 nm dipyridamole enhanced the potency of fludrocortisone by over 135 fold . specifically , 947 nm fludrocortisone alone was required to achieve a 52 % reduction of tnfα secretion . a similar reduction ( 49 %) was measured for the combination of 7 nm fludrocortisone and 495 nm dipyridamole . further , the addition of 248 nm dipyridamole resulted in a supramaximal effect on the inhibition of tnfα secretion at fludrocortisone concentrations as low as 59 nm . a compound matrix of dipyridamole and prednisolone were prepared according to the method of example 1 . the initial stock solution of dipyridamole was 16 mg / ml , and prednisolone was 1 . 6 mg / ml . assay for tnfα suppressing activity by the combination of dipyridamole and prednisolone the compound dilution matrix of example 3 , was assayed using the tnfα elisa method of example 2 . the results are shown in table 3 . together , dipyridamole and prednisolone were able to suppress tnfα secretion in blood stimulated with phorbol 12 - myristate 13 - acetate and ionomycin to a greater extent than either compound alone . specifically , dipyridamole greatly increased the potency of prednisolone . prednisolone alone , at a concentration of 250 nm , can suppress tnfα secretion by 38 %. the same level of suppression ( 41 %) can be achieved by only 1 nm prednisolone in combination with 2 μm dipyridamole . this represents a shift in the potency of prednisolone of over 250 - fold . further , the addition of 2 μm dipyridamole to 250 nm prednisolone resulted in a supramaximal effect ( 57 %), compared to prednisolone alone ( 38 %). the combination of low doses of prednisolone and dipyridamole , therefore , results in the inhibition tnfα to levels previously unattainable without a high risk of glucocorticoid - induced side effects . various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention . although the invention has been described in connection with specific desired embodiments , it should be understood that the invention as claimed should not be unduly limited to such specific embodiments . indeed , various modifications of the described modes for carrying out the invention that are obvious to those skilled in the fields of medicine , immunology , pharmacology , endocrinology , or related fields are intended to be within the scope of the invention . all publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually incorporated by reference .

the invention features a method for treating a patient having an immunoinflammatory disorder , by administering to the patient a tetra - substituted pyrimidopyrimidine , and a corticosteroid simultaneously or within 14 days of each other in amounts sufficient to reduce or inhibit immunoinflammation .

the preferred embodiment and best mode of the invention is shown in fig1 through 13 . “ batter ” as used herein in the application is meant to encompass cake batter , dough , malleable ice cream , gelatin or a malleable dessert which sets up in a rigid or semi - rigid shape . referring to the figures , a molding or baking assembly 20 according to the invention is adapted to shape or mold cake batter , other compositions of baking goods or complimentary desserts such as ice cream , gelatins , puddings into a concentric domed layered dessert having a semispherical or hemispherical shape . the outer dome pan or bowl 22 is typically symmetrical with a concavo - convex spherical shape . the outer dome mold is constructed with a bowl body 24 having a spherical or curved closed bottom surface 26 and an open end 28 forming an interior chamber or cavity 29 . the open end 28 is formed with a curved or rolled outer lip or rim 30 as shown in fig2 and 4 and has two handles 31 secured to the exterior of the outer dome bowl extending outward from the rim opposite each other . the outer lip 30 is curved in a circular configuration and preferably has a diameter of about 0 . 25 inches . a base ring member 32 is secured to the bottom surface 26 of the bowl body 24 to provide a flat base surface during working and / or cooking . the ring member 32 is preferably constructed of 22 gage c1018 cold rolled steel with a bell shaped exterior surface having a side wall 34 having a curved bottom edge 36 and a planar top edge 37 which has four tabs 38 outwardly extending therefrom bent at an angle ranging from about 120 to 130 °, preferably about 124 °. the ring member 32 is secured to the base section of the bowl body 24 by welding or braising . each tab 38 is positioned on the ring circumference 90 ° from the other adjacent tabs located on the circular top edge 37 and has a length of approximately 1 inch . the base ring 32 preferably has a diameter of 4 . 25 inches and a height of about 1 . 07 inches when used with a 8 . 38 inch outer diameter bowl having a depth of 3 . 98 to 4 . 0 inches . when ring member 32 is mounted or secured to the bowl body 24 , there is a clearance ranging from about 0 . 40 to about 0 . 60 inches , preferably about 0 . 47 inches from the lowest outer bottom surface of the bowl to the top of the support area upon which the ring member 32 is seated . if desired , a bimetallic thermometer can be attached to the ring member 32 which thermometer would turn an appropriate color upon reaching the desired cooking temperature allowing the cook to ascertain that the desired temperature has been reached . the bowl body 24 and base ring 32 is preferably integrally constructed of sheet steel or stainless steel but can be constructed of copper , aluminum , cast iron , pyrex , glass , porcelain , ceramic or any type of microwaveable material at a uniform desired thickness commonly used for baking pans and containers . if desired , the bowl body can have its external surface coated with a non - corroding material such as tin or chromium . the bowl 24 therefore may be constructed of a single sheet of metal formed into the desired shape . the inside smooth surface 25 of the bowl is preferably coated with one or more nonstick coatings , such as for example teflon ® ( i . e ., fluorocarbon polymers ), ( e . g ., tetrafluroethlene and fluorinated ethylene propylene ). the interior surface 25 of the bowl 24 , which contacts the batter or dessert composition , is covered with teflon ® in the preferred embodiment to ease the removal of the baked or chilled product from the bowl . the radial sloping of the inner wall 25 further eases removal of the final dessert composition . it will be appreciated by those skilled in the art that other shapes and geometries of pan assemblies are possible , and that the specifics of material of which it is made can be changed without departing from scope of the invention . for example , the mold may be formed as a cone , or other shape . additionally , it can be stamped from a solid piece of material or spun from aluminum instead of formed from a sheet . the cover 50 has an integral curved bowl 51 as shown in fig8 through 10 . the inner dome bowl 51 is typically symmetrical with a concavo - convex spherical shape constructed with a bowl body 52 having a spherical or curved closed bottom surface 54 and an open end 60 forming chamber 55 . the bowl body 52 extends away from cover 50 so that it will be seated in cavity 29 . the cover 50 is substantially circular shaped with handles 62 which are shaped to fit over the outer bowl handles 31 . the ends 64 of the handles 62 are rolled or bent in a “ c ” configuration as shown in fig8 so that the bottom portion 66 fits under the lower surface of handles 31 of the bowl , locking the same in position . if desired , the cover 50 and inner bowl 51 can be constructed of porous material such as high temperature teflon coated high temperature fiberglass ranging from 5 to 10 mils in thickness or a stainless steel wire cloth also teflon coated on both sides , both of which are breathable an allow an air flow of 50 cfm which vents moisture during baking without batter coming through . the porous material has a sieve opening for the stainless steel wire cloth ranging from 0 . 0165 + or − 0 . 0005 and the stainless steel is stme 1187 . the inside and outside surfaces of the bowl 52 are preferably coated with one or more nonstick coatings , such as for example teflon ® ( i . e ., fluorocarbon polymers ), ( e . g ., tetrafluroethiene and fluorinated ethylene propylene ). alternately the bowl body 51 can be constructed of sheet steel , stainless steel , copper , aluminum , cast iron , pyrex , glass , porcelain , ceramic or any type of microwaveable material at a uniform desired thickness commonly used for baking pans and containers . the interior surface 53 of the bowl 51 , which contacts the batter or dessert composition is smooth and is covered with teflon ® in the preferred embodiment to ease the removal of the baked or chilled product from the bowl . the radial sloping of the inner wall 53 further eases removal of the final dessert composition . it will be appreciated by those skilled in the art that other shapes and geometries of pan assemblies are possible , and that the specifics of material of which it is made can be changed without departing from scope of the invention . the inner bowl 51 is mounted in the outer bowl cavity 29 by placing the cover 50 on the rim 30 so that the handles 62 are offset from the outer bowl handles 31 . the cover 50 is then rotated so that the ends 64 of the handles 62 engage the outer bowl handles 31 so that the bottom portion 66 are positioned under the bottom surface of outer bowl 31 . in an alternative embodiments as shown in fig1 , a wire handle member 70 can be optionally mounted in yokes 72 which are mounted to the top surface of the cover 50 . the handle is of a curved shaped with end sections 71 extending outward to fit into the yokes . the handle 70 can be rotated upward to allow twisting and removal of the cover 50 from the dome bowl 24 . in operation cake batter is poured , about ⅔ to ¾ full , in the bowl body 24 and the cover 50 and its integral inner bowl 51 is placed in chamber or cavity 29 of the outer dome pan 22 down into the batter in chamber 29 and the cover rotated so that both handles are aligned and locked . a second cake batter of a different flavor as for example chocolate is poured in the chamber of bowl 51 about ⅔ to ¾ of the depth of the bowl 52 . after the batter 24 is molded and baked by the application of heat to the bowls , the cover 50 is removed and the inner dome mold is taken out of its nesting position in the outer mold bowl 24 leaving a cavity in the cake . the teflon ® coating of the interior and exterior surface of the inner mold bowl 51 facilitates removal of the mold without tearing or damaging the final baked product . the baked cake is then removed from the inner mold bowl body 51 , the teflon ® coating of the interior surface of the inner bowl mold facilitating the dessert removal . the result is a baked goods , which is hemispherically shaped and ready to eat . the teflon ® coating of the interior surface 25 of the outer dome mold 24 facilitates removal of the baked product without tearing or damaging the final baked product . the interior cake or other optional filling is then placed in the cavity formed by inner mold bowl body 51 and the composite assembly is inverted onto a serving area for frosting , icing or other decoration preparatory to being served . the result is a covered dual domed cake or dessert which is domed shaped as a hemisphere and ready to eat . the baked goods may be filled or coated with ice cream , pudding , icing or other sweet filling for a dessert pastry . although aluminum , sheet steel and / or stainless steel is preferred for the concavo - convex outer bowl body , any suitable structural material could be used in its place , as for example , alloyed steel , copper , brass , cast iron or even glass or ceramic , such as stoneware . the inner bowl body has the same structural body as that of the preferred embodiment . the principles , preferred embodiments and modes of operation of the present invention have been described in the foregoing specification . however ; the invention should not be construed as limited to the particular embodiments which have been described above . instead , the embodiments described here should be regarded as illustrative rather than restrictive . variations and changes may be made by others without departing from the scope of the present inventions defined by the following claims .

an apparatus assembly for forming a compound dessert in a predetermined dome shape including a first outer mold having a dome shaped bowl with a closed semi - spherical end and an open end , and a ring shaped support base secured to said closed end of bowl body . a cover including a second dome shaped bowl of a smaller diameter is mounted in the chamber formed in the first mold bowl and the cover is mounted to an extended portion of the outer mold .

fig1 is a schematic , pictorial illustration of a system 20 for cardiac ablation therapy , in accordance with an embodiment of the present invention . an operator 26 inserts a catheter 28 through a blood vessel into a chamber of a heart 24 of a subject 22 , and manipulates the catheter so that a distal end 32 of the catheter contacts the endocardium in an area that is to be treated . the distal tip of the catheter is perforated to enable optimal irrigation of the treatment area , as shown and described hereinbelow . in other respects , however , system 20 resembles systems for cardiac ablation treatment that are known in the art , such as the above - mentioned biosense webster system , and the components of such systems may be adapted for use in system 20 . after positioning distal end 32 at an ablation site , and ensuring that the tip is in contact with the endocardium at the site , operator 26 actuates a radio frequency ( rf ) energy generator 44 in a control console 42 to supply rf energy via a cable 38 to distal end 32 . meanwhile , an irrigation pump 48 supplies a cooling fluid , such as saline solution , via a tube 40 and a lumen in catheter 28 to the distal end . operation of the rf energy generator and the irrigation pump may be coordinated in order to give the appropriate volume of irrigation during ablation , so as to cool the tip of the catheter and the tissue without overloading the heart with irrigation fluid . a temperature sensor ( not shown in the figures ) in distal end 32 may provide feedback to console 42 for use in controlling the rf energy dosage and / or irrigation volume . fig2 is a schematic sectional view of distal end 32 of catheter 28 in engagement with endocardial tissue in heart 24 , in accordance with an embodiment of the present invention . the catheter terminates in a distal tip 50 , which is fixed to the distal end of an insertion tube 60 of the catheter . the distal tip typically comprises a conductive material , such as platinum , while the insertion tube has an insulating flexible outer sheath . the outer surface of the distal tip is penetrated by multiple perforations 52 , which are distributed over the surface of the distal tip both longitudinally ( i . e ., along the direction parallel to the longitudinal axis of catheter 28 ) and circumferentially ( along circumferences around the axis ). fig3 is a schematic side view of distal tip 50 , showing details of perforations 52 , in accordance with an embodiment of the present invention . the distal tip is hollow , with an outer surface 66 that encloses an interior space 64 . perforations 52 extend from the outer surface into the interior space . for cardiac ablation applications , the distal tip shown in fig3 is typically about 2 . 5 mm in diameter and 6 mm long , with a wall thickness in the distal part of the tip of about 0 . 25 mm . these dimensions , however , are given solely by way of illustration , and larger or smaller dimensions may be used depending on application requirements . the edges of the distal tip , at both the distal and proximal extremities of the tip , are typically rounded in order to avoid possible concentration of the rf electric field around the edges . typically , distal tip 50 has at least eight perforations , which are less than 0 . 5 mm in diameter , in order to distribute the irrigation over the tip both longitudinally and circumferentially without overloading the heart with the cooling fluid . the inventors have found it advantageous , however , to have at least fifty perforations in the distal tip , with diameters no greater that 0 . 2 mm . in the actual embodiment that is shown in fig3 , tip 50 has ninety - six perforations , with diameters of approximately 0 . 1 mm . the sizes of the perforations may optionally be varied over the length of the distal tip to compensate for pressure variation and ensure equal flow over the entire length . for this purpose , the perforations at and near the most distal part of the tip may be made larger than the more proximal perforations , which are nearer to the fluid inlet . returning now to fig2 , the proximal end of distal tip 50 is closed off by a plug 54 , which has a fluid inlet 56 feeding interior space 64 . a lumen 58 passing through insertion tube 60 of catheter 28 conveys fluid from irrigation pump 48 ( fig1 ) to inlet 56 , filling interior space 64 . the fluid exits tip 50 through perforations 52 to the surrounding tissue . a conductor conveys rf energy from rf generator 44 to the conductive tip , which thus serves as an electrode for delivering the energy in order to ablate the tissue . fig4 is a schematic side view of apparatus used in creating perforations 52 in distal tip 50 , in accordance with an embodiment of the present invention . in this embodiment , the perforations in the tip are produced by electrical spark discharge . tip 50 is mounted in a suitable rotating jig 70 ( such as a lathe chuck ). a needle electrode 72 , such as a carbon needle , is held at a potential of several thousand volts by a high - voltage power supply 76 . a motion assembly 74 gradually brings the needle electrode into proximity with the point on the catheter tip at which a perforation is to be made . the procedure is typically carried out in a controlled gas environment ( such as an argon atmosphere ). at a distance of about 1 mm , a spark jumps from the electrode to the catheter tip . the discharge creates a small perforation , typically about 100 μm in diameter , in the tip . the size of the hole may be controlled by varying the discharge voltage . jig then rotates tip 50 so that the location of the next perforation is positioned opposite needle electrode 72 , and the next perforation is created in similar fashion . the electrode is shifted longitudinally along the catheter tip to make multiple sets of holes , which are distributed longitudinally and circumferentially over the catheter tip as described above . this method of creating holes in distal tip 50 permits a large number of holes to be made precisely and inexpensively , without structurally weakening the catheter tip . it allows the sizes of the irrigation holes to be controlled in production to give precisely the desired volume of irrigation , without clogging of the holes on the one hand or overloading of the heart with irrigation fluid on the other . although the embodiments described above relate specifically to catheters used in rf ablation treatment within the heart , the principles of the present invention may similarly be applied to other organs and in other types of therapy that involve application of energy to body tissues . for example , a device with a similar sort of irrigated tip may be used in therapies that involve microwave - based or ultrasonic tissue heating . it will thus be appreciated that the embodiments described above are cited by way of example , and that the present invention is not limited to what has been particularly shown and described hereinabove . rather , the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove , as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not disclosed in the prior art .

a medical device includes an insertion tube , having a distal end for insertion into a body of a subject . a distal tip is fixed to the distal end of the insertion tube and is coupled to apply energy to tissue inside the body . the distal tip has an outer surface with a plurality of perforations through the outer surface , which are distributed circumferentially and longitudinally over the distal tip . a lumen passes through the insertion tube and is coupled to deliver a fluid to the tissue via the perforations .

now with reference to the drawing , there is depicted therein a kite , generally indicated at 10 , comprising a sheet material 12 , support sticks or members 14 , 16 , respectively , and means for balancing the weight of the kite , generally indicated at 18 . with more particularity , the kite 10 hereof comprises a sheet material 12 which is of light weight . the material 12 may be of any suitable manufacture such as paper , sheet polyethylene and the like . conventionally , the material 12 has a quadrangular configuration having a longitudinal length greater than the latitudinal length . the material 12 hereof is depicted as being double layered , having layers 20 , 22 and wherein the layer 20 terminates at the apeces thereof short of the terminus of layer 22 to define openings 24 through which the ends of the support members are inserted . in this manner the support members are enveloped by the sheet material 12 . it is to be understood , however , that the construction of the sheet material as a single layer connected or otherwise secured to the termini of the support members is equally applicable herein . referring again to the drawing , and as previously noted , the present kite , also , includes support members 14 , 16 . the support members extend substantially perpendicular to each other . in order to maintain the perpendicular relationship therebetween , at the point of intersection of the members , they are provided with mating notches 26 , 28 , respectively . in this manner , the support members are interengageable . for purposes of facilitating an understanding of what is set forth hereinafter , the support member 14 will be referred to as the longitudinally - directed member and the support member 16 will be referred to as the latitudinally - directed member . the longitudinal member 14 has each end thereof provided with a slot 30 . the slots 30 define a string retaining slot when the kite is strung . as clearly shown in fig3 the lowermost end of the longitudinal member 14 is provided with a threaded profile or thread 32 . the thread 32 threadably receives thereon means 18 for balancing the weight of the kite . the means 18 can comprise any suitable internally threaded member , such as a screw , bolt , nut or the like . by providing the threaded connection between the means 18 and the support member 14 , the means 18 is positionally adjustable thereon . it should further be noted that the means 18 provided on the end of the longitudinal member 14 , also functions as the tail of the kite . disposed along the axis of the member 14 are annular grooves 34 , 36 , one each on each side of the notch 26 . the grooves 34 , 36 define string retaining means when the kite is strung . the latitudinally - directed member 16 is constructed analogously to member 14 . however , each end of the member 16 has a threaded profile or thread 36 , 38 , each of which receives a means 18 . each end of the member 16 is slotted in the manner heretofore described , with slotes 40 , 42 , respectively . each end of the member 16 is provided with an annular string retaining groove 44 , 46 , respectively . in practicing the present invention , the apeces of the quadrangular sheet material are mounted on the ends of the support members . a string 48 is then strung around the periphery of the sheet material , through the slots 30 , 40 and 42 and then around the annular grooves 34 , 36 , 44 and 46 . in fabricating the support members 14 , 16 and the means 18 , any suitable material , such as a synthetic resin or the like can be used . in deploying the kite 10 , if the kite , when lofted , is spinning then by rotating the means 18 either inwardly or outwardly , this effect can be obviated . it is apparent from the preceding that there is provided hereby a kite of simple construction which effectively compensates for weight distribution problems as well as for aerodynamic conditions .

a kite including a lightweight sheet material and a support structure . the sheet material is secured to the support structure . the support structure has at least one end thereof provided with a threaded profile . a threaded fastener is rotatably positionable on the support member to thereby balance the weight of the kite .

fig1 to 17 illustrate elements and details of a dosing device 10 , which can be used to discharge a defined quantity of free - flowing media , in particular powder - form material such as ceramic powder for the dental field . however , the cases of application given as examples in this regard should not be understood as limiting the scope of protection , even though they are preferred . the device 10 comprises a housing 12 , which is closed on its topside by a cover that will be referred to as hood 14 hereinafter . the hood 14 can be material - bonded to the housing 12 by means of ultrasonic welding . the housing 12 comprises a cylindrical - shape main body 16 , which is closed on the bottom by a bottom wall 18 , which also can be material - bonded to the housing body 16 by means of ultrasonic welding . the free - flowing medium to be discharged in a dosed manner is charged into the housing 12 with its bottom wall 18 removed . subsequently , the housing 12 is closed by the bottom wall 18 . thus the housing 12 constitutes a storage container . to be able to reproducibly discharge a dosed quantity of the medium , a dosing device in form of a slider 20 is provided , which will be explained in more detail on the basis of fig1 to 17 in connection with fig9 to 12 . the slider 20 is movable in the hood 14 perpendicularly to the longitudinal axis of the housing 12 . for this purpose , the hood 14 features a cut - out as an opening 22 , which can engage a front wall 24 of the slider 20 , to be pushed into the hood 14 against the force of tension springs 26 , 28 . on its top , the hood 14 features a flattened region 30 , from which protrudes a projecting part 32 with a hollow cylinder geometry , into which a cylindrical - shape lock element 34 can be inserted , to position the slider 20 in the position illustrated in fig1 and 3 . the lock element 34 can feature a lid element 35 of a flange - like embodiment to facilitate problem - free handling . the hood 14 has a cylindrical geometry with two opposite outside surfaces 36 , 37 extending at an angle . the surfaces 36 , 37 extend alongside the slider 24 . in the remaining surfaces , the circumferential surface of the hood 30 approximates sections of a cylinder circumferential wall surface . furthermore , the outer side of the hood 14 continues with a flush alignment into the outer surface of the main or base body 16 of the housing 12 . the housing 12 , i . e . the cylinder - shaped base body 16 , at its upper side changes into a head section 38 or extension , which has a truncated - cone geometry and features a funnel shape on the inside . the head section 38 surrounds a first outlet 40 . the head section 38 can be a component manufactured separately by e . g . injection moulding and can be material - bonded to the base body 16 , e . g . using ultrasonic welding . from the head section 38 extends a guide way 42 for the slider 20 . the guide way 42 comprises a plate - shaped base section 44 , — also referred to as base element —, which is covered by a pipe - section - shaped element 46 with an arc - shaped cross - section and an inside geometry that matches the effective circumferential geometry of the slider 20 . this provides an accurate guide way for the slider 20 . the guide way 42 extends perpendicular to the longitudinal axis of the housing 12 . the base section 44 features a cutout , which is to be referred to as second opening and which opens into the first outlet 40 . the curved element 46 features an opening 48 as third opening , which extends flush with the hollow - cylinder - shaped projecting part 32 that surrounds a second outlet 50 . a pin element , which can be referred to as axle 56 and which is fixed in the region at the rear side of the slider 20 and extends at a right angle to the latter &# 39 ; s two longitudinal sides , passes through longitudinal slits 52 , 54 , which extend along the base element 44 in the region of the third opening 48 . pin - shaped projections 58 , 60 protrude from the forward region of the curved element 46 , in particular in a direction that corresponds to that of the axle 56 . the tension springs 26 , 28 are mounted in between the laterally protruding sections of the axle 56 and the projections 58 , 60 , as a result of which the slider 20 is acted upon by a force in the direction toward the front end of the guide way 42 and thus the opening 22 in the hood 14 . the slider 20 has a base body 62 , which comprises a base plate 64 and — extending from the latter — ridge - shaped longitudinal - side - wall sections 66 , 68 . in between the latter extend boundary walls 70 , 72 , 74 . the front boundary walls 72 , 74 represent rib - like reinforcements . in contrast , a rear partition wall 70 together with a rear boundary wall 76 of the slider surround a receptacle 80 , into which can flow the medium to be transferred from the housing 12 . the receptacle 80 is open at its lower side , and consequently has an opening ( fourth opening ) 82 . this opening 82 can be aligned with the second opening ( not illustrated ) of the plate - shaped base section 44 of the guide way 42 , which in turn connects to the first outlet 40 . the receptacle 80 and thus its opening 82 is aligned with the first outlet 40 when the slider 20 is exclusively acted upon by the forces exerted by the tension springs 26 , 28 . in this case , the forward textured front or boundary wall 24 of the slider 20 is located outside the hood 14 . in this position , the receptacle 80 is accessible via the opening 82 , whereas the remaining region is covered by the guide way 42 , i . e . the curved element 46 . for filling the receptacle 80 in this position of the slider 20 , the dosing device 10 must be rotated by approximately 180 °. subsequently the slider 20 is pushed into the hood 14 against the force of the springs 26 , 28 . this closes the opening 82 of the receptacle 80 . when the slider 20 has been pushed into the hood 14 — this movement is restricted by the interaction between the axle 56 and the limits of the slits 52 , 54 — the receptacle 80 with its upper opening 84 located opposite its bottom wall opening reaches true alignment with the third opening 48 and thus the second outlet 50 , so that the medium contained in the receptacle 80 can be discharged . subsequently , the lock element 34 can be inserted via the second opening 50 so that it penetrates all the way to the slider 20 , i . e . the receptacle 80 , in order to arrest the slider 20 . in this position the front wall 24 of the slider 20 is approximately aligned with the exterior surface of the hood 14 , as is shown schematically in the illustrations of fig1 to 4 . the invention provides with uncomplicated mechanical measures a dosing device for the dosed discharge of a free - flowing medium , in particular ceramic powder , which can be used as a single - use dosing device . of course the design is also suitable for repeated use . in this case , the bottom wall 18 would have to close the base body 20 in a detachable manner . the individual component parts of the device 10 consist of plastic and can be injection - moulded parts . the guide way 42 can as a separate part be joined by ultrasonic welding to the cap - shaped head section 38 of the housing 12 . other fastening methods are also feasible . fig1 to 20 illustrate a further embodiment of the invention &# 39 ; s dosing device 100 , which in regard to the arrangement of the slider , the housing containing the fluid medium to be discharged , and the cover corresponds to the device of fig1 to 17 , so that identical reference symbols can be used for equivalent elements . in this respect we also refer to the explanations in connection with fig1 to 17 . divergent from the embodiment example explained above and supplementary to it , the device 100 comprises an oscillating device 102 , which preferably is embodied as an unbalanced motor . the oscillating device 102 , which in the following will be referred to as unbalanced motor for simplicity , is activated when medium is to be discharged . in this , the unbalanced motor serves to ensure that the required amount of free - flowing material can flow via the first outlet 40 into the receptacle 80 , i . e . the dosing chamber in the slider 20 , so that it can be discharged after aligning the receptacle 20 with the second outlet . thus the unbalanced motor 102 ensures the consistent discharge of medium from the housing 12 . at the same time it is ensured that no material or powder residue remains in the housing 12 , which allows optimal utilization . in accordance with the embodiment example of fig1 to 20 , the unbalanced motor 102 is located in a housing section 104 , which preferably can be screw - mounted to the housing 12 and which together with the bottom 18 of the housing 12 forms a quasi double bottom . the housing section 104 houses a circuit board 108 for the electrical wiring of the unbalanced motor 112 . the drawing illustrates a battery such as a button cell 106 , which is connected to the unbalanced motor 102 , in particular via the circuit board 108 . for opening and closing the electric circuit , a reed contact 110 is provided , which is actuated via a magnet 112 , which is arranged moveable along the longitudinal direction of the housing 12 in a receptacle 114 . the receptacle 114 extends from the bottom wall 116 of the housing section 104 , so that when the device 100 has been put down or is held in a position in which the cover 14 is facing upward , the magnet 112 will be sufficiently distant from the reed contact 110 for the latter not to close , with the result that the electric circuit for the unbalanced motor 102 is interrupted . when the device 110 is rotated , i . e . to discharge free - flowing medium , the magnet 112 moves in the receptacle 114 forming a guide way in the direction towards the reed contact 110 , so that the latter is closed and the unbalanced motor 102 is activated . the vibration generated by the unbalanced motor 102 causes the free - flowing or powder - form material present in the housing 12 to be conveyed in the direction towards the first outlet 40 , to reproducibly fill the receptacle 80 in the slider 20 . in its boundary wall 118 that is located opposite its bottom wall 116 , the housing section 104 features a metal insert part 120 , which has a screw thread and can be screwed into a threaded bush 123 , which extends from or passes through the bottom wall 18 of the housing 12 . fig1 further illustrates that the base element 44 of the guide way 42 for the slider 20 can be covered by foil 122 , which is to be removed prior to the first use of the device 10 / 100 . this ensures that the interior of the housing 12 , i . e . the storage reservoir , is sealed airtight during transport and storage , providing protection against ingress of humidity . as illustrated in fig2 , the receptacle 114 — which consists of plastic — has the shape of a pipe that extends from the interior side of the bottom wall 116 of the second housing 104 . on the outside and in extension of the receptacle 114 , the bottom wall 116 features a receiver such as a cavity 124 , into which a metal part such as a small steel plate or plain washer 126 can be inserted and wedged , which holds the magnet 112 in a position in the region of the bottom wall 116 , i . e . in the part of the pipe or receptacle 114 that extends from the interior side of the bottom wall 116 . as a result , the magnet 112 will be at a sufficiently large distance from the reed contact 110 , so that the latter will not be actuated , and the circuit that includes the unbalanced motor 112 will not be closed . this provides a simple shipping brace . when the dosing device 10 is to be operated it is only necessary to remove the metal part 126 from the receiver 124 located in the bottom wall 116 , so that the magnet 112 can be moved by gravity within the receptacle 114 . consequently , the reed contact 110 is actuated and thus the circuit that contains the unbalanced motor 102 is closed , if the dosing device 10 is rotated in such a manner that its head , i . e . the second outlet 50 , points downward . consequently , activation of the unbalanced motor 102 causes the powder - form medium present in the housing 12 to vibrate , giving rise to flowability , so that the required volume of powder material can flow into the receptacle 80 of the slider 20 that constitutes a dosing chamber .

a device for the dosed discharge of a powder - form medium , in particular ceramic powder for dental purposes , including a storage container with a first outlet , as well as a slider with a receptacle for a quantity of medium to be dosed , which can be selectively aligned with a first outlet or a second outlet , through which the medium can be discharged . in order to achieve reproducible discharge of a defined quantity of free - flowing medium in an uncomplicated design , and since there is no requirement for re - usability after emptying the storage container , the invention proposes that the slider be connected to at least one spring element , which admits a force upon the slider to align the receptacle with the first receptacle , and that the receptacle can be secured by a lock element in a position aligned with the second outlet .

referring now more specifically to fig1 and 8 of the drawings , there may be seen an overhead track assembly referred to in general by the reference numeral 10 . the track assembly 10 includes a suitably supported tubular track 12 , see fig4 provided with a longitudinal slot 14 in its lower periphery extending the full length of the track 12 . a chain 16 extends through the track 12 and may be driven in any convenient manner by reversible drive means ( not shown ) housed within or adjacent a bucket filling station 18 . longitudinally spaced areas of the chain 16 include pairs of depending hangers 20 from which the opposite ends of a longitudinal central tubular bar 22 of a clam - type bucket assembly referred to in general by the reference numeral 24 is removably supported through the utilization of hanger brackets 26 and removable fasteners 28 . at predetermined locations along the track 10 a plurality of latch trip operator support brackets 30 are clamp supported , each bracket 30 pivotally supporting a latch trip operator arm 32 therefrom which may swing in a counterclockwise direction as viewed in fig1 from a depending substantially vertical position to a substantially horizontal position with no resistance . however , each bracket 30 further includes an abutment 34 supported therefrom which limits swinging of the latch trip operator 32 in a clockwise direction as viewed in fig1 . the clam - type bucket assemblies 24 each include a pair of substantially identical inner and outer clam bucket halves 34 and 36 . the opposite ends of the halves 34 and 36 have pairs of mounting straps 38 and 40 supported therefrom having adjacent overlapped ends . the overlapped ends of the mounting straps 38 are provided with longitudinal slots 42 and the overlapped ends of the mounting straps 40 include lateral pins 44 supported therefrom slidably received in the corresponding slots and provided with rollers 46 journaled thereon outwardly of the slots 42 . in addition , each pair of corresponding bucket ends includes support straps 48 and 50 which are downwardly and outwardly inclined and have their outer ends pivotally anchored relative to the corresponding ends of the mounting straps 38 and 40 through the utilization of pivot fasteners 52 , the upper adjacent ends of the support strap 48 and 50 being secured together and to the corresponding ends of the tubular bar 22 . journaled centrally through the tubular bar 22 is an operating rod 52 whose opposite ends project outwardly from the tubular bar 22 and have c - shaped latches 54 supported therefrom through the utilization of fasteners 56 , the upper end of one of the fasteners 56 including an eye 58 , see fig7 . the c - shaped latches are supported from the operating rod 52 at the free ends of the upper arms thereof and the free ends of the lower arms thereof include depending abutment flanges 60 for purpose to be hereinafter more fully set forth . the left hand end of the bucket assembly 24 as illustrated in fig1 supports a bracket 64 from the corresponding support strap 50 and a vertical journaled sleeve 66 is mounted from the bracket 64 and pivotally mounts one end of a multi - angle latch trip 68 therefrom whose base end is loosely received through the eye 58 . in addition , an expansion spring 70 extends between and has its opposite ends anchored relative to the eye 58 and the pivot fastener 52 pivotally supporting the support strap 48 to the mounting strap 38 , the latch trip being engageable by the latch trip operator 32 . finally , the bucket half 34 includes electronically readable identification means 72 thereon which may be read at the bucket filling station 18 to determine the quantity and mix of feed to be discharged into the bucket assembly 24 . in operation , the bucket assembly 24 moves along the track 10 in the direction of the arrow 74 in fig1 past feeding stations to be occupied by particular cows to be fed , the cows either having electronic readable identification tags thereon or being trained or otherwise caused to enter respective feeding stations 76 . when the feeding is to begin , the chain 16 is driven along the track intermittently such that each bucket assembly 24 enters and stops within the station 18 in position to have feed placed thereinto . the identification means 72 of each bucket 24 is read at the bucket filling station 18 and the appropriate quantity and mix of feed is placed within the bucket . after each of the bucket assemblies 24 has had the proper quantity and mix of feed placed therein , the chain 16 moves the bucket assemblies 24 further along the track 10 and as each bucket assembly 24 passes the respective feeding station 76 , movement of the chain 16 is stopped and the chain is then moved in a reverse direction . as a bucket assembly 24 first moves past the respective feeding station 76 in the direction of the arrow 74 in fig1 the latch trip 68 engages the approach side of the depending latch trip operator 32 and swings the latter in a counterclockwise direction as viewed in fig1 until the latch trip 68 moves beneath the latch trip operator 32 and the latter returns by gravity to the substantially vertical position thereof illustrated in fig1 . then , as the chain 16 is reversed in direction , the latch trip 68 again engages the lower end of the latch trip operator and swings it in a clockwise direction until the upper extended end 80 of the latch trip operator 32 engages the abutment 34 to terminate its swinging movement . thereafter , continued movement of the bucket assembly 24 to the left as viewed in fig1 of the drawings causes the latch trip operator 32 to swing the latch trip 68 in a counterclockwise direction as viewed from above thereby rotating the latch 54 from the latched positions thereof illustrated in fig1 and 7 to the unlatched position thereof illustrated in fig4 whereby the roller 46 passes outwardly beyond the free end of the lower arm of the c - shaped latch 54 to enable the roller to drop downwardly along the flange 60 to the position thereof illustrated in fig4 thereby enabling the weight of the feed within the bucket assembly 24 to swing the bucket halves 34 and 36 to the open positions thereof illustrated in fig4 and thus discharge the feed from the bucket assembly 24 into the feed station 76 . inasmuch as the pivot connections between the support straps 48 and 50 and the bucket halves 34 and 36 and defined by the pivot fasteners 52 as shown in fig4 are disposed outward of the lateral centers of gravity of the bucket halves 34 and 36 , as soon as the feed within the bucket assembly 24 is discharged therefrom , the bucket halves 34 and 36 swing back toward the closed positions thereof sufficient to raise the roller 46 to a level slightly above the free end of the lower arms of the latches 54 whereupon the expansion spring 70 , exerting a pull on the eye 58 , will cause the latches 54 to again cam latch the bucket halves 34 and 36 tightly in their closed positions illustrated in fig1 and 5 . if the bucket assemblies 24 are properly spaced along the track 10 according to the spacing between the feeding stations 76 , all of the buckets 24 may be simultaneously opened as they simultaneously are reversed over the corresponding feeding stations 76 . however , if such predetermined spacing is not provided , as each bucket assembly 24 having feed therein passes forwardly over and then reverses relative to the corresponding feeding station 76 that bucket 24 will have its load feed discharged therefrom . with the instant invention proper quantity and mix of feed may be dispensed into each bucket assembly at the bucket filling station 18 by conventional known structure through reading of the identification means 72 on each of the bucket assemblies 74 . thereafter , proper discharging of the proper quantity and mix of feed at each feeding station 76 is readily carried out merely by reverse movement of the chain 16 at the proper time , all of which may be automatically controlled . from a comparison of fig4 and 5 of the drawings it may be seen that the clam - type bucket assemblies 24 vary insignificantly in total height and width between open and closed positions . this enables the bucket assemblies 24 and the track 10 to be readily erected and utilized within a feed building which may have limited clearance because of supporting posts or beams . further , if it is desired , immediately before entering the bucket filling station 18 the upper inclined edges 84 ( see fig6 ) of the bucket halves 34 and 36 may be engaged by yieldable abutments exerting downward pressure sufficient to even more tightly close the bucket halves 34 and 36 relative to each other . as this occurs , the expansion spring 70 will be operative to further rotate the latches 54 and tightly cam latch the bucket halves 34 and 36 into even more tightly closed positions . the foregoing is considered as illustrative only of the principles of the invention . further , since numerous modifications and changes readily will occur to those skilled in the art , it is not desired to limit the invention to the exact construction and operation shown and described and , accordingly , all suitable modifications and equivalents may be resorted to , falling within the scope of the invention .

an overhead track construction is provided including clam - type buckets supported from the track for guided movement therealong . the track extends past predetermined feeding stations into which material contained within the buckets is to be released and each of the buckets includes latch structure for releasably retaining the bucket halves thereof in closed positions . each of the feeding locations includes track mounted latch release structure inoperative to release the latches of the buckets moving therepast in one direction but operative to engage and release the latches of the buckets moving therepast in the opposite direction .

dermal fibroblasts are skin cells responsible for the production of collagen that contribute to the formation of connective tissue fibers and growth factors that promote skin - barrier integrity and wound healing . in normal wound healing , fibroblasts are recruited from the surrounding intact tissue into the granulation tissue to proliferate and regenerate a new dermal layer in response to various factors presented in the wound fluid . during normal aging , dermal fibroblasts lose both the ability to proliferate and the capacity to secrete growth factors ( e . g ., egf , fgf7 / kgf , tgfβ , collagen ) involved in normal wound healing . a high - throughput screen designed to identify small molecules that promote fibroblast proliferation and increase secretion of proteins ( e . g ., egf , fgf7 / kgf , tgfβ , collagen ) is described herein . a growth factor is a naturally occurring substance capable of stimulating cellular growth , proliferation and cellular differentiation . growth factors are important for regulating a variety of cellular processes . growth factors typically act as signaling molecules between cells . examples are cytokines and hormones that bind to specific receptors on the surface of their target cells . they often promote cell differentiation and maturation , which varies between growth factors . for example , bone morphogenic proteins stimulate bone cell differentiation , while fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel differentiation ( angiogenesis ). examples of growth factors and families of growth factors include , but are not limited to : adrenomedullin ( am ), angiopoietin ( ang ), autocrine motility factor , bone morphogenetic proteins ( bmps ), brain - derived neurotrophic factor ( bdnf ), epidermal growth factor ( egf ), erythropoietin ( epo ), fibroblast growth factor ( fgf ), glial cell line - derived neurotrophic factor ( gdnf ), granulocyte colony - stimulating factor ( g - csf ), granulocyte macrophage colony - stimulating factor ( gm - csf ), growth differentiation factor - 9 ( gdf9 ), hepatocyte growth factor ( hgf ), hepatoma - derived growth factor ( hdgf ), insulin - like growth factor ( igf ), migration - stimulating factor , myostatin ( gdf - 8 ), nerve growth factor ( ngf ) and other neurotrophins , platelet - derived growth factor ( pdgf ), thrombopoietin ( tpo ), transforming growth factor alpha ( tgf - α ), transforming growth factor beta ( tgf - β ), tumor necrosis factor - alpha ( tnf - α ), vascular endothelial growth factor ( vegf ), wnt signaling pathway , placental growth factor ( pigf ), fetal bovine somatotrophin ( fbs ), il - 1 , il - 2 , il - 3 , il - 4 , il - 5 , il - 6 , il - 7 , bfgf and vegf . fibroblasts secrete soluble factors that diffuse to the overlying epidermis and influence keratinocytes in a paracrine manner and release cytokines and growth factors that have autocrine and paracrine effects . autocrine activity includes the transforming growth factor ( tgf )- β - induced synthesis and secretion of connective tissue growth factor which promotes collagen synthesis as well as fibroblast proliferation . paracrine activity affects keratinocyte growth and differentiation , specifically through fibroblast secretion of keratinocyte growth factor ( kgf ), granulocyte - macrophage colony - stimulating factor , interleukin ( il )- 6 and fibroblast growth factor ( fgf )- 10 . in response , keratinocytes synthesize il - 1 and parathyroid hormone - related peptide which , in turn , stimulate fibroblasts to produce kgf and thus a double paracrine loop exists . furthermore , keratinocytes cultured alone express il - 1 relatively weakly but when co - cultured with fibroblasts show increased expression of il - 1 and c - jun . therefore , fibroblasts incorporated into a dermal substrate play a role in producing ecm and stimulatory growth factors , which provides the optimum environment to support epidermis formation and to facilitate wound healing . fibroblast density is an important factor to consider for the development of normal epidermal morphology and keratinocyte differentiation and that the optimum density still needs to be established . fibroblasts also contribute to basement membrane formation partly by producing collagen types iv and vii , laminin 5 and nidogen , but also through the secretion of cytokines that stimulate keratinocytes to produce basement membrane components . tgf - β secreted by fibroblasts induces the synthesis of collagen types iv and vii by keratinocytes . neovascularization and lymphangiogenesis are also important processes for the maintenance of normal skin homeostasis and wound healing , for which fibroblasts have an important paracrine role . members of the vascular endothelial growth factor ( vegf ) family include vegf - a , - b , - c and - d , which are produced by normal human fibroblasts and are important in regulating vascular and lymphatic endothelial cell proliferation through specific receptors . vegf - a is well known to be involved in the activation of resident endothelial cells and endothelial progenitor cells capable of vasculogenesis ; vegf - b is less mitogenic for endothelial cells while vegf - c and - d have the same receptor specificity , binding to vegf receptor 2 ( vegf - r2 ) to mediate angiogenesis and binding to vegf - r3 to influence lymphangiogenesis . fgf - 1 encourages the body &# 39 ; s own adhesive tissue to develop and effectively seal the wound , thereby stymieing infection and mitigating scar formation . using fgf to stimulate fibroblast activity is an effective means of sealing tissue due to the robust nature of collagen which makes up connective tissue . to seal together tissues the human body uses collagen and elastin to obtain superior shear strength . type i collagen , which includes collagen strands bundled into strong fibrils has a unique tri - helical structure that increases its structural integrity . the following examples are intended to illustrate but not limit the invention . for the proliferation assay , human dermal fibroblast ( hdf ) were plated into 96 well black / clear bottom tissue - culture treated plates ( corning ) at 1 , 000 cells / well in dmem ( gibco ) 15 % fbs ( hyclone ). on the next day cells were treated with the small molecule library ( torcris 1120 biologically active compounds ) at 2 . 5 μm final concentration . after 3 days of treatment , cells were fixed and stained with dapi and analyzed using roche cellavista high - content imaging system ( see fig1 ). from the high - throughput proliferation screening assay it was found that abt702 dihydrochloride ( adenosine kinase antagonist ), fenobam ( mglu 5 receptor antagonist ) and sx 011 ( p38 mapk antagonist ), induced the highest proliferation level in hdfs at concentration of 200 nm ( see fig2 ). for fgf7 production assay hdfs were plated into 96 well clear tissue - culture treated plates ( falcon ) at 19 , 000 cells / well in dmem ( gibco ) 1 × n2 / b27 supplement ( invitrogen ). on the next day cells were treated with the small molecule library ( torcris 1120 biologically active compounds ) at 2 . 5 μm final concentration . after 3 days of treatment , supernatants were collected and analyzed for fgf7 content using fgf7 human elisa kit ( abcam ) and with biotek synergy 2 multi - detection microplate reader ( see fig1 ). from the high - throughput screening assay for fgf7 production assay it was found that prostaglandin e 2 at concentration of 25 μm induced the highest production level of fgf7 in hdfs ( see fig3 ). for tgfβ1 production assay hdfs were plated into 96 well clear tissue - culture treated plates ( falcon ) at 19 , 000 cells / well in dmem ( gibco ) 1 × n2 / b27 supplement ( invitrogen ). on the next day cells were treated with the small molecule library ( torcris 1120 biologically active compounds ) at 2 . 5 μm final concentration . after 3 days of treatment , supernatants were collected and analyzed for tgfμ1 content using tgfμ1 human elisa kit ( abeam ) and with biotek synergy 2 multi - detection microplate reader ( see fig1 ). from the high - throughput screening assay for tgfβ1 production assay it was found that proxyfan oxalate ( histamine h 3 receptor signaling agonist ) at concentration of 24 nm , m - 3m3fbs ( phospholipase c signaling ) at concentration of 24 nm , kb - r7943 mesylate at concentration of 1 . 6 μm and ly294002 hydrochloride at concentration of 98 nm induced the highest production level of tgfμ1 in hdfs ( see fig4 ). for egf production assay hdfs were plated into 96 well clear tissue - culture treated plates ( falcon ) at 19 , 000 cells / well in dmem ( gibco ) 1 × n2 / b27 supplement ( invitrogen ). on the next day cells were treated with the small molecule library ( torcris 1120 biologically active compounds ) at 2 . 5 μm final concentration . after 3 days of treatment , supernatants were collected and analyzed for egf content using egf human elisa kit ( abeam ) and with biotek synergy 2 multi - detection microplate reader ( see fig1 ). from the high - throughput screening assay for egf production assay it was found that cd 437 and cd 1530 ( retinoid rar signaling agonists ) at concentrations of 25 and 12 . 5 μm , cy 208 - 243 ( dopamine d1 receptor agonist ) at concentrations of 12 . 5 μm and psb 06126 ( ntpdase 3 antagonist ) at concentration of 12 . 5 μm , induced the highest production level of egf in hdfs ( see fig5 ). for collagen type 1 production assay hdfs were plated into 96 well clear tissue - culture treated plates ( falcon ) at 5 , 000 cells / well in dmem ( gibco ) 1 × n2 supplement ( invitrogen ). on the next day cells were treated with the small molecule library ( torcris 1120 biologically active compounds ) at 2 . 5 μm final concentration . after 3 days of treatment , supernatants were collected and analyzed for collagen type 1 content using procollagen type 1c - peptide eia kit ( takara ) and with biotek synergy 2 multi - detection microplate reader ( see fig1 ). from the high - throughput screening assay for collagen type 1 assay it was found that dipyridamole ( adenosine transport inhibitor ) at concentration of 390 nm , methyllycaconitine citrate ( α7 neuronal nicotinic receptor antagonist ) at concentration of 390 nm , cilostazol ( pde3a antagonist ) at concentration of 6 . 25 μm , clemastine fumarate ( h4 receptor antagonist ) at concentration of 780 nm and win 64338 ( bradykinin b2 receptor antagonist ) at concentration of 97 . 5 nm induced the highest production level of egf in hdfs ( see fig1 ). although the invention has been described with reference to the above example , it will be understood that modifications and variations are encompassed within the spirit and scope of the invention . accordingly , the invention is limited only by the following claims .

provided herein are small molecules for the induction of fibroblast proliferation and increased secretion or production of proteins . the small molecules described herein can be used for the promotion of skin regeneration . also provided herein are methods for promoting skin regeneration and wound healing .

the outer layer portion of the coat - core tablet of the present invention is a sustained release matrix layer and contains compound i and a gel - forming water - soluble polymer . the outer layer portion may contain the gel - forming water - soluble polymer in an amount of 16 % ( w / w ) or more , preferably in an amount of 18 % ( w / w ) or more , more preferably in the range of 20 to 60 % ( w / w ), further preferably 20 to 55 % ( w / w ), and further more preferably 35 to 45 % ( w / w ) with respect to the weight of the outer layer portion . when the content of the water - soluble polymer is 15 % ( w / w ) or lower , the outer layer portion is rapidly eroded and disintegrated at a ph value higher than neutral and the dissolution rate of compound i is elevated , resulting in occasional occurrence of burst , which is not preferable . when the content is within the above - mentioned range , erosion or disintegration of the outer layer portion is insusceptible to the influence of mechanical disintegration force such as peristaltic movements of the digestive tract and eating and changes in ph in the digestive tract so that compound i can be released at a constant rate . a water - insoluble polymer having an effect of suppressing disintegration may be added at that time , but it is preferable not to add such a polymer . the gel - forming water - soluble polymer is a water - soluble polymer that swells and becomes gel upon contact with water , and includes , for example , hydroxypropylcellulose , hydroxypropylmethylcellulose , carmellose , carmellose sodium , methylcellulose , hydroxyethylcellulose , hydroxyethylmethylcellulose , pregelatinized starch , sodium alginate , gelatin , agar , tragacanth , xanthan gum , guar gum , gum arabic , carrageenan , carboxy vinyl polymer , polyethylene oxide , vinyl acetate povidone polymer matrix , polyvinyl alcohol , polyvinylpyrrolidone , pullulan , sodium polyacrylate , and polyoxyethylene ( 160 ) polyoxypropylene ( 30 ) glycol , which may be used singly or in combination of two or more . among the gel - forming water - soluble polymers described above , hydroxypropylcellulose , hydroxypropylmethylcellulose methylcellulose , sodium alginate , carboxyvinyl polymer , and carmellose sodium are preferable , and hydroxypropylmethylcellulose , hydroxypropylcellulose , sodium alginate , carboxyvinyl polymer , and carmellose sodium are more preferable , and hydroxypropylmethylcellulose is particularly preferable . sodium alginate having a grade of about 900 to about 1 , 110 mpa · s in terms of a viscosity of a 1 % ( w / v ) aqueous solution at 20 ° c . at ph 6 . 4 - 7 . 0 measured by bl type cylinder rheometer may be preferably used . carboxyvinyl polymer having a grade of about 4 , 000 to about 11 , 000 mpa · s or that of about 29 , 400 to about 39 , 400 in terms of a viscosity of a 0 . 5 % ( w / v ) aqueous solution at ph 7 . 5 specified by the viscosity testing method for carboxyvinyl polymer of japanese pharmaceutical excipients can be use and that of about 29 , 400 to about 39 , 400 in terms of a viscosity of a 0 . 5 % ( w / v ) aqueous solution at ph 7 . 5 is preferable . carmellose sodium having a grade of about 320 mpa · s in terms of a viscosity of a 1 % ( w / w ) aqueous solution measured by b type rheometer may be preferably used . hydroxypropylcellulose having a grade of about 150 to about 400 mpa · s or that of about 1 , 000 to about 4 , 000 in terms of a viscosity of a 2 % ( w / w ) aqueous solution may be preferably used singly or in combination of the two at any weight ratio . there are various viscosity grades of hydroxypropylmethylcellulose determined by the hypromellose viscosity test of the japanese pharmacopoeia . as regards the viscosity grade of hydropropylmethylcellulose in the outer layer portion , a grade of about 40 to 60 mpa · s , or a grade of about 80 to about 120 mpa · s , or a grade of about 320 to about 480 mpa s , or a grade of about 3 , 000 to about 5 , 600 mpa · s , or a grade of about 7 , 500 to about 14 , 000 mpa · s , or a grade of about 11 , 250 to about 21 , 000 mpa · s , or a grade of about 75 , 000 to about 140 , 000 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c . may be used . hydroxypropylmethylcellulose having any of these viscosity grades may be used singly or multiple types of hydroxypropylmethylcellulose having these viscosity grades may be mixed at any weight ratio and incorporated in the outer layer portion . desirably , however , it is preferable to use hydroxypropylmethylcellulose having a grade of about 40 to 60 mpa · s , or a grade of about 80 to about 120 mpa · s , or a grade of about 320 to about 480 mpa · s , or a grade of about 3 , 000 to about 5 , 600 mpa · s , or a grade of about 7 , 500 to about 14 , 000 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c . ; more preferably to use hydroxypropylmethylcellulose having a grade of about 40 to 60 mpa · s , or a grade of about 80 to about 120 mpa · s , or a grade of about 320 to about 480 mpa · s , or a grade of about 3 , 000 to about 5 , 600 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c . ; further more preferably to use hydroxypropylmethylcellulose having a grade of about 80 to about 120 mpa · s or a grade of about 3 , 000 to about 5 , 600 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c ., which can be used singly or mixed at any weight ratio and incorporated in the outer layer portion . desirably , the outer layer portion contains hydroxypropylmethylcellulose having a grade of about 80 to about 120 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c . in an amount of 16 % ( w / w ) or more , preferably in an amount of 18 % ( w / w ) or more , more preferably in the range of 20 to 60 % ( w / w ), further preferably 20 to 55 % ( w / w ), and further more preferably 35 to 45 % ( w / w ) with respect to the weight of the outer layer portion ; or hydroxypropylmethylcellulose having a grade of about 80 to about 120 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c . in an amount of 8 % ( w / w ) or more , preferably in an amount of 9 % ( w / w ) or more , more preferably in the range of 10 to 30 % ( w / w ), further preferably 10 to 27 . 5 % ( w / w ), and further more preferably 17 . 5 to 22 . 5 % ( w / w ) with respect to the weight of the outer layer portion in mixture with hydroxypropylmethylcellulose having a grade of about 3 , 000 to about 5 , 600 mpa · s in terms of a viscosity of a 2 % ( w / w ) aqueous solution at 20 ° c . in an amount of 8 % ( w / w ) or more , preferably in an amount of 9 % ( w / w ) or more , more preferably in the range of 10 to 30 % ( w / w ), further preferably 10 to 27 . 5 % ( w / w ), and further more preferably 17 . 5 to 22 . 5 % ( w / w ) with respect to the weight of the outer layer portion . the final composition of the gel - forming water - soluble polymer ( s ) used in the outer layer portion in terms of the type and viscosity grade is desirably adjusted to achieve the dissolution rates of compound i determined by the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket as follows : 5 to 30 %, preferably 5 to 25 %, more preferably 10 to 20 % at 60 minutes later , 25 to 55 %, preferably 30 to 50 %, more preferably 35 to 45 % at 150 minutes later , 70 % or higher , preferably 80 % or higher , more preferably 85 % at 240 minutes later ; or to achieve the dissolution rates of compound i determined by the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket as follows : 5 to 30 %, preferably 5 to 25 %, more preferably 10 to 20 % at 120 minutes later , 25 to 55 %, preferably 30 to 50 %, more preferably 35 to 45 % at 300 minutes later , 70 % or higher , preferably 80 % or higher , more preferably 85 % or higher at 480 minutes later . the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket used in the present specification was conducted under the following conditions : test fluid : 900 ml of diluted mcilvaine buffer at ph 6 . 0 stationary basket : a 40 - mesh basket is fixed at the position in the middle between the surface of a test fluid and the bottom of a vessel and about 23 mm from the side wall of a vessel of the dissolution test fluid . the water - insoluble polymer that is a molecule having an effect of suppressing disintegration includes , for example , ethylcellulose , cellulose acetate , aminoalkyl methacrylate copolymers rs , polylactic acid , and polyglycolic acid . further , the outer layer may contain , in addition to the gel - forming water - soluble polymer , as required , for example , sugars such as lactose , white sugar , glucose , fructose , trehalose , mannitol , sorbitol , xylitol , maltitol , and erythritol ; starches , such as wheat starch , corn starch , potato starch , partly pregelatinized starch , dextrin , hydroxypropyl starch , and carboxymethyl starch ; celluloses such as microcrystalline cellulose ; inorganic salts such as light anhydrous silicic acid , synthetic aluminum silicate , magnesium aluminometasilicate , and calcium phosphate ; fats and oils such as paraffin , waxes , and higher fatty acids ; disintegrants such as carmellose , carmellose sodium , croscarmellose sodium , carmellose calcium , starches , crospovidone , low - substituted hydroxypropylcellulose , microcrystalline cellulose , and powder cellulose ; binders such as hydroxypropylcellulose and polyvinylpyrrolidone ; fluidizers or lubricants such as magnesium stearate , calcium stearate , talc , and synthetic aluminum silicate ; colorants such as various pigments ; and dissolution aids such as various surfactants ; and the like . the release rate of compound i from the inner core of the coat - core tablet of the present invention is preferably higher than that from the outer layer portion . although ingredients contained in the inner core are not particularly limited , the inner core is preferably a tablet containing compound i and a disintegrant or a tablet containing compound i and a gelling agent . the disintegrants contained in the inner core are substances that disintegrate the inner core rapidly with a small volume of water to allow release of compound i . the properties of disintegrating the inner core rapidly with a small volume of water refer to such properties that when an inner core ( diameter 2 to 9 mm ) is immersed in 1 ml of the 2nd fluid ( ph 6 . 8 ) of the dissolution test of the japanese pharmacopoeia at 37 ° c ., the inner core is disintegrated and dispersed within 10 minutes , preferably within 5 minutes . the properties that allow rapid release of a drug is , for example , such properties that when an inner core is subjected to the dissolution test by the paddle method of the japanese pharmacopoeia ( test fluid : 900 ml of the 2nd fluid for the dissolution test of the japanese pharmacopoeia , temperature : 37 ° c ., rotation number : 50 rotations / minute ), the drug dissolution rate of 80 % is achieved within 20 minutes , preferably within 15 minutes , more preferably within 10 minutes . as the disintegrants , for example , carmellose , carmellose sodium , croscarmellose sodium , carmellose calcium , low - substituted hydroxypropylcellulose , starches such as carboxymethyl starch sodium , partly pregelatinized starch , pregelatinized starch , crospovidone , and the like may be used singly or in combination of two or more . among the disintegrants described above , carboxymethyl starch sodium , partly pregelatinized starch , and croscarmellose sodium are preferable , and croscarmellose sodium is particularly preferable . the inner core may contain the disintegrants in an amount in the range of 1 to 50 % ( w / w ), preferably 1 to 30 % ( w / w ), more preferably 1 to 20 % ( w / w ) with respect to the weight of the inner core . the inner core may contain , in addition to the disintegrants , as required , for example , sugars such as lactose , white sugar , glucose , fructose , trehalose , mannitol , sorbitol , xylitol , maltitol , and erythritol ; starches such as wheat starch , corn starch , potato starch , partly pregelatinized starch , dextrin , hydroxypropyl starch , and carboxymethyl starch ; celluloses such as microcrystalline cellulose ; inorganic salts such as light anhydrous silicic acid , synthetic aluminum silicate , magnesium aluminometasilicate , and calcium phosphate ; fats and oils such as paraffin , waxes , and higher fatty acids ; binders such as hydroxypropylcellulose and polyvinylpyrrolidone ; fluidizers or lubricants such as magnesium stearate , calcium stearate , talc , and synthetic aluminum silicate ; colorants such as various pigments ; dissolution aids such as various surfactants ; and the like . the gelling agent contained in the inner core is a substance that is gelled rapidly with a small amount of water . the properties of gelling rapidly with a small amount of digestive juice or water is , for example , such properties that when an inner core with a diameter of 6 mm ( 8r tablet ), a thickness of 3 . 4 mm , and a mass of 100 mg is immersed in 1 ml of the 2nd fluid of the dissolution test of the japanese pharmacopoeia at 37 ° c ., the inner core is completely gelled within 1 hour , preferably within 45 minutes ; or when an inner core with a diameter of 5 mm ( flat tablet ), a thickness of 2 . 0 mm , and a mass of 50 mg is immersed in 1 ml of the 2nd fluid of the dissolution test of the japanese pharmacopoeia at 37 ° c ., the inner core is completely gelled within 45 minutes , preferably with 30 minutes . as the gelling agent , for example , the gel - forming water - soluble polymer used for the outer layer described above may be used . for example , hydroxypropylcellulose , hydroxypropylmethylcellulose , carmellose , carmellose sodium , methylcellulose , hydroxyethylcellulose , hydroxyethylmethylcellulose , pregelatinized starch , sodium alginate , gelatin , agar , tragacanth , xanthan gum , guar gum , gum arabic , carrageenan , carboxy vinyl polymer , polyethylene oxide , vinyl acetate povidone polymer matrix , polyvinyl alcohol , polyvinylpyrrolidone , pullulan , sodium polyacrylate , polyoxyethylene ( 160 ) polyoxypropylene ( 30 ) glycol , and the like may be used singly or in combination of two or more . among the gelling agents described above , sodium alginate , carmellose sodium , and carboxy vinyl polymer are preferable , and carboxy vinyl polymer is particularly preferable . carboxy vinyl polymer having a grade of viscosity of about 4 , 000 to 11 , 000 mpa · s or a grade of viscosity of about 29 , 400 to 39 , 400 mpa · s , as a viscosity grade defined by the viscosity test for carboxy vinyl polymer in accordance with the japanese pharmaceutical excipients in terms of a 0 . 5 % ( w / v ) aqueous solution at ph 7 . 5 , may be used in the present invention , and it is preferable to use carboxy vinyl polymer of a grade of viscosity of about 29 , 400 to 39 , 400 mpa · s in terms of a 0 . 5 % ( w / v ) aqueous solution at ph 7 . 5 . the inner core can contain the gelling agent in an amount in the range of 5 to 50 % ( w / w ), preferably 5 to 40 % ( w / w ), more preferably 5 to 30 % ( w / w ) with respect to the weight of the inner core . the inner core may contain , in addition to the gelling agents , as required , for example , sugars such as lactose , white sugar , glucose , fructose , trehalose , mannitol , sorbitol , xylitol , maltitol , and erythritol ; starches such as wheat starch , corn starch , potato starch , partly pregelatinized starch , dextrin , hydroxypropyl starch , and carboxymethyl starch ; celluloses such as microcrystalline cellulose ; inorganic salts such as light anhydrous silicic acid , synthetic aluminum silicate , magnesium aluminometasilicate , and calcium phosphate ; fats and oils such as paraffin , waxes , and higher fatty acids ; disintegrants such as carmellose , carmellose sodium , croscarmellose sodium , carmellose calcium , starches , crospovidone , low - substituted hydroxypropylcellulose , microcrystalline cellulose , and powder cellulose ; binders such as hydroxypropylcellulose and polyvinylpyrrolidone ; fluidizers or lubricants such as magnesium stearate , calcium stearate , talc , and synthetic aluminum silicate ; colorants such as various pigments ; dissolution aids such as various surfactants ; and the like . the coat - core tablet comprising the inner core and the outer layer portion having the above compositions can be manufactured by the method known per se . the inner core may be obtained by conventional methods such as direct compression , granulation compression , or pill making . the outer layer portion may also be obtained by conventional methods such as wet granulation or dry granulation . the coat - core tablet may be manufactured by coating the inner core with the outer layer portion using a dry coater tablet press . the diameter of the coat - core tablet of the present invention is not particularly limited , as far as the tablet can be administered orally and swallowed . the diameter of the coat - core tablet is generally in the range of 4 to 12 mm , and the diameter of the inner core is generally in the range of 2 to 9 mm . the weight ratio of the outer layer portion to the inner layer of the coat - core tablet of the present invention is not particularly limited , although the ratio affects the thickness of the outer layer of the coat - core tablet formed . the weight ratio of the outer layer portion to the inner core can be selected from the range of 10 / 90 to 95 / 5 , more preferably 20 / 80 to 95 / 5 , further more preferably 30 / 70 to 95 / 5 . the outer layer portion must have a certain thickness in order to avoid erosion of the inner core and the thickness is preferably 1 mm or more , and more preferably 1 . 5 mm or more . desirably , the final weight ratio of the outer layer to the inner core is determined by adjusting the thickness of the outer layer portion so that the dissolution rates of compound i at a given time after the start of the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket are : 5 to 30 %, preferably 5 to 25 %, more preferably 10 to 20 % at 60 minutes , 25 to 55 %, preferably 30 to 50 %, more preferably 35 to 45 % at 150 minutes , 70 % or higher , preferably 80 % or higher , more preferably 85 % or higher at 240 minutes ; or by adjusting the thickness of the outer layer portion so that the dissolution rates of compound i by the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket are : 5 to 30 %, preferably 5 to 25 %, more preferably 10 to 20 % at 120 minutes , 25 to 55 %, preferably 30 to 50 %, more preferably 35 to 45 % at 300 minutes , 70 % or higher , preferably 80 % or higher , more preferably 85 % or higher at 480 minutes ; and the final weight ratio of the outer layer portion to the inner core is determined based on the thickness of the outer layer portion and the size and weight of the whole coat - core tablet . the final weight ratio of compound i contained in the outer layer portion to compound i contained in the inner core in the coat - core tablet of the present invention is not particularly limited , although the ratio affects the amount of a drug absorbed in the upper digestive tract ( the stomach and the small intestine ) and in the lower digestive tract ( the colon ). the weight ratio can be determined appropriately depending on the weight and the size , the weight ratio of the outer layer portion to the inner core , the manufacturing processability of the outer layer portion and the inner core , and the like of the coat - core tablet . the weight ratio of compound i contained in the outer layer portion to compound i contained in the inner core may be in the range of 5 / 95 to 95 / 5 , preferably 10 / 90 to 95 / 5 , further more preferably 15 / 85 to 95 / 5 . the weight ratio of compound i contained in the outer layer portion to compound i contained in the inner core is preferably adjusted so that the dissolution rates of compound i at a given time after the start of the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket are : 5 to 30 %, preferably 5 to 25 %, more preferably 10 to 20 % at 60 minutes , 25 to 55 %, preferably 30 to 50 %, more preferably 35 to 45 % at 150 minutes , 70 % or higher , preferably 80 % or higher , more preferably 85 % or higher at 240 minutes ; or so that the dissolution rates of compound i by the dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket are : 5 to 30 %, preferably 5 to 25 %, more preferably 10 to 20 % at 120 minutes , 25 to 55 %, preferably 30 to 50 %, more preferably 35 to 45 % at 300 minutes , 70 % or higher , preferably 80 % or higher , more preferably 85 % or higher at 480 minutes . the characteristics of compound i incorporated in the outer layer portion of the coat - core tablet of the present invention are not particularly limited ; however , compound i is preferably a drug having an average particle diameter as determined by an image analysis or by a particle size distribution measurement by using laser diffraction scattering ( the median of a diameter in terms of volume conversion in the case of the measurement of particle size distribution by laser diffraction scattering ) of 5 . 0 μm or more , further preferably of 8 . 0 μm or more . when the average particle diameter is smaller than 5 . 0 μm , the dissolution rate of compound i is increased and the dissolution rate from the outer layer portion , especially that at a ph value higher than neutral becomes high , and as a result , it is sometimes difficult to release compound i at a constant rate in the digestive tract in the region from the stomach to the lower part of the small intestine . further , the characteristics of compound i incorporated in the inner core of the coat - core tablet of the present invention are not particularly limited , but compound i is preferably finely milled crystals . the average particle diameter as determined by an image analysis or by a particle size distribution measurement by using laser diffraction scattering ( the median of a diameter in terms of volume conversion in the case of the measurement of particle size distribution by laser diffraction scattering ) is preferably 0 . 1 to 8 . 0 μm , more preferably 1 . 0 to 8 . 0 μm , further preferably 1 . 0 to 5 . 0 μm . the inner core may be subjected to film coating before it is coated by the outer layer portion . the film coating agents include , for example , cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose ; water - soluble coating substrates such as polyvinyl alcohol and polyvinyl alcohol copolymer ; cellulose derivative enteric coating substrates such as hydroxypropylmethylcellulose phthalate , hydroxypropylmethylcellulose acetate succinate , carboxymethylethylcellulose , and cellulose acetate phtalate ; and enteric film coating substrates such as methacrylic acid copolymers and shellac . the coat - core tablet may be further provided with a water - soluble film coating . as the film coating substrates , it is suitable to use hydroxypropylmethylcellulose preferably with a viscosity of 100 mpa · s or lower , particularly preferably with a viscosity of 17 . 5 mpa · s or lower in terms of a 2 % ( w / w ) aqueous solution at 20 ° c . these film coating substrates may contain , as required , plasticizers such as polyethylene glycol , fluidizers such as talc , and colorants such as various pigments . the drug applied to the coat - core tablet of the present invention includes , in addition to compound i , xanthine oxidase inhibitors , and further 2 - arylthiazole derivatives including compound i . the amount of the drug contained in one coat - core tablet of the present invention is not particularly limited , but 5 mg to 200 mg , preferably 5 mg to 160 mg of the drug may be contained . when the coat - core tablet of the present invention is administered to a human , compound i preferably exhibits pharmacokinetics in the blood satisfying the following ( a ), ( b ), and ( c ): ( a ) the plasma concentration of compound i at the second peak in the plasma concentration - time profile is 0 . 2 μg / ml or higher , or the plasma concentration at 24 hours after administration is 0 . 05 μg / ml or higher , in 80 mg dose of compound i ; ( b ) the maximum blood concentration ( cmax ) of compound i is less than 2 . 0 μg / ml . more preferably , the maximum blood concentration ( cmax ) is 0 . 8 to 2 . 0 μg / ml , or the maximum blood concentration ( cmax ) is 0 . 3 to 0 . 8 μg / ml , in 80 mg dose of compound i ; ( c ) the ratio of the area under the plasma concentration - time curve from time zero to time infinity ( auc ∞ ( ng · hr / ml )) to the maximum blood concentration ( cmax ( ng / ml )), auc ∞: cmax , is 5 . 0 : 1 to 20 : 1 . more preferably , the ratio of the area under the plasma concentration - time curve from time zero to time infinity ( aucco ( ng · hr / ml )) to the maximum blood concentration ( cmax ( ng / ml )), auc ∞: cmax , is 5 . 0 : 1 to 7 . 5 : 1 , or the ratio of the area under the plasma concentration - time curve from time zero to time infinity ( aucoo ( ng · hr / ml )) to the maximum blood concentration ( cmax ( ng / ml )), auc ∞: cmax , is 7 . 5 : 1 to 15 . 0 : 1 , in 80 mg dose of compound i . examples of the present invention will be described below . the present invention is not limited by the following examples , however . here , compound i , incorporated in the outer layer portion , having an average particle diameter ( the median of a diameter calculated by volume conversion in the measurement of particle size distribution by laser diffraction scattering ) of 8 . 0 μm or more was used , and compound i , incorporated in the inner core , having an average particle diameter ( the median of a diameter calculated by volume conversion in the measurement of particle size distribution by laser diffraction scattering ) of 1 . 0 to 5 . 0 μm was used . metolose 90sh - 100sr , metolose 90sh - 4000sr , and metolose 90sh - 100000sr are the trade names of shin - etsu chemical co ., ltd ., and refer to hydroxypropylmethylcellulose 2208 of viscosity grades of about 80 to about 120 mpa · s , about 3 , 000 to about 5 , 600 mpa · s , and about 75 , 000 to about 140 , 000 mpa · s , respectively , in terms of a 2 % ( w / w ) aqueous solution at 20 ° c . metolose 60sh - 50 and tc - 5r are the trade names of shin - etsu chemical co ., ltd ., and refer to hydroxypropylmethylcellulose 2910 of viscosity grades of about 40 to about 60 mpa · s and about 5 . 2 to about 7 . 0 mpa · s , respectively , in terms of a 2 % ( w / w ) aqueous solution at 20 ° c . eudragit rspo is the trade name of evonik degussa japan co ., ltd ., and refers to an aminoalkyl methacrylate copolymer rs . opadry ii green is the trade name of colorcon japan llc ., and is a premixed additive to which an additive for water - soluble film coating is mixed in advance . as hydroxypropylcellulose , hydroxypropylcelluloses of nippon soda co ., ltd ., of viscosity grades of about 3 . 0 to about 5 . 9 mpa · s ( hpc - sl ), about 6 . 0 to about 10 . 0 mpa · s ( hpc - l ), and about 150 to about 400 mpa · s ( hpc - m ) in terms of 2 % ( w / w ) aqueous solution at 20 ° c . were used . the above - described raw materials were mixed homogeneously , and the mixture was granulated by fluidized bed granulation , then dried , and subjected to particle size regulation . to 97 . 0 % ( w / w ) of the powder obtained , 2 . 0 % ( w / w ) of croscarmellose sodium and 1 . 0 % ( w / w ) of magnesium stearate were added and mixed . the mixture was subjected to tabletting by a rotary tabletting machine ( ht - ap6ss - u ; hata iron works co ., ltd .) under a compression force of about 550 kg to obtain inner cores ( diameter : 6 mm , thickness : 3 . 2 mm ), each tablet having a mass of 100 mg . the above - described raw materials were mixed , and the mixture was granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . this composition was used for the outer layer portion , and tabletted together with the inner core previously prepared by a dry coater tablet press ( libra 45dc ; kikusui seisakusho ltd .) under a compression force of about 1 ton to obtain coat - core tablets ( diameter : 10 mm , thickness : 6 . 5 mm ), each tablet having a mass of 502 mg and containing 80 mg of compound i . the above - described raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . the mixture was tabletted by a rotary tabletting machine ( ht - ap6ss - u ; hata iron works co ., ltd .) under a compression force of about 350 kg to obtain inner cores ( diameter : 6 mm , thickness : 3 . 4 mm ), each tablet having a mass of 100 . 5 mg . the above - described raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . this composition was used for the outer layer portion and tabletted together with the inner core previously prepared by a dry coater tablet press ( libra 45dc ; kikusui seisakusho ltd .) under a compression force of about 1 ton to obtain coat - core tablets ( diameter : 10 mm , thickness : 6 . 5 mm ), each tablet containing 80 mg of compound i and having a mass of 502 . 5 mg . the above - described raw materials were mixed homogenously , granulated by fluidized bed granulation , then dried , and subjected to particle size regulation . to 97 . 0 % ( w / w ) of the powder obtained , 2 . 0 % ( w / w ) of croscarmellose sodium and 1 . 0 % ( w / w ) of magnesium stearate were added and mixed . the mixture was tabletted by a rotary tabletting machine ( ht - ap6ss - u ; hata iron works co ., ltd .) under a compression force of about 550 kg to obtain inner cores ( diameter : 6 mm , thickness : 3 . 2 mm ), each tablet having a mass of 100 mg . the above - described raw materials were mixed homogenously and granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . this composition was used for the outer layer portion and tabletted together with the inner core previously prepared by a dry coater tablet press ( libra 45dc ; kikusui seisakusho ltd .) under a compression force of about 1 ton to obtain coat - core tablets ( diameter : 10 mm , thickness : 6 . 5 mm ), each tablet containing 80 mg of compound i and having a mass of 502 mg . the above - described raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . the mixture was tabletted by a rotary tabletting machine ( ht - ap6ss - u ; hata iron works co ., ltd .) under a compression force of about 350 kg to obtain inner cores ( diameter : 6 mm , thickness : 3 . 4 mm ), each tablet having a mass of 100 . 5 mg . the above - described raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . this composition was used for the outer layer portion and tabletted together with the inner core previously prepared by a dry coater tablet press ( libra 45dc ; kikusui seisakusho ltd .) under a compression force of about 1 ton to obtain coat - core tablets ( diameter : 10 mm , thickness : 6 . 5 mm ), each tablet containing 80 mg of compound i and having a mass of 502 . 5 mg . compound i , lactose monohydrate , microcrystalline cellulose , hydroxypropylcellulose , and croscarmellose sodium shown in table 9 were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , magnesium stearate and silicon dioxide were added and mixed , and the mixture was subjected to compression molding with oval - shaped punches and dies to obtain tablets , each tablet having a weight of 500 mg . this tablet was coated with opadry ii to obtain a coated tablet of 520 mg . the coat - core tablet of example 1 was subjected to a dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket . the conditions of the test were as follows : test fluid : 900 ml of diluted mcllvaine buffer at ph 6 . 0 stationary basket : a 40 - mesh basket was fixed at the position in the middle between the surface of a test fluid and the bottom of the vessel and about 23 mm from the side wall of a vessel of the dissolution test fluid . as shown in fig1 , the dissolution profile was confirmed in which compound i was dissolved from the outer layer portion at a constant rate up to 3 to 4 hours after the start of the test and then the inner core was exposed and dissolution of compound i from the inner core was started . the coat - core tablet of example 2 was subjected to a dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket . the conditions of the test were as follows : test fluid : 900 ml of diluted mcllvaine buffer at ph 6 . 0 stationary basket : a 40 - mesh basket was fixed at the position in the middle between the surface of s test fluid and the bottom of the vessel and about 23 mm from the side wall of a vessel of the dissolution test fluid . as shown in fig2 . the dissolution profile was confirmed in which compound i was dissolved from the outer layer portion at a constant rate up to 3 to 4 hours after the start of the test and then the inner core was exposed and dissolution of compound i from the inner core was started the coat - core tablet of example 3 was subjected to a dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket . the conditions of the test were as follows : test fluid : 900 ml of diluted mcllvaine buffer at ph 6 . 0 stationary basket : a 40 - mesh basket was fixed at the position in the middle between the surface of a test fluid and the bottom of a vessel and about 23 mm from the side wall of a vessel of the dissolution test fluid . as shown in fig3 , the dissolution profile was confirmed in which compound i was dissolved from the outer layer portion at a constant rate up to 6 to 7 hours after the start of the test and then the inner core was exposed and dissolution of compound i from the inner core was started . the coat - core tablet of example 4 was subjected to a dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket . the conditions of the test were as follows : test fluid : 900 ml of diluted mcllvaine buffer at ph 6 . 0 stationary basket : a 40 - mesh basket was fixed at the position in the middle between the surface of a test fluid and the bottom of a vessel and about 23 mm from the side wall of a vessel of the dissolution test fluid . as shown in fig4 , the dissolution profile was confirmed in which compound i was dissolved from the outer layer portion at a constant rate by 6 to 7 hours after the start of the test and then the inner core was exposed and dissolution of compound i from the inner core was started . the above - described raw materials were mixed homogenously , granulated by fluidized bed granulation , then dried , and subjected to particle size regulation . to 97 . 0 % ( w / w ) of the powder obtained , 2 . 0 % ( w / w ) of croscarmellose sodium and 1 . 0 % ( w / w ) of magnesium stearate were added and mixed . the mixture was tabletted by a rotary tabletting machine ( ht - ap6ss - u ; hata iron works co ., ltd .) under a compression force of about 550 kg to obtain inner cores ( diameter : 6 mm , thickness : 3 . 2 mm ), each tablet having a mass of 100 mg . the inner core was subjected to a dissolution test by the paddle method of the dissolution test of the japanese pharmacopoeia . the conditions of the test were as follows : test fluid : 900 ml of the 2nd fluid for dissolution test of the japanese pharmacopoeia number of rotation : 50 rotations / minute as shown in fig5 , it was confirmed that 80 % or more of compound i was dissolved within 10 minutes after the start of the test . the above - described raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . the mixture was tabletted by a rotary tabletting machine ( ht - ap6ss - u ; hata iron works co ., ltd .) under a compression force of 350 kg to obtain inner core 1 having the size shown below . inner core 1 : a tablet having a mass of 100 mg , a diameter of 6 mm 8r , and a thickness of 3 . 4 mm in addition , inner core 2 having the size shown below was manufactured using a simple tablet forming machine ( hand press ) under a compression force of 400 kg . inner core 2 : a tablet having a mass of 50 mg , with a form of plane disk having a diameter of 5 mm and a thickness of 2 . 0 mm . to a 12 - well plate for cell culture , 1 ml / well of a test fluid ( the 2nd fluid for dissolution test of the japanese pharmacopoeia ) at 37 ° c . was charged , and one tablet of the inner core 1 or inner core 2 was placed in each well and incubated at 37 ° c . the inner cores were removed at predetermined timings and cut by a cutter to obtain a cross section , which was observed visually for gellation . it was confirmed that the inner cores 1 and 2 were completely gelled at 40 and 30 minutes , respectively , after the test fluid was added . the above - listed raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . 150 mg of this composition was subjected to compression molding using a simple tablet forming machine ( hand press ) to obtain a tablet having a diameter of 7 mm and a hardness of about 6 kgf and containing only the outer layer portion ingredients . these outer layer portion tablets 1 to 4 were subjected to a disintegration test in accordance with the disintegration test of the japanese pharmacopoeia . the conditions of the test were as follows : 900 ml of the 2nd fluid for dissolution test of the japanese pharmacopoeia ( ph 6 . 8 ), or one table was placed in a sinker for the dissolution test of the japanese pharmacopoeia and charged in a disintegration test machine . the above - listed raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . 150 mg of this composition was subjected to compression molding using a simple tablet forming machine ( hand press ) to obtain a tablet having a diameter of 7 mm and a hardness of about 6 kgf and containing only the outer layer portion ingredients . these placebo tablets 1 to 4 were subjected to a disintegration test in accordance with the dissolution test of the japanese pharmacopoeia . the conditions of the test were as follows : 900 ml of the 2nd fluid for dissolution test of the japanese pharmacopoeia ( ph 6 . 8 ), or one table was placed in a sinker for the dissolution test of the japanese pharmacopoeia and charged in a disintegration test machine . the results show that the disintegration times of the outer layer portion tablet 2 and the outer layer portion tablet 4 were markedly influenced by ph , and the disintegration time was short at ph 7 . 4 and varied among the tablets as shown in fig6 . as shown in fig7 , on the other hand , the disintegration times of the placebo tablets were not influenced by ph for any of the formulations . from the above results , it was confirmed that , when the content of hydroxypropylmethylcellulose in the outer layer portion containing compound i was low , the disintegration of the tablet was faster , the sustainability of the tablet was lost and the variation of disintegration among the tablets became larger with the increase in ph . the above - listed raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . 150 mg of this composition was subjected to compression molding using a simple tablet forming machine ( hand press ) to obtain a tablet having a diameter of 7 mm and a hardness of about 6 kgf and containing only the outer layer portion ingredients . these outer layer portion tablets 5 to 7 were subjected to a disintegration test in accordance with the disintegration test of the japanese pharmacopoeia . the conditions of the test were as follows : 900 ml of the 2nd fluid for dissolution test of the japanese pharmacopoeia ( ph 6 . 8 ), or one table was placed in a sinker for the dissolution test of the japanese pharmacopoeia and charged in a disintegration test machine . the results show that the disintegration times of the outer layer portion tablet 5 and the outer layer portion tablet 6 were not influenced by ph . however , the disintegration time of the outer layer portion tablet 7 had a tendency to be longer at ph 7 . 4 than that of the outer layer portion tablet 5 and 6 at ph 7 . 4 as shown in fig8 . the above - listed raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . 502 mg of this composition was subjected to compression molding by a simple tablet forming machine ( hand press ) with a compression force shown below to obtain a tablet having a diameter of 10 mm and containing only the outer layer portion ingredients . hardness of the tablets obtained was measured using a tablet hardness tester ( toyama sangyo co ., ltd . ): compression forces : 6 kn , 9 kn , 12 kn , and 15 kn as a result , as shown in fig9 , the hardness was the highest for the outer layer portion tablet 8 containing 40 % of hydroxypropylmethylcellulose , followed by the outer layer portion tablet 9 containing 15 % of hydroxypropylmethylcellulose , and the lowest for the outer layer portion tablet 10 and the outer layer portion tablet 11 each containing 60 % of hydroxypropylmethylcellulose . from the above results , it was confirmed that the outer layer portion tablet containing 40 % of hydroxypropylmethylcellulose had better compression moldability than the outer layer portion tablets having hydroxypropylmethylcellulose contents other than 40 %. the above - listed raw materials were mixed homogenously , granulated by wet agitation granulation , then dried , and subjected to particle size regulation . to the powder obtained , 0 . 5 % ( w / w ) of magnesium stearate was added and mixed . 502 mg of this composition was subjected to compression molding by a simple tablet forming machine ( hand press ) to obtain a tablet having a diameter of 10 mm and a hardness of about 9 kgf and containing only the outer layer portion ingredients . the outer layer portion tablets 12 and 13 were subjected to a dissolution test using modified paddle method of the dissolution test of the japanese pharmacopoeia with a stationary basket . the conditions of the test were as follows : test fluid : 900 ml of the 2nd fluid for dissolution test ( ph 6 . 8 ) of the japanese pharmacopoeia stationary basket : an 8 - mesh basket was fixed at the position 23 mm from the side wall of a vessel of a dissolution test fluid , with the bottom of a basket being 1 cm from the upper side of the paddle . as a result , as shown in fig1 , the dissolution rate of compound i from the outer layer portion 12 was similar to that from the outer layer portion 13 at 50 rotations / minute . the dissolution rates of compound i from the outer layer portions 12 and 13 at 200 rotations / minute were faster than the dissolution rates at 50 rotations / minute in a similar degree . from the above results , it was confirmed that influence of mechanical load on dissolution was similar in the dissolution behavior for the outer layer portion tablet 12 and the outer layer portion tablet 13 . a total of 5 preparations , the coat - core tablets ( containing 80 mg of compound i ) of examples 1 , 2 , 3 and 4 and the tablet ( containing 80 mg of compound i ) of comparative example 1 , were administered orally to 35 healthy adults once daily under fasting in 5 separate periods by a cross - over method . the wash out period between the administration was 7 days . blood was collected from the subjects over time after administration , and the concentrations of compound i in the plasma were quantified . the graph showing the changes in the plasma concentration of compound i after administration of these preparations is shown in fig1 , and the pharmacokinetic parameters are shown in table 17 .

disclosed is a controlled release nucleated tablet which is composed of an inner nucleus and an outer layer that covers the inner nucleus and is capable of maintaining the level of 2 -- 4 - methyl - 5 - thiazolecarboxylic acid in the blood to a certain value or higher for a long period of time . the controlled release nucleated tablet is characterized in that the inner nucleus contains 2 -- 4 - methyl - 5 - thiazolecarboxylic acid and the outer layer contains 2 -- 4 - methyl - 5 - thiazolecarboxylic acid and a gel - forming water - soluble polymer that is in an amount of 16 % or more relative to the weight of the outer layer .

one aspect of the present invention is to include an indigestible carbohydrate such as insulin , oligofructoses , fructo - oligosaccharides , lactulose , galcto - oligosaccharides , xylo - oligosaccharides , resistant starches , in formula . in addition to offering food for species of bacteriodetes and selecting for their growth , production of short chain fatty acids ( scfas ) in the colon will suppress pathogenic bacteria and viruses from invading and colonizing the gi tract , partially inhibit hepatic cholesterol biosynthesis , serve as nutrients for colonocytes , reduce colon ph , increase mineral absorption , and serve as ligand to stimulate release of peptide yy ( pyy ) and glucagon - like peptide - 1 ( glp - 1 ) into the blood , pyy and glp - 1 are hormones produced and released from the colon into the blood , pyy signals satiety , glp - 1 stimulates the glucose sensing ability of the insulin secreting cell , prevents that cell from apoptosis , stimulates proliferation of those pancreatic beta cells and inhibits gastric emptying . glp - 1 also stimulates satiety but this may be due to its important role in decreasing gastric emptying . ghrelin is a hormone secreted by the stomach that stimulates appetite , ghrelin is unique because it must be acylated with a medium chain fatty acid ( mcfa ) on the 3rd residue to bind and trigger its receptor ( ghs - r1a ) ( 10 ). ghrelin comprised with octanoic ( c - 8 )- or decanoic ( c - 10 )- mcfas are the most common forms of active ghrelin ( 10 ). there are also circulating carboxylesterases that cleave the acyl bond linking the fatty acid to the ghrelin backbone and render ghrelin inactive ( 11 ) with respect to appetite and nutrient consumption but may be beneficial for the treatment of t2dm ( 12 ). the acylating enzyme in the stomach cell that synthesizes ghrelin was identified about 3 years ago ( 13 , 14 ) and is now a drug target for several groups . the enzyme termed goat ( ghrelin o - acyltransferase ), has a high affinity for mcfas but can acetylate ghrelin with fatty acids of different lengths . not only does goat prefer mcfas , but ghrelin that is acylated with a mcfa is much more potent than ghrelin forced to by synthesized with either a small or long chain fatty acid ( 15 ). interestingly , levels of circulating medium chain fatty acids at any time point are relatively low when compared to long chain fatty acids . this primarily a result of diet . modern diets and most foods are rich in long chain fatty acids , mcfas are abundant in coconut oil and human breast milk . short chain fatty acids ( scfas ) are also rarely in the food chain ; they can be found in small quantities in butter and coconut . however , they are produced in large quantities by the microflora in the colon on a byproduct of polysaccharide consumption by the microbiota of the bacteriodetes division . recent evidence indicates that goat can use a scfa to acylate ghrelin , rendering the hormone inactive at its receptor ( 16 ). thus , another novel aspect of the present invention is a formula designed to significantly enhance production of scfas by microbiota to serve as substrates for goat , render an inactive ghrelin and consequently decrease appetite . while aspects of the present invention are aimed at increasing the population of colonic microbiota that garners carbohydrates , there is the possibility of those microorganisms redirecting their carbohydrate - harvesting activities from dietary to host polysaccharides according to nutrient availability ( 7 ). the colon mucus layer comprised of mucins , which are glycoproteins that have o - linked oligosaccharides or o - glycans , which account for up to 80 % of the mass of mucin ( 17 ). the colon mucus layer covers the gastrointestinal epithelium where if provides a protective layer from the rich intestinal microbiome as well as any pathogens . such endogenous source of glycans in the microbiome habitat could offer alternative nutrients . however , when dietary glycans are present , it appears that harvesting energy from the diet is preferred ( 7 ). recently , evidence that bile salts are bacteriostatic to cecal microbiota was presented ( 24 ). moreover , the data indicate that microbiota of the bacteroidetes phylum are most sensitive to bile salts . secretion of bile salts into the intestinal tract is stimulated by fat ingestion . thus , ingestion of fat containing food increases bile secretion , which in turn decreases the numbers of bacteriodetes microbiota . viscous beta - glucan encapsulates or sequesters bile acids ( 25 ) and thus has the ability to preserve members of the bacteroidetes , even when fat is ingested . thus , an important aspect of the present invention includes dietary glycans . most are indigestible carbohydrates . since glycans are also in abundance in yeast walls , one source of dietary glycans is from yeast . other sources include dietary beta - glucan . bata - glucan is a natural polysaccharide that can be isolated from oat , barley and wheat most commonly , but also from baker &# 39 ; s yeast , certain fungi , mushrooms , and bacteria . addition of beta - glucan is an important component of the present invention to maintain the mucosa protective barrier as well as to offer nutrients to microbiota that prefer to forage on carbohydrates and would increase the b : f ratio . another means to alter an imbalance between microbiota belonging to bacteroidetes and firmicutes phyla is to suppress the growth of members of one division . such bacteriostatic or bactericidal actions for members of firmicutes division are reported for a number of phenolic compounds that are present in large quantities in berries and other fruits ( 18 ). anthocyanins are the predominating group of phenolic compounds present in berries and are especially abundant ( 18 ). a large proportion of dietary polyphenolics remain unabsorbed in the gut lumen where they become concentrated in the ileum and colon . up to 85 % of blueberry anthocyanins enter the colon ( 19 ) and appear to exert more growth suppressing effects on members of the firmicutes division than the bacteroidetes division ( 20 , 21 ). although blueberry powder , blueberry pomace , or blueberry extract containing such polyphenolics is preferred , the present invention preferably includes any fruit or berry ingredient preparation containing similar phenolics such as those listed in reference 18 . the three preferred classes of ingredients , fermentable polysaccharides , beta - glucans , and berry extracts , can be prepared in any type of edible product such as powder to mix in liquid , a bar , smoothie , yogurt , shake , etc . the blend may also be prepared in a capsule or compressed into a tablet . preferably , the formulation is to be ingested twice per day in between the first and second meals as well as between the second and third meals . it is preferred that each dose of the formulation contain at least about 4 g of indigestible polysaccharide , at least about 2 g beta - glucan and at least about 4 g of berry powder extract ( the equivalent of 2 cups ( 16 ounces ) or 0 . 47 liters whole blueberries containing about 800 mg of total phenolics , 100 mg of anthocyanins and 6900 μmoles te antioxidant activity ). it is preferred that the dose be administered twice per day within 1 hour prior to meal 1 or within 1 hour prior to meal 2 , as well as within 1 hour prior to meal 3 . these are our best estimates but the formulation may change . ranges of ingredients preferably include about 2 - 120 mg / kg of body weight of indigestible polysaccharide , about 2 - 80 mg / kg of body weight of beta - glucan and about 2 - 120 mg / kg of body weight of blueberry powdered extract or any fruit or berry ingredient preparation containing similar phenolics such as those listed in reference 18 . ranges of these ingredients more preferably include about 10 - 80 mg / kg of body weight of indigestible polysaccharide , about 5 - 50 mg / kg of body weight of beta - glucan and about 10 - 80 mg / kg of body weight of blueberry powder or any fruit or berry ingredient preparation containing similar phenolics such as those listed in reference 18 . ranges of these ingredients most preferably include about 20 - 60 - 320 mg / kg of body weight of indigestible polysaccharide that is a fermentable fiber or resistant starch , about 10 - 30 mg / kg of body weight of beta - glucan and about 20 - 60 - 320 mg / kg of body weight of blueberry powdered extract or any fruit or berry ingredient preparation containing similar phenolics such as those listed in reference 18 . one of these ingredients in a formulation is preferable to none , any two are preferable to only one , and most preferably all three are present in a formulation of the present invention that contains less than 70 usable calories ( cal or kcal ) ( 293 kilojoules ). the calorie or joule content of the formulation can be calculated from derived constants determined for macronutrients in the formula . however , the majority of ingredients in the formula is not digested and absorbed and thus is not assimilated or utilized for energy in the human body . a usable calorie or joule is only the calorie or joule that is assimilated or utilized for energy in the human body . a preferred indigestible carbohydrate is insulin and can be found naturally in banana , asparagus , garlic , onions and wheat flour at low levels . to consume a sufficient quantity of achieve levels in the most preferred dose is possible but that would contribute significant usable calories or joules to the daily caloric intake of individuals who already have an unhealthy weight ( see table below ) because the foods also contains usable calories or joules . insulin content of raw jerusalem artichoke , chicory root , and agave is high . ingestion of a purified preparation of insulin contributes significantly less usable calories or joules to daily caloric intake than does ingestion of a vegetable containing insulin ( see table 1 ). to obtain the desired dose of insulin by eating the more common vegetable would contribute about 40 - times the calories or joules that purified insulin contributes . beta - glucan can be found naturally in oats , barley , mushrooms and baker &# 39 ; s yeast . to consume a sufficient quantity of these foods to achieve levels in the most preferred dose is possible but that would contribute significant useable calories or joules to the daily calorie intake of individuals who already have an unhealthy weight ( see table 2 ) because the foods also contains usable calories or joules . polyphenolics can be divided into major groups of anthocyanidins and flavonoids . they are found naturally in blueberry , cranberry , raspberry , and strawberry . these berries contain different levels of anthocyanidins and flavonoids according to reference 22 and the abbreviated table below . blueberries contain the broadest spectrum of polyphenolic compounds . further , ingestion of the equivalent of 2 cups ( 16 ounces or 0 . 4 liters ) of fresh blueberries provides sufficient bioactive compounds to improve insulin sensitivity in insulin resistant patients as demonstrated in reference 23 . to consume a sufficient quantity ( 2 cups ( 16 ounces ) or 0 . 47 liters ) to achieve levels in the most preferred dose of blueberry is possible but that would contribute significant useable calories or joules to the daily calorie intake of individuals who already have an unhealthy weight ( see table 5 ) because the food also contains usable calories or joules , especially sugar . pomace is the solid remains of blueberry after pressing for juice and thus removes sugar and water when manufacturing berry juice . pomace contains indigestible carbohydrate that accounts for 85 % of calories or joules . pomace can be extracted with solvents such as alcohol or water to remove other useable calories . blueberry extracts of pomace contain less than 10 useable calories ( 42 kilojoules ). in some eases dosing may be once a day to initiate treatment and to acclimate the gi microbiome for up to 1 week and then switched to twice daily dosing . in other cases twice daily administration of half the optimal dose is desired such as in children or the elderly . in some cases optimal twice daily dosing may be changed to a daily dosing regimen to maintain the changes stimulated by twice daily dosing . in other cases the twice daily dosing may be switched to twice daily dosing of half the most preferred dose such as in children or adults who cannot tolerate preferred dosing . the present invention can be used in combination with drugs . for example , broad spectrum antibiotics prescribed for systemic infections are not completely absorbed by the upper gi system and make it to the microbiota environment . this will temporarily alter the gi microbiome and it may be desirable to ingest the formulation of the present invention during antibiotic therapy , in preparation for a course of antibiotics , or following such intervention . specific antibiotics may target gram positive or gram negative bacteria . treatment with a gram positive antibiotic before -, during -, or following ingestion of the above combination of prebiotics of the present invention could improve the desired outcome . because the formulation of the present invention is expected to increase glp - 1 levels , it may be desirable to combine that intervention with a dpp - iv ( dipeptidy peptidase type iv ) inhibitor such as vildagliptin , sitagliptin , or others in this class . this will greatly prolong the half - life of glp - 1 released from the colon and the combination would be preferred over the dpp - iv inhibitor alone or an injection of a glp - 1 peptide agonist such as byetta . the present invention can also be combined with other diabetes interventions such as biguanides . an example includes metformin ( glucophage , glucophage xr , riomet , fortamet , and glumetza ). in fact , combined use of the present invention with metformin may not only improve blood glucose regulation but will counter the diarrhea side effect often associated with metformin ( see example 5 ). this is a potentially important clinical observation . metformin is recommended as the initial drug of choice for the treatment of type - 2 diabetes ( 26 ). metformin has been reported to cause a 20 % incidence of diarrhea in diabetic patients taking the drug compared to only 6 % of diabetic patients not taking metformin ( 27 ). in fact , diarrhea with metformin is a sufficient problem that some diabetic patients cannot tolerate the drug . since metformin has a good safety record , causes an approximate 2 - 3 kg weight loss and is a low - cost generic medication , increasing the tolerance to metformin while increasing its efficacy using a safe food supplement could have beneficial public health consequences . the present invention may also be combined with alpha glucosidase inhibitors such as precose ( acarbose ) and glyset ( miglitol ) that are effective in controlling blood glucose but are poorly tolerated because of associated diarrhea . in addition , some drugs such as atypical antipsychotics and insulin cause weight gain in some patients . the present invention could be combined with such drugs to combat the weight gain without intervening with antipsychotic efficacy . the present invention can be used to treat other diseases and syndromes , irritable bowel syndrome ( ibs ) is a disorder characterized by abdominal pain or discomfort , and altered bowel habit ( chronic or recurrent diarrhea , constipation , or both — either mixed or in alternation ). ibs with constipation is sometimes referred to as ibs - c or constipation - predominant ibs . ibs with diarrhea is sometimes referred to as ibs - d . the key symptom of ibs is abdominal pain or discomfort anywhere in the abdomen . it may change over time . the impact of ibs can range from mild inconvenience to severe debilitation . persons with moderate to severe ibs must struggle with symptoms that often impair their physical , emotional , economic , educational and social well - being . the exact cause of ibs is not known . treatments are available for ibs to help manage symptoms but none appear to address the etiology . fecal microbiota of patients suffering with ibs have a 2 - fold decrease in the ratio of the bacteroidetes to firmicutes when compared with healthy individuals ( 28 ). thus , the present invention that stimulates an increase in the ratio of members of the bacteroidetes phylum to the firmicutes phylum should be an efficacious and safe therapeutic to treat ibs . the present invention can be used in preparation for fecal transplant or fecal bacteriotherapy and its follow up . fecal microbiota transplantation is the process of transplantation of fecal microbiota from a healthy individual into a recipient as a treatment for diseases such as infection by clostridium difficile ( 29 ) or more recently , type 2 diabetes ( 30 ). guidelines for both the donor and the recipient are being prepared and will likely indicate strategies for both the donor and the recipient . the use of the present invention in preparation of both subjects for the procedure and continues use by the recipient after transplantation will increase the probability of a successful outcome . the present invention can also be used in preparation for fecal banking . such practice will permit a subject to prepare a specific fecal sample for banking until needed . this may occur to preparation of prolonged antibiotic surgery , cancer chemotherapy and an unforeseen chronic illness . the present invention can be used to treat ocular diseases . recently , it was demonstrated that the microbiota of a conventional raised laboratory mouse adversely alters the ocular lens ( 31 ). the present invention is designed to cause a shift in the gi microbiome . thus the invention will be useful in prevention of cataracts . another eye syndrome is commonly called dry - eye syndrome ( des ). traditionally , des has been thought of as a deficiency of tears at the ocular surface . in recent years , however , investigators have shown that des is much more complex than previously thought , and that “ tear film dysfunction syndrome ” might more accurately describe the condition . tear film dysfunction can be broken down into two basic etiologic classification : insufficient tear production or increased evaporation of tears from the eye surface ( 32 ). the tear film is made up of lipid , aqueous and mucin components . individuals with dry eye syndrome can be deficient in any of these components and all appear to be related , in part , to healthy gi function . thus , the present invention will be useful in treating des . formula a is made of 4 . 7 g dried blueberry pomace extract powder from milne fruit products ( prosser , wash ., product no . fg20155 ), 9 . 22 g oat well 22 ® beta glucan from creanutrition ( sweden ), 4 . 4 g agave insulin ( inufib ) from the iidea company ( tiaquepaque , jal , mexico ), with inactive ingredients preferably added for flavor , mouth feel , texture and mixing , including 8 . 5 g erythritol , 0 . 5 g soy protein , 0 . 4 g xanthan gum , 0 . 38 g citric acid , 0 . 14 g stevia , and 0 . 4 g natural flavor that are not believed to affect the efficacy of formula a . formula a is to be added to a liquid such as 180 ml of water , milk , juice , etc ., mixed and consumed as a suspension . the dried blueberry pomace extract powder used in connection with the present invention is preferably blueberry extract powder , product no . fg20155 , available from milne fruit products of prosser , wash . formula a is used in the examples below . one dose of formula a provides 120 % of the recommended daily dietary allowance ( rda ) of antioxidant activity for children and adults as well as 30 % dietary fiber for men and 50 % dietary fiber for women , 60 % dietary fiber for children aged 1 - 3 , 45 % dietary fiber for children aged 4 - 8 , 36 % dietary fiber for boys of ages 9 - 13 , and 45 % dietary fiber for girls of ages 9 - 13 . preferably a dose of formula a is taken at least once per day , more preferably at least twice per day , and even more preferably at least 3 times per day . each dose of formula a is analyzed to contain active and inactive ingredients described in the table 8 : homan study utilizing formula a to increase the ratio of gastrointestinal microbiota in phylum bacteroidetes to microbiota of firmicutes phylum , improve glucose regulative and improve body composition a ) the required number of subjects are properly screened to fulfill the necessary qualifications . this study is expected to demonstrate that overweight subjects with impaired fasting blood glucose on an ad libitum diet who take formula a either within 1 hour prior to meal 1 or within 1 hour prior to meal 2 , as well as within 1 hour prior to meal 3 for 4 weeks : 1 . eliminate stool containing a greater ratio of microbiota species from the bacteroidetes phylum to firmicutes phylum than this ratio of microbiota in their stool at the start of the intervention , and when compared to subjects consuming a placebo , and 2 . have an improved oral glucose tolerance test ( ogtt ) as measured by blood glucose and insulin levels before , during , and at 120 minutes after ingestion of 75 g glucose when compared to their initial ogtt , and when compared to subjects consuming placebo , and 3 . have lower overnight fasting blood glucose levels as measured by a blood glucose monitor before ingesting a morning meal when compared to their overnight fasting blood glucose value at the start of the intervention , and when compared to subjects consuming placebo . 4 . experience an improved body composition as measured by a decrease in body weight , a decrease in body fat or % body fat , a decrease in waist circumference measurements , and 5 . experience decreased appetite before a meal , increased satiety during the meal , when compared to subjects consuming placebo , and 6 . are found to have elevated glp - 1 as well as pyy levels with reduced active ghrelin levels after a standardized meal when the values are compared to those of subjects consuming placebo on week 3 of the intervention . in this study , subjects consume either 180 ml of formula a formula or a placebo containing the same total dietary fiber level as formula a but as inactive cellulose orally within 1 hour prior to consumption of either meal 1 or meal 2 and within 1 hour prior to consumption of meal 3 each day . placebo formula contains cellulose with food coloring and flavor to match the total dietary fiber content ( 8 . 75 g ) of formula a . placebo is prepared by merlin development at the same time they prepare formula a subjects report weekly for measurements and assessment of any side effects . they are asked to collect a stool sample before initiating either formula a or placebo intervention as well as at the end of the 4 week treatment period . they are also asked to record any side effects and their frequency ( checklist assessment ). they are asked to record appetite ( how hungry are you ) and satiety ( how full are you ) during the standardized meal at the 3 rd week of intervention . they are provided with the proper paper work to record these . a total of 30 subjects is selected , 15 assigned to formula a and 15 assigned to placebo . qualifications of subjects 1 ) healthy men and women between the ages of 18 and 70 with a bmi between 25 and 35 are eligible . 2 ) fasting blood glucose between 100 and 125 mg / dl . 3 ) stable weight over 2 months a ) take medications affecting glucose , b ) take medications affecting insulin , c ) take medications affecting body weight , d ) take medications affecting bacterial flora , e ) have intestinal disease or a recent history of intestinal disease , f ) have had surgery on stomach or intestine , g ) are hypothyroid , h ) are pregnant , i ) have heart disease . different tests are performed at the screening of potential participants , at the beginning of the study , and at the end of the 4 week treatment period . 1 ) screening : subjects are screened to exclude hypothyroidism , pregnancy , and heart disease . the following tests can suffice for this : t4 ( thyroxia ), t3 ( triiodotyronine ), tsh ( thyroid stimulating hormone ), urine pregnancy test , blood pressure & amp ; ecg ( electrocardiogram ). 2 ) beginning of study : subjects passing the initial screen are evaluated at the beginning of week # 1 as follows : a ) fasting blood glucose and insulin levels . b ) sma 20 ( sequential multi - channel analysis with computer 20 , a metabolic panel with 20 different analytes ), including , uric acid , and liver function tests c ) triglycerides d ) cholesterol , including fractions e ) glycosylated hemoglobin a1 ( hgba1 ) f ) weight , taken on the same scale each time g ) body fat % and total body fat , determined by dxa ( dual - energy x - ray absorptiometry ). h ) height i ) waist and hip measurements j ) blood glucose , insulin , glp - 1 , pyy and gherlin responses to a 75 g oral glucose challenge k ) assessment of appetite and satiety using a visual analog scale l ) stool is collected and stored frozen but not analyzed until the end of study . a ) all labs and assessments done in step 2 at beginning of study , b ) analysis of the fecal microbiome dna from both the initial sample and the final sample . subjects selected for participation are allowed an ad libitum diet and are given an evaluation sheet to assess their appetite and satiety before and after a meal . foods excluded include alcohol . low calorie or joule liquids , are stressed in place of high calorie or joule liquids such as fruit juices , milk , sweet tea ( tea with sugar ), regular soft drinks , coffee with sugar , etc . the subjects are randomly assigned to either formula a or placebo treatments . both the experimenter and the subjects are blinded to who receive formula a or the placebo . the subjects are encouraged to consume either treatment within 1 hour prior to either breakfast or lunch and within 1 hour prior to dinner . subjects are given a 4 weeks supply of either formula a or placebo at the onset and are instructed to consume the entire 180 ml volume within 1 hour prior to either meals 1 or 2 , as well as another 180 ml volume containing either formula a or placebo within 1 hour prior to meal 3 . ad libitum diets are followed for 4 weeks , but the volunteers are instructed to consume either formula a or placebo as their only between meal snack . 1 ) increases the ratio bacteroidetes species to firmicutes species in fecal samples when samples at the end of study are compared to samples at the onset of study ; and when the ratio of species is compared to samples from the placebo group 2 ) improves the blood glucose and insulin responses to an ogtt by decreasing the areas under the insulin curve ( improved insulin sensitivity ); 3 ) decrease fasting blood glucose values 4 ) produces weight loss , loss of body fat , and ( or ) decrease of body fat % 5 ) increases glp - 1 and pyy response to the oral glucose challenge and decreases the fasting ghrelin levels at 1 hour after the both the ogtt and the standardized meal when comparing final values to the initial measurements of the ogtt , and when comparing to those findings of the placebo group during the standardized meal ; and 6 ) decreases stool ph ; 7 ) increases stool scfa . if subjects took formula a for periods longer than 4 weeks , particularly for at least 8 weeks , the subjects would experience significant weight loss that was primarily fat loss . human study utilizing either formula a or a placebo snack replacement to increase the ratio of gastrointestinal microbiota in phylum bacteroidetes to microbiota of firmicutes phylum , improve glucose regulation and improve body composition a ) the required number of subjects are properly screened to fulfill the necessary qualifications , this study is expected to demonstrate that overweight subjects with impaired fasting blood glucose on an ad libitum diet who take formula a , but not those assigned to consume a placebo , within 2 hours prior to consuming either meal 1 or meal 2 , as well as within 2 hours prior to consuming meal 3 as a snack replacement for 4 weeks : 1 . eliminate stool containing a greater ratio of microbiota species from the bacteroidetes phylum to firmicutes phylum than this ratio of microbiota in their stool at the start of the intervention , and 2 . have an improved oral glucose tolerance test ( ogtt ) as measured by blood glucose and insulin levels before , during , and at 120 minutes after ingestion of 75 g glucose when compared to their initial ogtt , and 3 . experience an improved body composition as measured by a decrease in body weight , a decrease in body fat or % body fat , a decrease in waist circumference measurements , and 4 . experience lower fasting blood glucose levels when compared to either the initial values or those of the placebo group , and 5 . experience decreased appetite before a meal , increased satiety during the meal , and 6 . are found to have elevated glp - 1 as well as pyy levels with reduced active ghrelin levels at 1 hour after both the ogtt and the standardized meal when the values are compared to those at the initiation of the trial ( ogtt ) or the placebo group ( standardized meal test ). in this study , subjects are randomly selected to consume 180 ml of either formula a formula or placebo formula orally within 2 hours prior to ingestion of either meals 1 or 2 as well as within 2 hours prior to consumption of meal 3 each day . the subjects and experimenters are blinded to the treatment assignments . placebo formula contains cellulose with food coloring and flavor to match the total dietary fiber content ( 8 . 75 g ) of formula a . placebo is prepared by merlin development at the same time they prepare formula a . both formulations are coded by merlin development and the code is maintained with them as well as is held in confidence by a pharmacist at the study clinic until all data are collected at the end of study . subjects report weekly for measurements and assessment of any side effects . they are asked to collect a stool sample before initiating formula a or placebo intervention as well as at the end of the 4 week treatment period . they are also asked to record any side effects and their frequency ( checklist assessment ). they are asked to record appetite ( how hungry are you ) and satiety ( how full are you ) during the ogtt at both the onset and at the end of the trial as well as during a 3 rd standardized meal . they are provided with the proper paper work to record these . a total of 30 subjects is selected . fifteen subjects are randomly assigned to consume formula a and the remaining 15 subjects are assigned to the formula a group . the demographics of each group are carefully matched . qualifications of subjects 1 ) healthy men and women between the ages of 18 and 70 with a bmi between 25 and 35 are eligible . 2 ) fasting blood glucose between 100 and 125 mg / dl . 3 ) stable weight over 2 months a ) take medications affecting glucose , b ) take medications affecting insulin , c ) take medications affecting body weight , d ) take medications affecting bacterial flora , e ) have intestinal disease or a recent history of intestinal disease , f ) have had surgery on stomach or intestine , g ) are hypothyroid , h ) are pregnant , different tests are performed at the screening of potential participants , at the beginning of the study , and at the end of the 4 week treatment period . 4 ) screening : subjects are screened to exclude hypothyroidism , pregnancy , and heart disease . the following tests can suffice for this : t4 ( thyroxin ), t3 ( triodotyronine ), tsh ( thyroid stimulating hormone ), urine pregnancy test , blood pressure & amp ; ecg ( electrocardiogram ). beginning of study : subjects passing the initial screen are evaluated at the beginning of week # 1 as follows : a ) fasting blood glucose and insulin levels , b ) sma 20 ( sequential multi - channel analysis with computer - 20 , a metabolic panel with 20 different analytes ), including , uric acid , and liver function tests d ) cholesterol , including fractions e ) glycoxylated hemoglobin a1 ( hgba1 ) f ) weight , taken on the same scale each time g ) body fat % and total body fat , determined by dxa ( dual - energy x - ray absorptiometry ), h ) height i ) waist and hip measurements j ) blood glucose , insulin , glp - 1 , pyy and ghrelin responses to a 75 g oral glucose challenge k ) assessment of appetite and satiety using a visual analog scale l ) stool is collected and stored frozen but not analyzed until the of study . 6 . end of study assessment : c ) all labs and assessments done in step 2 at beginning of study , d ) analysis of the fecal microbiome dna from both the initial sample and the final sample . study design subjects selected for participation are allowed an ad libitum diet and are given an evaluation sheet to assess their appetite and satiety before and after a meal foods excluded include alcohol , low calorie or joule liquids are stressed in place of high calorie or joule liquids such as fruit juices , milk , sweet tea ( tea with sugar ), regular soft drinks , coffee with sugar , etc . the subjects are encouraged to consume either formula a or placebo as their only between meal snack . duration subjects are given a 4 weeks supply of either formula a or placebo at the onset and are instructed to consume the entire 180 ml volume containing either formula within 2 hours prior to either meals 1 or 2 , as well as another 180 ml volume containing either formula within 2 hours prior to meal 3 . ad libitum diets are followed for 4 weeks , but the volunteers are instructed to consume either formula a or placebo as their only between meal snack . outcome this study is expected to demonstrate that formula a and not placebo : 1 ) increases the ratio of bacteroidetes species to firmicutes species in fecal samples when samples at the end of study are compared to samples at the onset of study : 2 ) improves the blood glucose and insulin responses to an ogtt by decreasing the areas under the insulin curve ( improved insulin sensitivity ); 3 ) produces weight loss , loss of body fat , and ( or ) decrease of body fat %; 4 ) increases glp - 1 and pyy response to the oral glucose challenge and decreases the fasting gherlin levels prior to the ogtt when comparing final values to the initial measurements ; 5 ) decreases stool ph ; 6 ) increases stool scfa . if subjects took formula a as a snack replacement for periods longer than 4 weeks , particularly for at least 8 weeks , the subjects would experience significant weight loss that was primarily fat loss . human study utilizing formula a in combination with an inhibitor of dipeptidyl peptidase - 4 ( dpp - 4 ) to increase the ratio of gastrointestinal microbiota in phylum bacteriodetes to microbiota of firmicutes phylum and improve glucose regulation by sustained elevation of glp - 1 a ) the required number of subjects are properly screened to fulfill the necessary qualifications . b ) appropriate laboratory evaluations are performed , c ) measures of positive primary and secondary outcome responses are recorded , d ) adverse events are documented , and e ) patients are adequately followed - up . this study is expected to demonstrate that type 2 diabetic ( t2d ) subjects with insulin resistance on an ad libitum diet who take a dpp - 4 inhibitor and formula a within 1 hour prior to either meal 1 or meal 2 , as well as within 1 hour prior to meal 3 for 4 weeks ; 1 . eliminate stool containing a greater ratio of microbiota species from the bacteroidetes phylum to firmicutes phylum than this ratio of microbiota in their stool at the start of the intervention and when compared to those only taking the dpp - 4 inhibitor , and 2 . have improved insulin sensitivity when compared to both initiation of the study and when compared to those only taking a dpp - 4 inhibitor . insulin sensitivity is measured by an oral glucose tolerance test ( ogtt ). this is performed by measuring blood glucose and insulin levels before , during , and at 120 minutes after ingestion of 75 g glucose when compared to their initial ogtt , and 3 . have improved fasting blood glucose values when compared to those only taking the dpp - 4 inhibitor , and 4 . experience an improved body composition as measured by a decrease in body weight , a decrease in body fat or % body fat , a decrease in waist circumference measurements when compared to their baseline values and when compared to those only taking the dpp - 4 inhibitor , and 5 . experience decreased , appetite before a standardized meal , increased satiety during that meal when compared to their baseline values and when compared to those only taking the dpp - 4 inhibitor , and 6 . are found to have elevated glp - 1 as well as pyy levels with reduced ghrelin levels at 1 hour after the both the ogtt and the standardized meal when the values are compared to their baseline values and when compared to those only taking the dpp - 4 inhibitor . in this study , t2d patients are randomly assigned to either consume 180 ml of formula a or a placebo formula containing cellulose orally within 1 hour prior to either meals 1 or 2 as well as within 1 hour prior to meal 3 each day . patients and experimenters are blinded to this assignment . all patients are also instructed to take sitagliptin ( januvia ®) recommended dose of 100 mg , once per day in the morning prior to meal 1 as a treatment to manage their diabetes . subject report weekly for measurements and assessment of any side effects . they are asked to collect a stool sample before the initiation of the trial as well as at the end of the 4 week treatment period . they are also asked to record any side effects and their frequency ( checklist assessment ). they are asked to record appetite ( how hungry are you ) and satiety ( how full are you ) during the ogtt at both the onset and at the end of the trial as well as before and during a standardized meals at the 3 rd week of treatments . they are provided with the proper paper work to record these . a total of 24 subjects is selected , 12 will be randomly assigned to receive januvia ®+ placebo ( a cellulose solution that contains the same total dietary fiber content as formula a and mimics formula a in color and taste ) or januvia ®+ formula a . qualifications of subjects 1 ) t2d men and women between the ages of 18 and 70 with a bmi between 25 and 35 are eligible , 2 ) fasting blood glucose between greater than 125 mg / dl , 3 ) stable weight over 2 months a ) take medications affecting glucose other than januvia , b ) take medications affecting insulin other than januvia , c ) take medications affecting body weight , d ) take mediations affecting bacterial flora , e ) have intestinal disease or a recent history of intestinal disease , f ) have had surgery on stomach or intestine , g ) are hypothyroid , h ) are pregnant , different tests are performed at the screening of potential participants , at the beginning of the study , and at the and of the 4 week treatment period . 7 ) screening : subjects are screened to exclude hypothyroidism , pregnancy , and heart disease . the following tests can suffice for this ; t4 , t3 , tsh , urine pregnancy test , blood pressure & amp ; ecg . fasting blood glucose , fasting insulin and hgba1 levels are also measured as an assessment of their diabetic state . 8 ) beginning of study : subjects passing the initial screen are evaluated at the beginning of week # 1 as follows : a ) fasting blood glucose , insulin , and hgba1 levels , b ) sma 20 , including uric acid and liver function tests c ) triglycerides d ) cholesterol , including fractions f ) weight . taken on the same scale each time g ) body fat % and total body fat , determined by dxa . h ) height i ) waist and hip measurements j ) blood glucose , insulin , glp - 1 , pyy and gherlin responses to a 75 g oral glucose challenge k ) assessment of appetite and satiety before , during and after a standardized meal using a visual analog scale l ) stool is collected and stored frozen but not analyzed until the end of study . e ) all labs and assessments done in step 2 at beginning of study , f ) analysis of the fecal microbiome dna from both the initial sample and the final sample . study design patients selected for participation are allowed an ad libitum diet and are given an evaluation sheet to assess their appetite and satiety . foods excluded include alcohol . low calorie or joule liquids are stressed in place of high calorie or joule liquids such as fruit juices , milk , sweet tea ( tea with sugar ), regular soft drinks , coffee with sugar , etc . all 24 patients are also instructed to take sitagliptin ( januvia ®) at the recommended dose of 100 mg , once per day in the morning with or without food as a treatment to manage their diabetes . 12 patients are randomly selected to also consume formula a before 2 or 3 daily meals and remaining 12 patients are instructed to consume a placebo before 2 of 3 daily meals . patients and investigators are blinded to whether the snack replacement is placebo or formula a . subjects are given a 4 weeks supply of sitagliptin and either formula a or placebo at the onset and are instructed to consume the entire 180 ml volume of either snack replacement within 1 hour prior to either meals 1 or 2 , as well as another 180 ml volume of snack replacement within 1 hour prior to meal 3 . all subjects are required to take 1 tablet of sitagliptin dally ( 100 mg ) in the morning with or without food . ad libitum diets are followed for 4 weeks . 1 ) increases the ratio of bacteroidetes species to firmicutes species in fecal samples when samples at the end of study from those assigned to formula a are compared to samples at the onset of study and when subjects taking januvia + formula a are compared to patients taking januvia + placebo . 2 ) improves the blood glucose and insulin responses to an ogtt by decreasing the areas under the insulin curve ( improved insulin sensitivity ) when subjects taking januvia + formula a are compared to patients taking januvia + placebo 3 ) produces weight loss , loss of body fat , and ( or ) decrease of body fat % when patients assigned to formula a are compared to samples at the onset of study and when subjects taking januvia + formula a compared to patients taking januvia + placebo . 4 ) produces decreased fasting blood glucose levels when subject taking januvia + formula a are compared to patients taking januvia + placebo , and 5 ) increases glp - 1 and pyy response to the oral glucose challenge and decreases the fasting ghrelin levels prior to the ogtt when patients assigned to formula a are compared to samples at the onset of study and when subjects taking januvia + formula a are compared to patients taking januvia + placebo . 6 ) decreases stool ph when patients assigned to the formula a arm are compared to samples at the onset of study and when subjects taking januvia + formula a are compared to patients taking januvia + placebo 7 ) increases stool scfa when patients assigned to the formula a arm are compared to samples at the onset of study and when subjects taking januvia + formula a are compared to patients taking januvia + placebo if subjects took formula a with other dpp - iv inhibitors or other formulations of januvia , the subjects are expected to also have significantly improved glucose regulation . study utilizing formula a snack replacement to increase the ratio of gastrointestinal microbiota in phylum bacteriodetes to microbiota of firmicutes phylum , improve glucose regulation and improve body composition in overweight childres a ) the required number of children are properly screened to fulfill the necessary qualifications and their parental consent is obtained , c ) measures of positive primary and secondary outcome responses are recorded , this study is expected to demonstrate that overweight children with prediabetes or at high risk of developing t2d ( type 2 diabetes ) on an ad libitum diet who take formula b ( identical active ingredients to formula a but formulated in a child friendly delivery system such as ice cream , jelled animals , cookies , etc .) within 1 hour prior to either meal 1 or meal 2 , as well as within 1 hour prior to meal 3 for 4 weeks : 1 . eliminate stool containing a greater ratio of microbiota species from the bacteroidetes phylum to firmicutes phylum than this ratio in their stool at the start of the intervention , and the intervention , and 2 . have an improved oral glucose tolerance test ( ogtt ) as measured by blood glucose and insulin levels before , during , and at 120 minutes after ingestion of 1 . 76 g glucose and insulin body weight up to 75 g glucose when compared to their initial ogtt , and 3 . experience an improved body composition as measured by a decrease in body weight , a decrease in body fat or % body fat , a decrease in waist circumference measurements , and 5 . experience decreased appetite before a meal , increased satiety during the meal , and 6 . are found to have elevated glp - 1 as well as pyy levels with reduced ghrelin levels 1 hour after the ogtt when the values are compared to those at the initiation of the trial . in this study , children consume 6 jelled animals of formula b formula ( each jelled animal contains about 20 g of formula b ) within 1 hour prior to either meals 1 or 2 as well as with 1 hour prior to meal 3 each day . subjects report weekly for measurements and assessment of any side effects . they are asked to collect a stool sample before initiating formula b intervention as well as at the end of the 4 week treatment period . they are also asked to report side effects to their parents who record them and their frequency ( checklist assessment ). the parents are instructed to ask and to record appetite ( how hungry are you ) and satiety ( how full are you ) before , during , and after a standardized 3 rd meal at the beginning of study and at the end . the investigators score the same assessment during the ogtt at both the onset and at the end of the trial as well as at home . the parents are provided with the proper paper work to record these . qualifications of subjects 1 ) healthy prepubertal boys and girls between the ages of 7 and 12 with a bmi between 25 and 30 are eligible . 2 ) fasting blood glucose between 100 and 125 mg / dl . a ) take medications affecting glucose , b ) take medications affecting insulin , c ) take medications affecting body weight , d ) take medications affecting bacterial flora , e ) have intestinal disease or a recent history of intestinal disease , f ) have had surgery on stomach or intestine , g ) are hypothyroid . different tests are performed at the screening of potential participants , at the beginning of the study , sad at the end of the 4 week treatment period . screening : children are screened , to exclude hypothyroidism and puberty . the following tests can suffice for this : t4 , t3 , tsh , a physical exam , and in questionable cases based on the physical exam or peripubertal presentations , a gonadotropin - releasing hormone challenge test . beginning of study : children passing the initial screen are evaluated at the beginning of week # 1 as follows : a ) fasting blood glucose and insulin levels . b ) sma 20 , including uric acid and liver function tests c ) triglycerides d .) cholesterol , including fractions e ) glycosylated hemoglobin a1 ( hgba1 ) f ) weight , taken on the same scale each time g ) body fat % and total body fat , determined by dxa . h ) height i ) waist and hip measurements j ) blood glucose , insulin , glp - 1 , pyy and ghrelin responses to a 1 . 75 g / kg ( up to 75 g ) oral glucose challenge k ) assessment of appetite and satiety using a visual analog scale l ) stool is collected and stored frozen but not analyzed until the end of the study . a ) all tabs and assessments done in step 2 at beginning of study , b ) analysis of the fecal microbiome dna from both the initial sample and the final sample . children selected for participation are allowed an ad libitum diet and their parents are given an evaluation sheet to assess their appetite and satiety . low calorie or joule liquids are stressed in place of high calorie or joule liquids such as fruit juices , milk , regular soft drinks , coffee with sugar , etc . the children are encouraged to consume formula b as their only between meal snack . other snacks such as candy , ice cream , milk shakes , cookies , potato chips , etc . are discouraged . children are given a 4 weeks supply of formula b at the onset and are instructed to consume the entire 6 jelled animals containing formula b within 1 hour prior to either meal 1 or 2 , as well as another 6 jelled animals containing formula b within 1 hour prior to meal 3 . ad libitum diets are followed for 4 weeks , but the children are instructed to consume formula b as their only between meal snack . 1 ) increases the ratio of bacteroidetes species to firmicutes species in fecal samples when samples at the end of study are compared to samples at the onset of study . 2 ) improves the blood glucose and insulin responses to ogtt by decreasing the areas under the insulin curve ( improved insulin sensitivity ) 3 ) produces weight toss , loss of body lat , and ( or ) decrease of body fat % 4 ) increases glp - 1 and pyy response to the oral glucose challenge and decreases the fasting ghrelin levels prior to the ogtt when comparing final values to the initial measurements . 5 ) decreases stool ph 6 ) increases stool scfa if children took formula a for periods longer than 4 weeks as a snack replacement , particularly for at least 8 weeks , the children would experience significant weight loss that was primarily fat loss . formula a augments the efficacy and gastrointestinal tolerability of metformin : a case report jh was a 30 year old caucasian male who gained 10 kg over the course of 8 months and developed lower back pain . he presented to his primary physician with that complaint . the patient was taking omeprazole ( 20 mg / d ), lisinopril ( 40 mg / d ), metoprolol ( 100 mg / d ), and hydrochlorothiazide ( 25 mg / d ) at the time of his presentation , had no allergies and had undergone no surgeries . he denied past hospitalizations , trauma with residua or blood transfusions . he had never smoked , drank 3 - 4 alcoholic drinks per week on average and had no history of intravenous drug use . he was a full - time law student and had no exposures to occupational toxins . during the 6 months prior to his presentation he had been sexually active with one woman . the patient &# 39 ; s mother and father were living and well . he had one sister who was living and well , and he had no children . there was no family history of diabetes . he had no complaint other than lower back pain . on physical examination he was 104 kg with a height of 165 cm and a body mass index ( bmi ) of 38 . 3 kg / m 2 . his blood pressure was 116 / 70 with a pulse rate of 80 / min and he was afebrile . urinalysis demonstrated presence of glucose , that was followed up by a non - fasting capillary blood glucose of 450 mg / dl glucose and a hemoglobin a1c of 8 . 8 % and a microalbumin / creatine ratio of 147 . his physician made the diagnosis of type 2 diabetes mellitus based on his age , lack of acidosis and a fasting blood sugar of 325 mg / dl . he was started on metformin 500 mg twice a day and was instructed to measure his fasting blood sugar on a dally basis . over the course of 7 days be was instructed to increase metformin to 100 mg twice a day . over the course of the next 9 days he developed persistent watery stools and his fasting blood sugar decreased to about 325 mg / dl . he knew from his contact with nume health , llc that the company was developing and testing a dietary supplement with a goal of increase insulin sensitivity through a salutary effect on the stool microbiome . on the 9th day of his treatment with 100 mg metformin dose , he added formula a taken twice a day within an hour before breakfast or lunch and within an hour before dinner . within two days of starting formula a his fasting glucose dropped from 325 mg / dl to 175 mg / dl and after 5 weeks of taking the formula a along with the metformin , his fasting blood glucose was 100 mg / dl ( fig1 ). fig1 shows fasting blood glucose levels at the start of 1000 mg metformin twice daily . formula a was added twice daily on day 9 and the combination was continued except from days 49 to 51 when daily dosing of formula a was missed . diarrhea was associated with metformin except when formula a was added . dividing the first 60 days of diabetes treatment into 10 day periods , his blood sugar and its variance ( standard deviation ) decreased from 344 ± 44 . 1 mg / dl in the first 10 days , to 182 . 2 ± 14 . 7 in the second 10 days , 123 . 0 ± 9 . 6 during the fifth 10 days , and 121 . 0 ± 11 . 8 during the sixth 10 days ( fig2 ). during this period , his weight decreased by 5 . 5 kg , and his watery stools reversed to soft regular formed bowel movements . after an additional month , he ran out of his formula a for 2 days . during that period , his blood sugar increased from 100 mg / dl to 133 mg / dl and his diarrhea returned . after resuming formula a his blood sugar returned to 113 mg / dl and his stools return to being formed and soft . his diabetic control and stools have remained under control on the combination of metformin and formula a at the time of this writing and he has lost about 5 . 5 kg body weight . his hemoglobin a1c decreased to 6 . 3 % and a microalbumin / creatine ratio was 16 . this case report is encouraging . not only did formula a appear to have a positive effect on fasting blood sugar , but the watery stools induced by treatment with metformin were normalized . this is a potentially important clinical observation . metformin has been recommended as the initial drug of choice for the treatment of type - 2 diabetes ( 26 ). metformin has been reported to cause a 20 % incidence of diarrhea in diabetic patients taking the drug compared to only 6 % of diabetic patients not taking metformin ( 27 ). in fact , diarrhea with metformin is a sufficient problem that some diabetic patients cannot tolerate the drug . since metformin has a good safety record , causes an approximate 2 - 3 kg weight loss and is a low - cost generic medication , increasing the tolerance to metformin while increasing its efficacy using a safe food supplement could have beneficial public health consequences . acarbose is another drug used to treat diabetes that is associated with the side effect of a watery stool because of its mechanisms of action . if formula a is used in conjunction with acarbose to treat type 2 diabetes , both better control of blood glucose and solid stool formation are expected . human study utilizing either formula a or a placebo to increase the ratio of gastrointestinal microbiota in phylum bacteroidetes to microbiota of firmicutes phylum and improve symptoms of irritable bowel syndrome ( ibs ) a ) the required number of subjects are properly screened to fulfill the necessary qualifications , c ) measures of positive primary and secondary outcome responses are recorded , this randomized , placebo - controlled clinical trial is expected to demonstrate the efficacy and tolerability of formula a in diarrhea - predominant humans with ibs . subjects assigned to consume formula a but not a placebo , within 1 hour prior to consuming either meal 1 or meal 2 , as well as within 1 hour prior to consuming meal 3 for 4 weeks : 1 . eliminate stool containing a greater ratio of microbiota species from the bacteroidetes phylum to firmicutes phylum , and in this study , subjects are randomly selected to consume 180 ml of either formula a formula or placebo formula orally within 1 hour prior to ingestion of either meals 1 or 2 as well as within 1 hour prior to consumption of meal 3 each day . the subjects and experimenters are blinded to the treatment assignments . placebo formula contains cellulose with food coloring and flavor to match the total dietary fiber content ( 8 . 75 g ) of formula a . placebo is prepared by merlin development at the same time they prepare formula a . both formulations are coded by merlin development and the code is maintained with them as well as is held in confidence by a pharmacist at the study clinic until all data are collected at the end of study . subjects report weekly for measurements and assessment of any side effects . they are asked to collect a stool sample before initiating formula a or placebo intervention as well as at the end of the 4 week treatment period . during the screening , treatment , and follow - up periods , daily and weekly symptom data are collected using an interactive telephone - based system . pain and bowel function data are collected during the screening phase to ensure that patients had a suitable symptom level as study entry . severity of pain and discomfort was assessed daily on a 5 - point scale ( 0 , none ; 1 , mild ; 2 , moderate ; 3 , intense ; and 4 , severe ). stool consistency data are monitored daily and scored as follows : 1 , very hard ; 2 , hard ; 3 , formed ; 4 , loose ; and 5 , watery . absence of stool was assigned a value of 0 . patients also record the ibs symptoms urgency ( 0 %, feel no need to evacuate - 100 %, feel severe need to evacuate , stood frequency (# of stools per day ) bloating ( 0 , no sensation of extended abdomen ; 1 , mild ; 2 , moderate ; 3 , severe ) and sense of incomplete evacuation ( 0 , sensation of complete evacuation ; 1 , incomplete ; 2 , constipated ) daily during the treatment and follow - up phases . patients with ibs and a diarrhea - predominant bowel pattern aged 18 years or older are enrolled in this study if their symptoms fulfilled the rome 1 criteria for ibs for at least 6 months . patients undergo a 2 - week screening evaluation to confirm sufficient level of pain stool consistency before randomization . since no objective criteria exist for subgrouping of ibs patients , physicians are asked to assess patients according to predominant pattern of bowel function based on the patient &# 39 ; s disease history . physicians are provided with a guideline based on the percentage of time the patient had experienced diarrhea . if diarrhea is present for ≧ 75 % of the time , then the patient is classified as being diarrhea predominant . patients are excluded if they are pregnant , breastfeeding , or not using approved methods of contraception ( if of child - bearing potential ); if an unstable medical or other gastrointestinal condition exists ; if them is a major psychiatric disorder or substance abuse within the previous 2 years ; if an investigational drug was used within 30 days of the screening phase ; or if a prohibited concurrent medication ( likely to interfere with gastrointestinal tract function or analgesia ) was used within 7 days before entering the screening phase . pairs and bowel function data are collected during the screening phase to ensure that patients had a suitable symptom level at study entry as described above . evaluations are performed at the screening of potential participants , at the beginning of the study , daily , and at the end of the 4 week treatment period . a ) severity of pain and discomfort is assessed on a 5 - point scale ( 0 , none ; 1 , mild ; 2 , moderate : 3 , intense ; and 4 , severe ), b ) stool consistency data are scored as follows : 1 , very hard ; 2 , hard ; 3 , formed ; 4 , loose ; and 5 , watery . absence , of stool was assigned a value of 0 , c ) urgency ( 0 %, feel no need to evacuate - 100 %, feel severe need to evacuate ), d ) stool frequency (# of stools per day ) e ) bloating ( 0 , no sensation of extended abdomen ; 1 , mild ; 2 , moderate ; 3 , severe ) f ) sense of incomplete evacuation ( 0 , sensation of complete evacuation ; 1 , incomplete ; 2 , constipated ) g ) body weight . stool is collected , and stored frozen but not analyzed until the end of study . analysts of the fecal microbiome dna from both the initial sample and the final sample . subjects selected for participation are allowed an ad libitum diet . foods excluded include alcohol . the subject are encouraged to consume either formula a or placebo within 1 hour prior to 2 meals each day with ingestion of the test agent being mandatory prior to the 3 rd meal . subjects are given a 4 week supply of either formula a or placebo at the onset and are instructed to consume the entire 180 ml volume containing either formula within 1 hour prior to either meals 1 and 2 , as well an another 180 ml volume containing either formula within 1 hour prior to meal 3 . subjects report weekly for measurements and assessment of ibs symptoms . during the screening and treatment periods , daily symptom data are collected using an interactive telephone - based system . this study is expected to demonstrate that formula a and not placebo : 1 ) increases the ratio of bacteroidetes species to firmicutes species in fecal sample when samples at the end of study are compared to samples at the onset of study ; 2 ) improves severity of pain and discomfort ; 3 ) increases stool consistency ; 4 ) decreases urgency to evacuate , 5 ) decreases stool frequency ; 6 ) decreases bloating 7 ) increases sense of complete evacuation . utilization of formula a to treat idiopathic diarrhea such as a parasitic infection , a viral infection and a symptomatic response to a food is expected to also improve the severity of pain and discomfort , increase stool consistency , decrease the a 55 year old woman with chronic diarrhea that was associated with c . difficile infection initially presents to her primary care physician diarrhea of 8 months duration that originally started shortly following treatment with cephalosporin and quinolone antibiotics for hack surgery and s pulmonary infection . during those eight months , she is repeatedly treated with metronidazole and vancomycin , and required several hospitalizations for intravenous hydration . the patient complains of loose small bowel movements every 15 minutes , accompanied by great urgency and rectal tenesmus . she wears diapers at all times and loses 10 % of her body weight . flexible sigmoidoscopy demonstrates classic pseudomembranous colitis . stool samples are positive for c . difficile toxins a and b , and stool culture confirms heavy growth of this bacterium . the patient is again treated with vancomycin , but fails to respond . she is subsequently prescribed nitazoxanide ( 2 - acetyloxy - n -( 5 - nitro - 2 - thiazolyl ) benzamide ), 500 mg orally , twice daily . ten days after discontinuation of nitazoxanide , the patient has recurrence of her original diarrheal symptoms . endoscopic analysis indicates return pseudomembranous colitis , and stool studies are again positive for c . difficile . despite two more cycles of nitazoxanide , including one lasting a full month , and continuous administration of florastor , a probiotic containing saccharomyces boalardii , the c . difficile - induced colitis reoccurs . since conventional treatment fails to resolve the c . diff . fecal bacteriotherapy is offered to break the cycle of occurrences and achieve a potential cure . informed consent is obtained from both the patient and the donor following discussion with each of the potential risks , benefits , and alternative options . the patient is maintained on nitazoxanide until the day before the procedure . the patient &# 39 ; s husband of 44 years ( donor ) is prescribed formula a 3 times a day for 2 weeks . fecal donor material is taken from him , who has no risk factors for blood - borne communicable diseases , has no recent exposure to antibiotics , has no gastrointestinal symptoms of any kind , and tests negative for common stool pathogens and c . difficile . bacteriotherapy is delivered into the patient &# 39 ; s right colon by way of a colonoscopy . the patient is expected to have her first solid bowel movement on the second day following treatment . it is expected that her abdominal pain gradually subsides , and at one month following bacteriotherapy and it is expected that her stool samples will be negative for c . difficile . the patient is expected to commence formula a twice a day . at six months follow - up , the patient is expected to report once daily formed stools . all measurements disclosed herein are at standard temperature and pressure , at sea level on earth , unless indicated otherwise . all materials used or intended to be used in a human being are biocompatible , unless indicated otherwise . the foregoing embodiments are presented by way of example only ; the scope of the present invention is to be limited only be the following claims .

compositions and methods for treating diabetes are presented herein . in particular , the present disclosure reaches compositions and methods for treating diabetes utilizing a gastrointestinal microbiome modulating composition .

the nomenclature of the pg compounds used herein is based on the numbering system of prostanoic acid represented in the above formula ( a ). the formula ( a ) shows a basic skeleton of the c - 20 pg compound , but the present invention is not limited to those having the same number of carbon atoms . in the formula ( a ), the numbering of the carbon atoms which constitute the basic skeleton of the pg compounds starts at the carboxylic acid ( numbered 1 ), and carbon atoms in the α - chain are numbered 2 to 7 towards the five - membered ring , those in the ring are 8 to 12 , and those in the ω - chain are 13 to 20 . when the number of carbon atoms is decreased in the α - chain , the number is deleted in the order starting from position 2 ; and when the number of carbon atoms is increased in the α - chain , compounds are named as substitution compounds having respective substituents at position 2 in place of carboxy group ( c - 1 ). similarly , when the number of carbon atoms is decreased in the ω - chain , the number is deleted in the order starting from position 20 ; and when the number of carbon atoms is increased in the ω - chain , compounds are named as substitution compounds having respective substituents at position 20 . stereochemistry of the compounds is the same as that of the above formula ( a ) unless otherwise specified . in general , each of pgd , pge and pgf represents a pg compound having hydroxy groups at positions 9 and / or 11 , but in the present specification they also include those having substituents other than the hydroxyl groups at positions 9 and / or 11 . such compounds are referred to as 9 - dehydroxy - 9 - substituted - pg compounds or 11 - dehydroxy - 11 - substituted - pg compounds . a pg compound having hydrogen in place of the hydroxy group is simply named as 9 - or 11 - dehydroxy compound . as stated above , the nomenclature of pg compounds is based on the prostanoic acid skeleton . however , in case the compound has a similar partial construction as a prostaglandin , the abbreviation of “ pg ” may be used . thus , a pg compound of which α - chain is extended by two carbon atoms , that is , having 9 carbon atoms in the α - chain is named as 2 - decarboxy - 2 -( 2 - carboxyethyl )- pg compound . similarly , a pg compound having 11 carbon atoms in the α - chain is named as 2 - decarboxy - 2 -( 4 - carboxybutyl )- pg compound . further , a pg compound of which ω - chain is extended by two carbon atoms , that is , having 10 carbon atoms in the ω - chain is named as 20 - ethyl - pg compound . these compounds , however , may also be named according to the iupac nomenclatures . according to the iupac naming system , for example , 13 , 14 - dihydro - 15 - keto - 16r , s - fluoro - pge 2 is ( z )- 7 -{( 1r , 2r , 3r )- 3 - hydroxy - 2 -[( 4r , s )- fluoro - 3 - oxo - 1octyl ]- 5 - oxocyclopentyl }- hept - 5 - enoic acid ; 13 , 14 - dihydro - 15 - keto - 20 - ethyl - 11 - dehydroxy - 11r - methyl - pge 2 methyl ester is methyl 7 -{( 1r , 2s , 3s )- 3 - methyl - 2 -[ 3 - oxo - 1 - decyl ]- 5 - oxocyclopentyl }- hept - 5 - enoate ; and 13 , 14 - dihydro - 6 , 15 - diketo - 19 - methyl - pge 2 ethyl ester is ethyl 7 -{( 1r , 2s , 3s )- 3 - hydroxy - 2 -( 7 - methyl - 3 - oxo - 1 - octyl )- 5 - oxocyclopentyl }- 6 - oxo - heptanoate . 13 , 14 - dihydro - 15 - keto - 20 - ethyl - pgf 2 α isopropyl ester is isopropyl ( z )- 7 -[( 1r , 2r , 3r , 5s )- 3 , 5 - dihydro - 2 -{ 3 - oxo - 1 - decyl )- cyclopentyl ]- hept - 5 - enoate ; and 13 , 14 - dihydro - 15 - keto - 20 - methyl - pgf 2 α methyl ester is methyl ( z )- 7 -[( 1r , 2r , 3r , 5s )- 3 , 5 - dihydroxy - 2 -{ 3 - oxo - 1 - nonyl }- cyclopentyl ]- hept - 5 - enoate . the 15 - keto - pg compound used in the present invention may be any derivative of a pg insofar as having an oxo group at position 15 in place of the hydroxy group , and may further include a compound having one double bond between positions 13 and 14 ( 15 - keto - pg type 1 compound ), two double bonds between positions 13 and 14 , and positions 5 and 6 ( 15 - keto - pg type 2 compound ), and three double bonds between positions 5 and 6 , positions 13 and 14 , and positions 17 and 18 ( 15 - keto - pg type 3 compound ), and a derivative thereof wherein the bond between the positions 13 and 14 is single bond , in place of the double bond ( 13 , 14 - dihydro - 15 - keto - pg compound ). typical examples of the pg compounds used in the present invention include 15 - keto - pg type 1 , 15 - keto - pg type 2 , 15 - keto - pg type 3 , 13 , 14 - dihydro - 15 - keto - pg type 1 , 13 , 14 - dihydro - 15 - keto - pg type 2 , 13 , 14 - dihydro - 15 - keto - pg type 3 and the derivatives thereof . examples of the substitution compounds or derivatives include a pg compound of which the carboxy group at the end of the alpha chain is esterified ; physiologically acceptable salt thereof ; an unsaturated derivative having a double bond between positions 2 and 3 or a triple bond between positions 5 and 6 ; pg compounds having substituent ( s ) on carbon atom ( s ) at position ( s ) 3 , 5 , 6 , 16 , 17 , 18 , 19 and / or 20 ; and pg compounds having lower alkyl or a hydroxy ( lower ) alkyl group at position 9 and / or 11 in place of the hydroxy group . according to the present invention , preferred substituents on the carbon atom at position ( s ) 3 , 17 , 18 and / or 19 include alkyl having 1 - 4 carbon atoms , especially methyl and ethyl . preferred substituents on the carbon atom at position 16 include lower alkyl such as methyl and ethyl , hydroxy , halogen atom such as chlorine and fluorine , and aryloxy such as trifluoromethylphenoxy . preferred substituents on the carbon atom at position 17 include halogen atom such as chlorine and fluorine . preferred substituents on the carbon atom at position 20 include saturated or unsaturated lower alkyl such as c 1 - 4 alkyl , lower alkoxy such as c 1 - 4 alkoxy , and lower alkoxy alkyl such as c 1 - 4 alkoxy - c 1 - 4 alkyl . preferred substituents on the carbon atom at position 5 include halogen atoms such as chlorine and fluorine . preferred substituents on the carbon atom at position 6 include an oxo group forming a carbonyl group . stereochemistry of pgs having hydroxy , lower alkyl or hydroxy ( lower ) alkyl substituent on the carbon atom at positions 9 and 11 may be α , β or a mixture thereof . further , the above described derivatives may have a ω chain shorter than that of the primary pgs and a substituent such as alkoxy , cyclohexyl , cyclohexyloxy , phenoxy and phenyl at the end of the truncated ω - chain . especially preferred compounds include a 13 , 14 - dihydro - 15 - keto - pg compound that has a single bond between positions 13 and 14 ; a 15 - keto - 20 - lower alkyl ( especially ethyl ) pg compound that has a lower alkyl , especially ethyl , at carbon atom of position 20 ; a 15 - keto - pgf compound that has hydroxy groups at positions 9 and position 11 of the five memberd ring . a preferred prostaglandin compound used in the present invention is represented by the formula ( i ): wherein l , m and n are hydrogen , hydroxy , halogen , lower alkyl , hydroxy ( lower ) alkyl , lower alkanoyloxy or oxo , wherein at least one of l and m is a group other than hydrogen , and the five - membered ring may have at least one double bond ; a is — ch 3 , or — ch 2 oh , — coch 2 oh , — cooh or a functional derivative thereof ; wherein r 4 and r 5 are hydrogen , hydroxy , halogen , lower alkyl , lower alkoxy or hydroxy ( lower ) alkyl , wherein r 4 and r 5 are not hydroxy and lower alkoxy at the same time ; r 1 is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue , which is unsubstituted or substituted with halogen , alkyl , hydroxy , oxo , aryl or heterocyclic group , and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur ; and ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue , which is unsubstituted or substituted with halogen , oxo , hydroxy , lower alkoxy , lower alkanoyloxy , cyclo ( lower ) alkyl , cyclo ( lower ) alkyloxy , aryl , aryloxy , heterocyclic group or hetrocyclic - oxy group ; lower alkoxy ; lower alkanoyloxy ; cyclo ( lower ) alkyl ; cyclo ( lower ) alkyloxy ; aryl ; aryloxy ; heterocyclic group ; heterocyclic - oxy group . a more preferred prostaglandin compound used in the present invention is represented by the formula ( ii ): wherein l and m are hydrogen , hydroxy , halogen , lower alkyl , hydroxy ( lower ) alkyl , lower alkanoyloxy or oxo , wherein at least one of l and m is a group other than hydrogen , and the five - inembered ring may have one or more double bonds ; a is — ch 3 , or — ch 2 oh , — coch 2 oh , — cooh or a functional derivative thereof ; wherein r 4 and r 5 are hydrogen , hydroxy , halogen , lower alkyl , lower alkoxy or hydroxy ( lower ) alkyl , wherein r 4 and r 5 are not hydroxy and lower alkoxy at the same time ; x 1 and x 2 are hydrogen , lower alkyl , or halogen ; r 1 is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue , which is unsubstituted or substituted with halogen , alkyl , hydroxy , oxo , aryl or heterocyclic group , and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur ; r 2 is a single bond or lower alkylene ; and r 3 is lower alkyl , lower alkoxy , lower alkanoyloxy , cyclo ( lower ) alkyl , cyclo ( lower ) alkyloxy , aryl , aryloxy , heterocyclic group or heterocyclic - oxy group . in the above formula , the term “ unsaturated ” in the definitions for r 1 and ra is intended to include at least one or more double bonds and / or triple bonds that are isolatedly , separately or serially present between carbon atoms of the main and / or side chains . according to the usual nomenclature , an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions , and an unsaturated bond between two distal positions is represented by denoting both of the positions . the term “ lower or medium aliphatic hydrocarbon ” refers to a straight or branched chain hydrocarbon group having 1 to 14 carbon atoms ( for a side chain , 1 to 3 carbon atoms are preferable ) and preferably 1 to 10 , especially 1 to 8 carbon atoms . the term “ lower ” throughout the specification is intended to include a group having 1 to 6 carbon atoms unless otherwise specified . the term “ lower alkyl ” refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes , for example , methyl , ethyl , propyl , isopropyl , butyl , isobutyl , t - butyl , pentyl and hexyl . the term “ lower alkylene ” refers to a straight or branched chain bivalent saturated hydrocarbon group containing 1 to 6 carbon atoms and includes , for example , methylene , ethylene , propylene , isopropylene , butylene , isobutylene , t - butylene , pentylene and hexylene . the term “ lower alkoxy ” refers to a group of lower alkyl - o —, wherein lower alkyl is as defined above . the term “ hydroxy ( lower ) alkyl ” refers to a lower alkyl as defined above which is substituted with at least one hydroxy group such as hydroxymethyl , 1 - hydroxyethyl , 2 - hydroxyethyl and 1 - methyl - 1 - hydroxyethyl . the term “ lower alkanoyloxy ” refers to a group represented by the formula rco — o —, wherein rco — is an acyl group formed by oxidation of a lower alkyl group as defined above , such as acetyl . the term “ cyclo ( lower ) alkyl ” refers to a cyclic group formed by cyclization of a lower alkyl group as defined above but contains three or more carbon atoms , and includes , for example , cyclopropyl , cyclobutyl , cyclopentyl and cyclohexyl . the term “ cyclo ( lower ) alkyloxy ” refers to the group of cyclo ( lower ) alkyl - o —, wherein cyclo ( lower ) alkyl is as defined above . the term “ aryl ” may include unsubstituted or substituted aromatic hydrocarbon rings ( preferably monocyclic groups ), for example , phenyl , tolyl , xylyl . examples of the substituents are halogen atom and halo ( lower ) alkyl , wherein halogen atom and lower alkyl are as defined above . the term “ aryloxy ” refers to a group represented by the formula aro —, wherein ar is aryl as defined above . the term “ heterocyclic group ” may include mono - to tri - cyclic , preferably monocyclic heterocyclic group which is 5 to 14 , preferably 5 to 10 membered ring having optionally substituted carbon atom and 1 to 4 , preferably 1 to 3 of 1 or 2 type of hetero atoms selected from nitrogen atom , oxygen atom and sulfur atom . examples of the heterocyclic group include furyl , thienyl , pyrrolyl , oxazolyl , isoxazolyl , thiazolyl , isothiazolyl , imidazolyl , pyrazolyl , furazanyl , pyranyl , pyridyl , pyridazinyl , pyrimidyl , pyrazinyl , 2 - pyrrolinyl , pyrrolidinyl , 2 - imidazolinyl , imidazolidinyl , 2 - pyrazolinyl , pyrazolidinyl , piperidino , piperazinyl , morpholino , indolyl , benzothienyl , quinolyl , isoquinolyl , purinyl , quinazolinyl , carbazolyl , acridinyl , phenanthridinyl , benzimidazolyl , benzimidazolinyl , benzothiazolyl , phenothiazinyl . examples of the substituent in this case include halogen , and halogen substituted lower alkyl group , wherein halogen atom and lower alkyl group are as described above . the term “ heterocyclic - oxy group ” means a group represented by the formula hco —, wherein hc is a heterocyclic group as described above . the term “ functional derivative ” of a includes salts , preferably pharmaceutically acceptable salts , ethers , esters and amides . suitable “ pharmaceutically acceptable salts ” include salts formed with non - toxic bases conventionally used in pharmaceutical field , for example a salt with an inorganic base such as an alkali metal salt ( such as sodium salt and potassium salt ), an alkaline earth metal salt ( such as calcium salt and magnesium salt ), an ammonium salt ; or a salt with an organic base , for example , an amine salt including such as methylamine salt , dimethylamine salt , cyclohexylamine salt , benzylamine salt , piperidine salt , ethylenediamine salt , ethanolamine salt , diethanolamine salt , triethanolamine salt , tris ( hydroxymethylamino ) ethane salt , monomethyl - monoethanolamine salt , procaine salt and caffeine salt ), a basic amino acid salt ( such as arginine salt and lysine salt ), tetraalkyl ammonium salt and the like . these salts may be prepared by a conventional process , for example from the corresponding acid and base or by salt interchange . examples of the ethers include alkyl ethers , for example , lower alkyl ethers such as methyl ether , ethyl ether , propyl ether , isopropyl ether , butyl ether , isobutyl ether , t - butyl ether , pentyl ether and 1 - cyclopropyl ethyl ether ; and medium or higher alkyl ethers such as octyl ether , diethylhexyl ether , lauryl ether and cetyl ether ; unsaturated ethers such as oleyl ether and linolenyl ether ; lower alkenyl ethers such as vinyl ether , allyl ether ; lower alkynyl ethers such as ethynyl ether and propynyl ether ; hydroxy ( lower ) alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether ; lower alkoxy ( lower ) alkyl ethers such as methoxymethyl ether and 1 - methoxyethyl ether ; optionally substituted aryl ethers such as phenyl ether , tosyl ether , t - butylphenyl ether , salicyl ether , 3 , 4 - di - methoxyphenyl ether and benzamidophenyl ether ; and aryl ( lower ) alkyl ethers such as benzyl ether , trityl ether and benzhydryl ether . examples of the esters include aliphatic esters , for example , lower alkyl esters such as methyl ester , ethyl ester , propyl ester , isopropyl ester , butyl ester , isobutyl ester , t - butyl ester , pentyl ester and 1 - cyclopropylethyl ester ; lower alkenyl esters such as vinyl ester and allyl ester : lower alkynyl esters such as ethynyl ester and propynyl ester ; hydroxy ( lower ) alkyl ester such as hydroxyethyl ester ; lower alkoxy ( lower ) alkyl esters such as methoxymethyl ester and 1 - methoxyethyl ester ; and optionally substituted aryl esters such as , for example , phenyl ester , tolyl ester , t - butylphenyl ester , salicyl ester , 3 , 4 - di - methoxyphenyl ester and benzamidophenyl ester ; and aryl ( lower ) alkyl ester such as benzyl ester , trityl ester and benzhydryl ester . the amide of a means a group represented by the formula - conr ′ r ″, wherein each of r ′ and r ″ is hydrogen , lower alkyl , aryl , alkyl - or aryl - sulfonyl , lower alkenyl and lower alkynyl , and include for example lower alkyl amides such as methylamide , ethylamide , dimethylamide and diethylamide ; arylamides such as anilide and toluidide ; and alkyl - or aryl - sulfonylamides such as methylsulfonylamide , ethylsulfonyl - amide and tolylsulfonylamide . preferred examples of l and m include hydrogen , hydroxy and oxo , and especially , a compound wherein both of l and m are hydroxy which has a 5 - membered ring structure of , so called , pgf type , or a compound wherein l is hydroxy and m is oxo which has a 5 - membered ring structure of , so called , pge type . preferred example of a is — cooh , its pharmaceutically acceptable salt , ester or amide thereof . preferred example of x 1 and x 2 is fluorine , so called 16 , 16 - difluoro type . preferred r 1 is a hydrocarbon residue containing 1 - 10 carbon atoms , preferably 6 - 10 carbon atoms . further , at least one carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur . examples of r 1 include , for example , the following groups : preferred ra is a hydrocarbon containing 1 - 10 carbon atoms , more preferably , 1 - 8 carbon atoms . ra may have one or two side chains having one carbon atom . the configuration of the ring and the α - and / or ω chains in the above formula ( i ) and ( ii ) may be the same as or different from that of the primary pgs . however , the present invention also includes a mixture of a compound having a primary type configuration and a compound of a non - primary type configuration . the typical example of the present compounds are 13 , 14 - dihydro - 15 - keto - 20 - ethyl - pgf compound or 13 , 14 - dihydro - 15 - keto - 17 - phenyl - 18 , 19 , 20 - trinor - prostaglandin f compound and its derivative or analogue , or 13 , 14 - dihydro - 17 - phenyl - 18 , 19 , 20 - trior - pgf 2α isopropyl ester , 16 -( 3 - trifluoromethyl phenoxy )- 17 , 18 , 19 , 20 - tetranor pgf 2α isopropyl ester or 17 - phenyl - 18 , 19 , 20 - trinor - pgf 2α n - ethylamide . in the present invention , the pg compound which is dihydro between 13 and 14 , and keto (═ o ) at 15 position may be in the keto - acetal equilibrium by formation of a hemiacetal between hydroxy at position 11 and keto at position 15 . for example , it has been revealed that when both of x 1 and x 2 are halogen atoms , especially , fluorine atoms , the compound contains a tautomeric isomer , bicyclic compound . if such tautomeric isomers as above are present , the proportion of both tautomeric isomers varies with the structure of the rest of the molecule or the kind of the substituent present . sometimes one isomer may predominantly be present in comparison with the other . however , it is to be appreciated that the present invention includes both isomers . further , the 15 - keto - pg compounds used in the invention include the bicyclic compound and analogs or derivatives thereof . wherein , a is — ch 3 , or — ch 2 oh , — coch 2 oh , — cooh or a functional derivative thereof ; x 1 ′ and x 2 ′ are hydrogen , lower alkyl , or halogen ; wherein r 4 ′ and r 5 ′ are hydrogen , hydroxy , halogen , lower alkyl , lower alkoxy or hydroxy ( lower ) alkyl , wherein r 4 ′ and r 5 ′ are not hydroxy and lower alkoxy at the same time . r 1 is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue , which is unsubstituted or substituted with halogen , alkyl , hydroxy , oxo , aryl or heterocyclic group , and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen , nitrogen or sulfur ; and r 2 ′ is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue , which is unsubstituted or substituted with halogen , oxo , hydroxy , lower alkoxy , lower alkanoyloxy , cyclo ( lower ) alkyl , cyclo ( lower ) alkyloxy , aryl , aryloxy , heterocyclic group or hetrocyclic - oxy group ; lower alkoxy ; lower alkanoyloxy ; cyclo ( lower ) alkyl ; cyclo ( lower ) alkyloxy ; aryl ; aryloxy ; heterocyclic group ; heterocyclic - oxy group . r 3 ′ is hydrogen , lower alkyl , cyclo ( lower ) alkyl , aryl or heterocyclic group . furthermore , while the compounds used in the invention may be represented by a formula or name based on keto - type regardless of the presence or absence of the isomers , it is to be noted that such structure or name does not intend to exclude the acetal type compound . in the present invention , any of isomers such as the individual tautomeric isomers , the mixture thereof , or optical isomers , the mixture thereof , a racemic mixture , and other steric isomers may be used in the same purpose . some of the compounds used in the present invention may be prepared by the method disclosed in u . s . pat . nos . 5 , 073 , 569 , 5 , 166 , 174 , 5 , 221 , 763 , 5 , 212 , 324 , 5 , 739 , 161 and 6 , 242 , 485 these cited references are herein incorporated by reference . the pg compounds described as above are useful as agent for treatment in the ophthalmic area which is useful for treatment of various symptoms in the ophthalmic area . the term “ ophthalmic solution ” used herein refers any form of liquid composition suitable for topical eye administration and the liquid composition may be in the form of solution , emulsion or suspension . the term “ treatment ” used herein refers to any means of control of a condition including prevention , cure , relief of the condition , and arrestation or relief of development of the condition . in the ophthalmic solution of the present invention , the pg compound , the active ingredient , may be any of the above described compounds . the amount of the pg compound in the ophthalmic solution is not limited as long as it is sufficient to provide the expected therapeutic effects . in general , the amount of the pg compound in the solution may be from 0 . 00001 to 10 w / w %, preferably , 0 . 0001 to 5 w / w %, more preferably 0 . 001 to 1 % of the solution . in this specification and claims , “ viscosity - increasing compound ” is selected from the group consisting of acrylate polymers , polyvinyl alcohols , glycerin , cellulose polymers and polyl - lactams . examples of the viscosity - increasing compounds include acrylate polymers , or also called as carboxyvinyl polymers , such as carbomer , for example carbopol ™ 941 , 934 , 940 , 941 , 971 , 974 , 980 and 981 , and polycarbophil , for example noveon ™ aa - 1 , ca - 1 and ca - 2 ; polyvinyl alcohols ; glycerin ; cellulose polymers such as methylcellulose , methylethylcellulose , hydroxypropylmethylcellulose , hydroxyethylcellulose , and carboxymethylcellulose ; and poly - lactams such as polyvinyl pyrrolidone . based on the necessity or purpose of the treatment , the viscosity - increasing compound may optionally be a combination of two or more above - described compounds . further , if it is required , the other viscosity - increasing compounds such as polyethylene glycol , dextran or gelatins may be admixed with the above described viscosity - increasing compounds of the present invention . the amount of the viscosity - increasing compound in the present ophthalmic solution may vary depending on the amount of the pg compound , or the kind or the molecular weight of the viscosity - increasing compound employed . generally , the amount of about 0 . 001 - 30 w / w %, preferably about 0 . 01 - 10 w / w % of the whole solution is enough to provide the expected effect . the ophthalmic solution of the present invention may be manufactured by a conventional manner , for example , by adding a pg compound and a viscosity - increasing compound to purified water , and dissolving or mixing them in the water . further , in order to improve the solubility of the pg compound to water , esters of polyoxyethylene sorbitane mono higher fatty acid such as polysorbate 80 , may be added to the purified water . alternatively , by mixing a pg compound with an ester of polyoxyethylene sorbitane mono higher fatty acid and then adding the mixture to purified water . the concentration of the esters of polyoxyethylene sorbitane mono higher fatty acid may vary depending on the amount of the pg , and in general , may be 0 . 01 - 10 w / w %, preferably , 0 . 05 - 5 w / w % of whole solution . in addition , the ophthalmic solution of the present invention may contain other active ingredients in so far as it does not act adverse to the purpose of the present invention . the ophthalmic solution of the present invention may further contain additives which have been employed in conventional ophthalmic solutions . for example , buffers or isotonic agents such as salts like phosphates , borates or sodium chloride , or saccharides such as mannitol ; preservatives such as benzalkonium chloride , benzethonium chloride , chloro butanol , or paraben . the ophthalmic solution of the invention is useful for treating glaucoma , cataract or optic nerve disorders , or for lowering the intraocular pressure or for increasing the choroidal blood flow . the ophthalmic solution of the present invention can provide enough therapeutic effect by , for example , administering once a day , since the duration of the effect of the pg compound is elongated . accordingly , the ophthalmic solution of the present invention may be useful for treatment of a various symptoms in the ophthalmic area . the present invention will be explained in more detail by means of the following examples , which are illustrated by way of example only and never intended to limit the scope of the present invention . twelve ( 12 ) mg of isopropyl unoprostone , 50 mg of carbopol ™ 940 and 90 mg of polysorbate 80 were admixed with 50 ml of purified water , more purified water was added to make the total volume 100 ml , and dissolved the mixture to provide ophthalmic solution 1 . ophthalmic solution 2 was prepared by the same manner as example 1 except for 200 mg of polyvinyl alcohol was added in place of carbopol 940 . ophthalmic solution 3 was prepared by the same manner as example 1 except for 150 mg of glycerin was added in place of carbopol 940 . ophthalmic solution 4 was prepared by the same manner as example 1 except for 20 mg of hydroxymethyl cellulose was added in place of carbopol 940 . ophthalmic solution 5 was prepared by the same manner as example 1 except for 100 mg of polyvinyl pyrrolidone was added in place of carbopol 940 .

the present invention relates to an ophthalmic solution comprising a prostaglandin compound and viscosity - increasing compound . the ophthalmic solution of the invention can provide elongated duration of the effect when administrated topically to the eyes of a patient .

the nutritional , pharmaceutical or dietetic preparation according to the invention can be manufactured in dry form , for example as bar , as powder , as tablet , but cookie or as cereal . the preparations can also have a liquid form , e . g . as drink , served as ready to drink , as pudding , as sauce as capable or as ( soup ) concentrate . the preparations are manufactured using methods that are known in the art . for example powders can be manufactured by spray - drying or drying on drums . spray - dried powders can be agglomerated in order to modify bulk density or solubility performance ( e . g ., wettability ). when powders are manufactured , methods for preventing sticking of the powder can be taken that are known in the art , e . g . the addition of specific agents such as tricalcium phosphate or silicon dioxide . when tablets are manufactured the usual tabletting agents ( such as magnesium stearate ) are included . in order to give the nutritional preparations optimal organoleptic properties , methods can be used that are known in the art , such as setting of ph and the addition of flavoring agents and colorants . also preservatives can be added to increase shelf life , and whose use in known in the art . appropriate amounts of the ingredients are blended in order to manufacture the final product . the final product can also comprise separate compartments that each may comprise part of total number or amount of the ingredients that are required . the final product can be packaged in a way that is suitable for the type of product that is selected . these ways are known in the art . for example liquids can be packaged in bottles or cartons , that have a volume that is appropriate for containing the volume that is required for 0 . 5 - 10 daily doses . powders can for example be packed in cans , bags or sachets . these packages can have a volume of typically 0 . 5 - 50 daily doses . the active components can be mixed with other ingredients that are suitable . for example powdered forms of the preparations according to the invention can use spray - dried proteins of dairy , vegetable or animal origin , such as skimmed milk powder , whey powder , egg white powder , potato protein , soy protein , etc . or hydrolysates , or mixtures thereof . it is preferred to use proteins that are relatively rich in histidine and glutamine and poor in tryptophan , such as caseins . specific synthetic amino acids , such as l - histidine , or peptides , such as alanyl - gluamine or glutamyl - glutamine , may be added to achieve this goal . when proteins are included in the nutritional preparations , the amount that is included depends on the application of the product . in complete formulae typically an amount of 5 - 120 g per daily dose is included . in complete formulae for young infants the amount will be in the range 5 - 15 g per daily dose and preferably 6 - 10 g per daily dose . in complete enteral nutrition for feeding surgery patients typically 50 - 120 g and preferably 60 - 90 g per daily dose are included . in supplements typically 0 - 60 g protein per daily dose will be included . in supplements for sportsmen and persons that temporarily have high protein requirements ( such as burn patients ) or deficiencies in amino acid status ( e . g . due to malnutrition ) up to 60 g protein per daily dose can be included . in other situations protein is not included in the product or present in lower amounts , typically 0 - 20 g per daily dose . in supplements it is advantageous to include free amino acids , especially histidine , in particular the l - isomer . in some cases the support of tnm should be combined with support of growth and anabolism . it appears that especially a mixture of histidine , the branched chain amino acids leucine and isoleucine , lysine , methionine and phenylalamine has anabolic properties . for example in products for sportsmen the following mixture of amino acids appeared to be especially beneficial for muscle growth , when consumed in an amount of more than 2 and preferably more than 4 g per daily dose : 3 - 10 wt % histidine , 5 - 15 wt % isoleucine , 10 - 23 wt % leucine , 10 - 23 wt % lysine , 5 - 15 wt % methionine , 5 - 15 wt %, phenylalamine and 5 - 15 wt % threonine . the product should in such a case contain no or little protein . when relative large amounts of proteins or amino acids are included in the product it is preferred to increase the amount of vitamin b6 in the product . the extra amount that should be included in the product can be determined by using the criterium : 2 mg extra vitamin b6 per 100 g protein equivalent . as vitamin b6 source , pyridoxine , pyridoxamine or pyridoxal or functional equivalents thereof can be used . also powdered carbohydrates can be used that should be able to serve as glucase provider . glucose syrup ( dried ) or starches and especially their hydrolysates are useful . in sweet products it is preferred to use malto - dextrins that are heavily hydrolyzed . in more salty products lightly hydrolyzed maltodextrins should be used , preferably those having a degree of hydrolyses below twelve . it is important to include glucose into the product , because it allows the biosynthesis of sufficient amounts of reducing equivalents and of chemical energy . both are essential for total nucleotide metabolism . in addition glucose can neutralize excess ribose , which reaction is supported by thiamine phosphate and magnesium . from glucose also extra ribose can be formed in those situation that : ( 1 ) too little ribose is administered via the claimed products or ( 2 ) too little ribose is present in tissue , relative to the requirements that are put by the specific conditions of the tissue . it is therefore preferred to include in the product 1 - 50 g glucose or its functional equivalent and more preferably 2 - 20 g is included . also 0 . 4 - 10 mg , and preferably 1 . 0 - 8 mg thiamin per daily doses , or its functional equivalents should be included . preferably the hydrochloric acid salt is used . as source of the active components either pure chemical substances or their functional equivalents such as racemic mixtures or food grade extracts of raw materials or mixtures thereof can be used as ingredients . d (−) ribose is a pentose sugar that can be purchased as crystalline product . ribose is also a main constituent of nucleic acids . these acids can be isolated from yeast or lives . either the nucleic acid fraction or extracts of hydrolysates thereof can be used as ribose source . it is preferred to use a preparation that comprises a higher amount of ribose than of the sum of nucleotides , nucleosides and nucleic acid bases , due to the imbalances in endogenous nucleotide concentrations that could occur . it is also possible to use rough extracts from carbohydrate hydrolysates . for example potato starch can be converted by an enzymatic process into a ribose - rich ingredient . most preferable ribose , when referred to in the specification , does not include nucleic acid bound ribose . it is preferred to use synthetic ribose , either as racemate , but most preferably as d (−) ribose . when d (−) ribose is used as ribose source per daily about 0 . 5 - 40 g should be included in particular 1 - 15 g and most preferably 2 - 10 g . when other materials are used as ribose source it depends on the ribose content of the ingredient how much of that raw ingredient should be included in the composition . where reference is made in this specification to folic acid or folate , all functional equivalents of folic acid are included . folate is a vitamin that can be purchased as free folic acid ( pteroyl - monoglutamic acid ) or folinic acid ( formyl - tetrahydrofolic acid ). also polyglutamate forms can be used as functional ingredient , especially when also zinc is present in the formulation . rich sources of folate are yeast and liver and extracts of some green vegetables ( broccoli , brussels sprouts , spinach ), or fruits ( citrus fruit ) on the condition they are standardized on folate content . it is preferred to use synthetic folic acid . in order to be effective the compositions should comprise at least 100 μg folate per daily dose . this limit is selected to support adequately total nucleotide metabolism in young infants . in adults the amounts that are required have to be higher ; preferably more than 250 μg have to be supplied per daily dose and most preferably more than 400 μg . in those adults that suffer from a genetically a compromised enzyme - system to metabolise folate even higher amounts are required , e . g . more than 1 mg / day . for normal adults it is most preferred to include maximally 5 mg folate in the product . when amounts above 4 μg folic / folate per kg body weight are supplied per day , it is preferred that at least 1 μg vitamin b12 per 100 mg folate is included . to observe an optimal effect it is required to include niacin into the product . niacin appears to have a synergistic effect when supplied together with ribose and folate , with regard to support of tnm and the formation of dna and rna . at least 4 mg niacin equivalents (= ne ) should be included , in products for adults in particular 30 - 200 mg ne per daily dose . it is thought that in this dose niacin provides in many persons extra reducing equivalents to diseased tissue to allow increased production of chemical energy and conversion of different forms of nucleotides and of folates and increase formation of dna and increase tissue levels of triphosphorylated forms of all nucleotides . it is also preferred to include magnesium in the formulae . it appears that magnesium deficiencies occur rather frequently . deficiencies will cause a decreased capacity to transfer activated phosphates to other molecules . magnesium should be present in an amount of at least 20 mg per daily dose . products for adults comprise preferably per daily dose ( dependant on the application of the product ) 100 - 500 mg . it is important to include several compounds that are able to influence rates of desirable metabolic patterns . for this reason the product should preferably include histidine . histidine is also added to neutralize excess beta - alanine and permit biosynthesis of sufficient carnoserine and anserine . typically the amount of histidine will be about 0 . 2 - 5 . 0 g per daily dose and preferably 0 . 3 - 3 g per daily dose . preferably glucose is also present when histidine is present , with a histidine to glucose weight ratio of 0 . 015 to 1 . 5 . the product should not be fortified with synthetic tryptophan or peptides . endogenous inorganic phosphate is an important regulator of pathways . in addition it is important to avoid deficiencies . when phosphate is included in the product , the amount per daily dose will be in the range 20 - 2000 mg , and preferably 100 - 1000 mg . citrate can be used in the form of pure cristalline citric acid or salts thereof , but also be present in extracts of fruit ( oranges , lime ). when citrate is included the ph of the final product should be in the range 3 - 8 and preferably 6 - 7 . 5 the amount of citrate per daily dose of product should be 0 . 1 - 6 g and preferably 0 . 3 - 3 g , dependant on the use of the product . orotate is defined as being those components that after consumptions that after consumption will provide orotate ions in the blood plasma . suitable sources are orotic acid ( 6 - carboxy - 2 , 4 - dihydroxypyrimidine ), salts thereof such as sodium or potassium or zinc salts , esters such as choline — or methyl esters and extracts that are rich in orotic acid such as certain extracts from liver . also precursors like arginine , glutamine or aspartate can be used . in order to be effective , the product should comprise 0 . 1 - 8 g orotate per daily dose . this amount is in general less than the amount of ribose or glutamine in the product and should be determined by using the criterium that about 0 . 04 - 0 . 3 g orotate is given per kg body weight . when arginine or aspartate is used as precursor for orotate , per day more than 1 g should be administered and preferably more than 5 grams . orotate is claimed to ensure proper biosynthesis of pyrimidines and to neutralise excess of ribose that may get formed in the specific conditions of that patient . this also would ensure sufficient tissue levels of beta - alamine , carnosine and anserine . it is found that inclusion of vitamin b12 in the product increases nucleotide levels in tissue . as source of vitamin b12 , cobalamines , such as cyanocobalamine can be used . the quantity should be 0 . 2 - 4000 μg and preferably 0 . 5 - 5 μg per daily doses . as mentioned above it is important to include vitamin b6 when the product is meant to be used for the prevention or treatment of some cerebral disorders or neurodegenerative diseases such as parkinson , huntington , alzheimer , adhd , depression , schizophrenia and mood disorders . this amount should be 2 - 10 mg and preferably 2 - 4 mg per daily dose . for other applications , such as infant formula , the product can comprise less vitamin b6 . in general the preparations according to the invention will comprise 0 . 3 - 10 and preferably 0 . 5 - 4 mg per daily dose . selenium is preferably included into the product to ensure a proper supply of this key component for the enzyme catalase . as selenium source selenium salts such as sodium selenite can be used but also extracts of raw materials that are rich in selenium such as selenium yeast . the amount to be included in 10 - 300 μg and in particular for products for adults 40 - 150 μg per daily doses . other food grade components such as lipids ( in general ), additional vitamins , minerals , trace elements , carmitine , creatine , coenzym q10 , conjugated linoleic acid ( cla ), alfa - lipoic acid or their functional analogues or fibre could be part of the composition , dependant on the application of the nutritional compositions . the use of these components for disease - specific nutritional compositions is disclosed in the prior art . long - chain polyunsaturated fatty acids , especially ω - 3 unsaturated fatty acids such as dha , epa and stearidonic acid are preferably included in compositions intended for enhancing the immune function of patients . these fatty acids may originate from known sources such as marine algal oils , fish oils , selected vegetable oils ( e . g . from echium ) or from synthetic sources . the invention also pertains to a method of enhancing uric acid antioxidant capacity in blood plasma , comprising administering an effective amount of at least one compound selected from ribose and folate . the effective amounts depend on the condition of the subject and on the required antioxidant power , and can be selected from those given in table 1 . other antioxidants may also be present , although preferably at lower doses than commonly used . conditions for which the compositions of the invention can be used include in general those conditions in which the biosynthetic capacity is insufficient , e . g . due to metabolic disorders or nutrient deficiencies . in such conditions large amounts of specific nucleotides and / or related metabolites are required locally , e . g ., due to diseases or local disorders or specific demands , and transport of nutrients and tnm components is imparted . persons that would benefit from these products are persons that have a general insufficiency to synthesize , salvage or convert nucleotides such as those suffering from protein - energy malnutrition and person that suffer from an inherited disturbance in the expression of one of the enzymes that are involved in tnm . the same general problem can occur in premature or young infants due to an under development of their enzyme systems . also many elderly persons and persons suffering from liver problems ( for example due to alcohol abuse or hepatitis ) have insufficient capacity for nucleotide synthesis due to imparted enzyme systems and need support of the most critical steps in tnm . the product is also meant to be used in those conditions that locally and sometimes temporarily very high requirements exist for nucleotides or related metabolites and the requirements cannot readily be met by available biochemical capacity . in case of trauma ( for example after an accident or surgery ) locally high amounts of all nucleotides must be generated in order to repair ( replace ) damaged tissue . during various inflammatory disorders during some stage lymphocytes rapidly proliferate , which puts high demands on nucleotide supply to synthesizing tissues . in addition it is beneficial to increase total antioxidant capacity of the relevant extracellular fluids , especially in those situations that an uncontrolled inflammatory reaction exits . high amounts of nucleotides must also be available locally during spermatogenesis , during lactation and in bone marrow during periods of ( increased ) synthesis of blood components . the product is therefore also claimed to be useful for improving subfertility , increasing milk quantity and quality of milk during lactation and useful when used after surgery . nutritional products according for these types of patients may be fortified with trace elements , minerals and vitamins to meet their nutritional requirements . products for use after surgery should preferably comprise a protein and lipid source isolated from egg or milk and growth factors , such as insulin - like growth factors and epidermal growth factors . under normal conditions gut epithelial cells have a relatively short half - life and are produced from specialized stem cells . during proliferation but also during maturation ( migration ) nucleotide and / or energy requirements of these cells are high . several gut disorders are associated with a very high throughput of gut epithelial cells , which requires local availability of large amounts of various nucleotides . inclusion of glutamine or its equivalents will further enhance the effectivity of the nutritional compositions of the invention , especially when administered at more than 1 g per daily dosage . also during recovery after chemo - or radiotherapy , large amounts of nucleotides must be available in the right relative proportions . during therapy large members of cells will die due to apoptosis and large amounts of nucleotides are released . once these have been metabolized extra biosynthetic capacity is required , to meet the high demands . the nutritional compositions of the invention will support recovery after damage due to chemotherapy especially in the mucosal tissue . temporary insufficiencies in biosynthetic capacity of nucleotides become in particular evident during ischaemic situations as may occur during trauma , surgery and cardio - and cerebro - vascular problems . the decreased blood supply causes that low amounts of nucleotides or related metabolites are offered to the underlying tissues . it is thought that by supplying the claimed product , the concentrations of the required nucleotides or related products are sufficiently higher to improve the status of tissue that suffers from a bad blood supply . in case the tissue is brain tissue , the product will decrease the amount of excitatory amino acids , such as glutamate , that will be released . also during and after heavy exercise , existing deficiencies in tissue nucleotide content and / or imparted capacity for tnm become evident . pools of atp will rapidly become depleted and it will take a relatively long time before tissue that has been damaged during exercise will be repaired or replaced . this will lead to muscle soreness and injuries . the product is also claimed to be useful in treatment of ms and fatigue . nucleotides play an important regulating role in cell metabolism , and can serve as donor or acceptor of amine groups in catabolism of asparatate in periods that demands on muscle are high and blood supply does not meet requirements . the product is further claimed to be useful in the prevention of cancer . without wanting to be bound by theory it is thought that adenine and prpp are involved in the polymerization of adp - ribose onto nuclear proteins , which are important for cell regulation and dna repair . improvement of the possibilities for repair of damaged dna then prevents the development of tumor cells . the product is further claimed to be especially useful in the prevention and treatment of rheumatoid arthritis and other joint problems . it is thought that the product operates by means of its effect on sulphation capacity . this would lead to an increase in concentrations and / or variety of sulphated polysaccharides in interstitial and synovial fluid , thus improving the lubricating properties . it is also claimed that the products improve immune function . without wanting to be bound by theory , we think that this effect is thought to the effect of the formulations on mucus composition and levels of endogenous amounts of glycoproteins , immunoglobulins and proteoglycans . these components are essential for proper functioning of membrane structures including their recognition function and the functioning of enzymes , in particular with regard to their specificity . this beneficial effect on the barrier function of mucus is claimed to be particularly relevant for persons suffering from respiratory infections or common cold . the preparations are further claimed to be useful in preventing problems with blood supply to tissues . this is thought to be due to the improvement of blood clotting parameters and the effect on microvascularisation . the products are further helpful in the treatment of cystic fibroses and treatment or prevention of malaria and tuberculose . the effect of the product is further enhanced by fortification with vitamin b6 , especially in an mount of more than 3 mg / day . the product is further claimed to be useful in the treatment of intoxications , e . g . due to drug abuse but also due to problems with bilirubine metabolism . it is thought that the product ensures sufficient glucuronidation or sulphation conjugation . the product also supports regulation of steroid metabolism . the product is also claimed to be useful in the treatment of pain as may become evident in attacks of migraine and pain on the chest after an infarct . it is thought that the product regulates the amount of adenosine in such a way that the vasodilatation effect is maintained and local sudden rises in concentration are avoided . the product is also claimed to be helpful in treating patients suffering from or at risk for developing renal failure , ischaemic events such as infarcts and cerebrovascular accidents , inflammatory bowel disease and cancer . this is thought to occur via restoration of tissue levels of beta - alanine , carnosine and anserine . in case the product is used in the treatment or prevention of cardio or cerebro vascular problems it is useful to include creatine , carmitine , coenzym q10 , tannine , vit b12 , vit b6 , zn and / or mg in the product . the product is also claimed to be beneficial in the treatment of disorders associated with imbalances in neurotransmitter levels in the brain . imbalances in neurotransmitter levels in the brain occur in persons that suffer from parkinson &# 39 ; s disease , alzheimer &# 39 ; s disease , adhd , schizophrenia , depression and mood disorders . the effect is thought to get obtained via an increase in effectivity of vitamin b6 , either co - administered or already present in the body , and a regulation of metabolism of dopamine , adrenaline , serotonin and noradrenaline .

trauma , surgery , inflammation , subfertility , lactation problems , gut disorders , infant nutrition , cancer , arthritis and other joints problems , vascular problems and cardio - or cerebro vascular problems , ischaemia , aging , impaired immune function , burns , sepsis , malnutrition , problems with liver or kidneys , malaria , cystic fibrosis , migraine , neurological problems , respiratory infections , improvement of sports results , muscle soreness , drug intoxication and pain can be treated with a nutritional composition containing effective amounts of ribose and folic acid , optionally combined with other components such as niacin , histidine , glutamine , orotate , vitamin b6 and other components .

referring now to the drawing and more particularly to fig1 a full ski guard assembly 10 is illustrated assembled on a pair of skis 12 . the ski guard assembly 10 includes a pair of ski tip guard assemblies 14 , 15 and a pair of ski tail guard assemblies 16 , 18 . as shown in fig2 and 5 each of the ski tip guard assemblies 14 , 15 and each of the ski tail guard assemblies 16 , 18 are formed as separable units which are adapted to fit over the ends of a wide range of different length skis and each is preferably made of impact resistent hard plastic material such as abs plastic that is easy to mold with known equipment . each of the ski tip guard assemblies 14 , 15 and each of the ski tail guard assemblies 16 , 18 comprise an outboard guard 20 and an inboard guard 22 that is slideably attached to it . each outboard guard 20 has a channel 24 that is closed at one end and open at an opposite end for removably receiving an end portion of a ski , and each inboard guard 22 has a complimentary channel 26 that is open at each end for removably receiving a portion of the ski adjacent the end portion of the ski as shown in fig1 . as shown in fig2 , 4 and 5 each of the outboard guards 20 includes a base wall 28 having integrally formed spaced side walls 30 , 32 that are integrally joined to either a tip wall 34 or a tail wall 36 to form a closed end for the channels 24 . on the other hand each of the inboard guards 22 includes a base wall 38 having integrally formed spaced side walls 40 , 42 but no end walls so that the channels 26 are open at both ends . the outboard guards 20 for the ski tip guard assemblies 14 , 15 and the ski tail guard assemblies 16 , 18 are nest inside their respective inboard guards 22 so that the side walls 30 , 32 are juxtaposed inside the respective side walls 40 , 42 . consequently all four inboard guards 22 are substantially identical and can be molded in the same die . on the other hand , the assemblies can be designed so that the four inboard guards 22 of the same size nested inside their respective outboard guards 20 so that the side walls 30 , 32 are juxtaposed outside the respective side walls 40 , 42 . these alternative inboard guards 22 can also be molded in the same die . the means for slideably attaching the inboard guards 22 to the outboard guard 20 so that they slide along the length of the skis 12 when the outboard guards 22 are installed on the end portion of the ski comprises each base wall 38 having a longitudinal slot 41 that receives a pin 39 that is carried by the associated base wall 28 and that moves in the longitudinal slot 41 when an inboard guard 22 moves relative to an outboard guard 20 in the longitudinal direction . the pin 39 is preferably a double headed rivet that has it heads below the outer surfaces of the base walls 28 as shown in fig5 so that the pin 43 does not scratch the bottom of the ski or interfere with attaching two guard assemblies together . the ski guard assemblies 14 , 15 , 16 and 18 include means to maintain a straight orientation of the outboard and inboard guards 20 and 22 with respect to each other . this includes the above pin and slot arrangement and further comprises the side walls 40 , 42 of the inboard guards 20 being slideably attached to the respective side walls 30 , 32 of the outboard guards 20 by pin and slot arrangements as shown in fig2 and 5 . specifically the outside side walls 40 and 42 carry pins 43 that extend inwardly into longitudinal slots 45 in the respective adjacent side walls 30 and 32 . these pin and slot arrangements also assist in slideably attaching the inboard guards 22 to the outboard guards 20 so that they slide along the length of the skis . the outboard guards 20 for the ski tip guard assemblies 14 , 15 have curved end portions to accommodate the tip end portions of the skis 12 as shown in fig1 and 2 while the outboard guards 20 for the ski tail guard assemblies 16 , 18 have straight end portions for accommodating the tail end portions of the skis 12 as shown in fig1 and 5 . two ski tip guard assemblies 14 , 15 are attached together with the channels 24 , 26 of their respective inboard and outboard guards 20 , 22 back - to - back as shown in fig1 - 5 . the ski tip guard assemblies 14 , 15 are preferably detachably secured together , for instance by velcro patches 44 on the bottom surfaces of the bottom walls 28 and 38 . two tail guard assemblies 16 , 18 are secured together in like manner and preferably also include velcro patches 44 for detachably securing them together . the tip guard assemblies 14 , 15 are installed by inserting the tips of the skis in the outboard guards 20 and then adjusting the length of the tip guard assemblies 14 , 15 by sliding the inboard guards 22 along the length of the skis . the pins 39 and 43 preferably have a tight tolerance so that any adjustment is held by friction . when the adjusted length is achieved , the inboard guards 22 are clamped to the skis 12 as shown in fig1 . the inboard guards 22 are clamped to the skis 12 for example by flexible straps 48 that are integrally attached to a side wall 40 or 42 of each inboard guard 22 at one end . these flexible straps 48 are wrapped around the pair of skis 12 ( and the pair of ski tip guard assemblies 14 , 15 ) and are attached to themselves by velcro patches 50 . the pair of ski tip guard assemblies 14 , 15 is preferably clamped to the skis 12 by two clamping straps 48 which are disposed in two pairs of locking slots 52 in the side walls 40 and 42 when the straps 48 are in a clamping position . the tail guard assemblies 16 , 18 are installed on the tails of the skis 12 and clamped to the skis 12 in like manner . the ski guard assemblies 14 , 15 , 16 and 18 each as an integral ski pole holder 54 in the form of a c - shaped clip . the integral ski pole holders 54 are preferably integrally attached to the side walls 40 and 42 of the inboard guards 22 so that a ski pole 56 may be carried in a protected position along each side of the pair of skis 12 as shown in fig1 . the ski pole holders 54 are also preferably between the pairs of locking grooves 52 so that the ski poles 56 can be clamped against the ski guards 14 , 15 , 16 and 18 by the flexible straps 48 . fig6 - 12 show a modified ski guard assembly that comprises one ski tip guard assembly 114 and one ski tail guard assembly 116 which are also adapted to fit over the ends of a wide range of different length skis . each is also preferably made of impact resistent hard plastic material such as abs plastic that is easy to mold with known equipment . the ski tip guard assembly 114 and the ski tail guard assembly 116 each comprise an outboard guard 120 and an inboard guard 122 that is slideably attached to it . each outboard guard 120 has a pair of back to back channels 124 that are closed at one end and open at an opposite end for removably receiving respective end portions of a pair of skis , and each inboard guard 122 has a pair of complimentary back - to - back channels 126 that are open at each end for removably receiving portions of the skis adjacent the end portions of the skis that are received into the outboard guard 120 . the outboard guard 120 include a base wall 128 having integrally formed spaced side walls 130 , 132 that are integrally joined to either tip walls 134 or tail walls 136 to form a closed end for the channels 124 . on the other hand each of the inboard guards 122 includes a base wall 138 having integrally formed spaced side walls 140 , 142 but no end walls so that the channels 126 are open at both ends . the outboard guards 120 for the ski tip guard assembly 114 and the ski tail guard assembly 116 are inside their respective inboard guards 122 so that the side walls 130 , 132 are juxtaposed inside the respective side walls 140 , 142 . with this arrangement , the inboard guards 122 are identical and can be molded in the same die . this feature can also be achieved by designing both inboard guards 122 to nest in the outboard guards 120 . the means for slideably attaching the inboard guards 122 to the outboard guards 120 so that they slide along the length of the skis when the outboard guards 122 are installed on the end portions of the skis comprise each base wall 138 having a longitudinal slot 141 that receives a pin 139 that is carried by the associated base wall 128 and that moves in the longitudinal slot 141 when an inboard guard 122 moves relative to an outboard guard 120 in the longitudinal direction . the pin 139 is preferably a double headed rivet that has its heads below the outer surfaces of the base walls 128 as shown in fig7 so that the pin 139 does not scratch the bottoms of the skis . the ski guard assemblies 114 and 116 include means to maintain a straight orientation of the outboard and inboard guards 120 and 122 with respect to each other . this includes the above pin and slot arrangement and further comprises aligned longitudinal slots 143 in the side walls 130 and 132 of outboard guards 120 slideably receiving the respective bottom walls 138 of the cooperating inboard guards 122 . these wall and slot arrangements also assist in slideably attaching the inboard guards 122 to the outboard guards 120 so that they slide along the length of the skis . the outboard guard 120 for the ski tip guard assembly 114 has a bifurcated end portion that is curved in opposite directions as shown in fig6 and 8 to accommodate the tip end portions of the a pair of skis arranged bottom to bottom as shown in fig1 . on the other hand , the outboard guard 120 for the ski tail guard assembly 116 has straight end portions as shown in fig1 and 12 for accommodating the tail end portions of the skis . the ski tip guard assembly 114 is installed by inserting the tips of a pair of skis ( that are arranged as shown in fig1 ) in the outboard guard 120 and then adjusting the length of the tip guard assembly 114 by sliding the inboard guard 122 along the length of the skis . again the pins 139 preferably have a tight tolerance to hold the adjustment frictionally . when the adjusted length is achieved , the inboard guard 122 is then clamped to the pair of skis . in this case , the inboard guard 122 is clamped to the pair of skis by a single strap 148 that is integrally attached to a side wall 142 of the inboard guard 122 at one end . the strap 148 is wrapped around the pair of skis and attached to itself by a velcro patch 150 as before . the ski tip guard assembly 114 is preferably clamped to the pair of skis by a single clamping strap 148 which is disposed in a pair of locking slots 152 in the side walls 140 and 142 when the strap 148 is in a clamping position . the tail guard assembly 116 is installed on the tails of the pair of skis and clamped to the pair of skis in like manner . the ski guard assemblies 114 and 116 each have a pair of integral ski pole holders 154 in the form of c - shaped clips . the integral ski pole holders 154 are preferably on the side walls 140 and 142 of the inboard guards 122 so that ski poles may be carried in protected positions along each side of the pair of skis as before . as demonstrated above , the ski guards of this invention are adjustable in length so that the ski guard protects a longer end portion at the tip or tail of the ski and / or extends the range of ski length that can be accommodated by a given configuration . in fact , i have found that ski guards of a given configuration can adequately protect skis ranging in length from 175 to 210 centimeters which is the most popular range of length for expensive downhill racing skis . moreover , in most instances the adjustable length ski guards of this invention can be extended so that they protect the entire end portions of the skis up to the central binding carrying portion which is protected to some extent by the binding itself . furthermore , the adjustable length ski guards of this invention can be adjusted so that they do not interfere with conventional car top ski carriers that clamp onto the ski itself . the adjustable length ski guards of this invention can be also be used with ordinary ski bags or with plastic bags supplied by airlines for shipping skis . consequently the adjustable length ski guard of this invention is also very versatile . obviously , many modifications and variations of the present invention in light of the above teachings may be made . it is , therefore , to be understood that , within the scope of the appended claims , the invention may be practiced otherwise than as specifically described .

a ski guard assembly for use with skis of different lengths that have tip and tail end portions , sides , tops with top corners and bottoms with bottom edges includes an outboard and an inboard guard . the outboard guard has a channel that is closed at one end and open at an opposite end for removably receiving an end portion of a ski . the inboard guard has a assembly complimentary channel that is open at each end for removably receiving a portion of the ski adjacent the end portion of the ski . the inboard guard is slideably attached to the outboard guard so that it slides along the length of the ski to adjust to the length of the assembly when the outboard guard member is installed on the end portion of the ski . the ski guard assembly is secured to the ski by clamping the inboard guard onto the ski after the length adjustment is made .

referring initially to fig1 , a system in accordance with the present invention is shown and is generally designated 10 . more specifically , as shown , the system 10 includes a laser unit 12 for generating an input laser beam 14 . for the present invention , the input laser beam 14 is preferably a pulsed laser beam wherein the pulses are ultra - short and each pulse has a duration measured in femto - seconds . further , the input laser beam 14 preferably has a wavelength ( λ i ) that is about 780 nm ( λ i = 780 nm ). fig1 also indicates that the input laser beam 14 is directed from the laser unit 12 , and onto the retina 16 of an eye 18 . as intended for the present invention , when the input light beam 14 ( λ i ) is incident on tissue in the retina 16 , it will interact with the tissue to generate a return light beam 20 . importantly , the return light beam 20 may include either , or both , of two different components that will have different wavelengths . stated differently , the return light beam 20 will include a first component having a wavelength ( λ r1 ) and a second component with a wavelength ( λ r2 ). note : λ i ≠ λ r1 ≠ λ r2 . still referring to fig1 it will be seen that , in addition to the laser unit 12 , the system 10 includes a sensor unit 22 and an active mirror 24 . specifically , these elements of the system 10 ( i . e . sensor unit 22 and active mirror 24 ) are used to pre - compensate the input beam 14 to create a diffraction limited spot on the retina 16 . on this point it is well known that the cornea 26 and lens 28 of the eye 18 will introduce optical aberrations into the input light beam 14 . also , the retina 16 will introduce phase aberrations that continue with the return light beam 20 . in order to measure the optical aberrations , the sensor unit 22 is preferably a wavefront sensor of a type well known in the pertinent art , such as a hartmann shack sensor . on the other hand , phase aberrations introduced by the retina 16 are preferably compensated for by pre - programming a computer to account for curvature of the retina 16 . it is known , however , that some phase aberrations can be detected by fluorescence wavefront analysis . therefore , the sensor unit 22 may also include this capability . once optical and phase aberrations in a return light beam 20 have been measured by the sensor unit 22 , the aberrations can then be used to program an active mirror 24 ( i . e . the computer used for operation of the active mirror 24 ). specifically , the active mirror 24 is to be programmed in a manner that will change the input light beam 14 to thereby effectively remove the aberrations from the return light beam 20 . alternatively , a customized phase plate 29 ( see fig5 ) of a type disclosed in co - pending u . s . application ser . no . 12 / 204 , 674 which is assigned to the same assignee as the present invention can be used with , or without , the active mirror 24 for this purpose . importantly , the now - compensated return light beam 20 can be used by the imaging unit 30 for imaging purposes . anatomically , an optic ( visual ) part 32 of the retina 16 comprises most of what is generally referred to as the fundus . as shown in fig2 , the sclera 34 is under the optic ( visual ) part 32 , and the optical nerve head 36 connects to the optic ( visual ) part 32 through the sclera 34 . in detail , with reference to fig2 and fig3 it will be seen that the optic ( visual ) part 32 of the retina 16 is curved and includes a retina - pigment - epithelium ( rpe ) 38 . the rpe 38 is a target tissue of interest for the present invention . anterior to the rpe 38 and identified in an anterior to posterior direction , are : nerve fibers 40 ; retinal ganglion cells 42 ; axion 44 ; bipolar cell 46 ; and a photo receptor 48 . of these , as indicated above , it is the rpe 38 with its lipofuscins that responds to the input beam ( λ i ) to generate a return beam ( λ r1 ) 20 due to tpef . referring now to fig4 , it will be seen that the optical nerve head 36 anatomically includes the lamina cribrosa ( lc ) 50 which is bounded by pre - laminar tissue 52 and post - laminar tissue 54 . as also indicated above , the lc 50 is also a target tissue of interest for the present invention . in this case , the lc 50 responds to the input beam 14 ( λ i ) to generate a return beam 20 ( λ r2 ) due to shg . additional aspects of aberration compensation for the present invention can be appreciated with reference to fig5 . there the sensor unit 22 is shown to include a lens array 56 , and a ccd camera 58 . this arrangement is typical for a wavefront sensor of the type commonly referred to as a hartmann - shack sensor . fig5 also indicates that a customized phase plate 29 can be used together with , or in lieu of , the active mirror 24 . in either case , the importance of the arrangement is to compensate the input beam 14 for aberrations that could otherwise diminish the efficacy of the imaging system 10 . anatomically , there are three sources for these aberrations ; all from the eye 18 itself . they are : 1 ] optical aberrations introduced by the anterior segment ( i . e . cornea 26 and lens 28 ); 2 ] phase aberrations introduced by the curvature of the retina 16 that relate to astigmatism ; and 3 ] phase aberrations introduced by the retina 16 . of all the aberrations introduced by an eye 18 into the input light beam 14 , optical aberrations are the most prominent , and are measured by the sensor unit 22 . to do this , a source 60 of infrared ( ir ) light radiates ir through pupil imaging optics 62 . also , the internal limiting membrane ( ilm ) 64 that defines the anterior surface of the retina 16 includes aberrational information in the light that is reflected from the retina 16 . after leaving the eye 18 , the optical aberrations that are introduced into the return beam 20 by the cornea 26 and lens 28 are processed by the sensor unit 22 . the resultant information is then programmed into the active mirror 24 . this essentially compensates for the first source of aberrations ( i . e . the anterior segments ). as for the second source of aberrations ( i . e . phase aberrations introduced by the curvature of the retina 16 ) it is well known that these aberrations can be measured in accordance with the angle of incidence , “ θ ”, between the input light beam 14 and the anterior surface of the retina 16 . accordingly , “ θ ” is determined by anatomical dimensions of the retina 16 . the resultant measurements involving “ θ ” are then also programmed into the computer - controlled active mirror 24 . the remaining aberrations from the third source ( i . e . the retina 16 ), although relatively minor , can be detected by a fluorescence wavefront sensor in the sensor unit 22 and used with the other information to further refine compensation corrections for the system 10 . as mentioned above , and as shown in fig5 , a custom phase plate 29 can be used in combination with the active mirror 24 , or in lieu thereof . in either configuration , the purpose is to pre - compensate the input light beam 14 so that aberrations introduced into the light beam 14 do not detract from the imaging capability of the system 10 . while the particular system and method for imaging retinal tissue with tissue generated light as herein shown and disclosed in detail is fully capable of obtaining the objects and providing the advantages herein before stated , it is to be understood that it is merely illustrative of the presently preferred embodiments of the invention and that no limitations are intended to the details of construction or design herein shown other than as described in the appended claims .

a system and method for imaging retinal tissues in an eye generates an input light beam having ultra - short pulses and an input wavelength to stimulate the tissue . depending on the particular type tissue being imaged , the retinal tissue responds to the input beam by generating a return beam of light having first and second components of different wavelengths . an imaging unit then receives the return light and images the tissue according to the return wavelength . additionally , a sensor unit is used to evaluate light returning from the retina to measure optical and phase aberrations introduced by the eye , and to program a compensator that compensates the input beam by removing the aberrations .

a collection of labeled cells will cast a field pattern in the water molecules immediately surrounding the cells . the field pattern can be approximated by a dipole field from a magnetized sphere . the dipole pattern demonstrates a classic field cross pattern , in which the local b z field is enhanced in the north and south poles and suppressed along the equator . the polarity of the field perturbation would be reversed for a diamagnetic agent . the dipole field pattern intensity falls off quickly . the field perturbation varies as δ ⁢ ⁢ b z ⁡ ( r , θ ) = δχ ⁢ ⁢ b o 3 ⁢ ( a r ) 3 ⁢ ( 3 ⁢ cos 2 ⁢ θ - 1 ) ( 1 ) where δχ is the difference in bulk magnetic susceptibility between the sphere and surroundings , α is the radius of the sphere , r is the distance from the sphere center , and θ is the angle relative to the main field , b o . hence , the field pattern from a smaller collection of cells will fall off more steeply than that from a larger collection . in practice , aglomerations of labeled cells may not be spherical , but this theory can be applied to the general case by summing the patterns from a group of spheres . instead of using the field gradient cast by the labeled cells to de - phase the nmr signal from nearby water molecules , we propose to use this gradient to selectively excite and refocus a narrow band of water molecules . this is similar in concept to slice - selective excitation , where a narrowband rf pulse is applied in the presence of a linear field gradient to select a particular slice . there are some notable differences : the field cast by a labeled cell is extremely localized and nonlinear . however , the pulse sequence is designed to extend the slice - selection concept to excite / refocus a thin shell of spins located at a particular frequency offset from the magnetized cells . fig1 illustrates the concept . in fig1 ( a ), the magnetic - field lines induced outside a magnetized sphere . in fig1 ( b ), by applying an rf pulse with carrier frequency ( s and bandwidth bw , the regions with thickness δx are excited . in fig1 ( c ), isofrequency contours surrounding a magnetized sphere ( δχ =− 500 ppm ) are shown , with the shaded regions showing the spatial extent of the regions that would be excited by a band - selective rf pulse with ω s =− 150 ppm and bw = 100 ppm . similar to conventional slice selection , a spatial shell of water is excited using the intense microgradient . since only this shell is excited , the image demonstrates positive contrast . note that positive frequency shifts will excite spins at the poles ( where the field is enhanced ) and negative frequency shifts will excite spins at the equator ( where the field is diminished ). a symmetric ( cos - modulated ) rf pulse will excite both the poles and the equator . the spatial distribution of this signal will be that of an “ onion layer ”. note that in conventional slice selection the gradient is refocused by a negative lobe of half the duration . because it is impossible to negate the gradient due to a magnetic particle , spin - echo refocusing pulses are currently thought to be critical . the theory above can be used to predict the net signal resulting from the new method , as a function of the volume of labeled cells . for a spin to contribute signal , its resonant frequency must fall within the bandwidth of the selective rf pulses :  γδ ⁢ ⁢ b z - ω s  ≤ 2 ⁢ π ⁢ ⁢ bw 2 ( 2 ) where ω s is the center - frequency shift of the rf pulses and bw is the bandwidth of the rf pulses . substituting eq . 1 for δb z gives :  γδχ ⁢ ⁢ b o 3 ⁢ ( a r ) 3 ⁢ f ⁡ ( θ ) - ω s  ≤ 2 ⁢ π ⁢ ⁢ bw 2 ( 3 ) now , the surfaces of the volume that satisfies eq . 3 can be parameterized as follows : r i a = k i ⁡ ( θ ) ⁢ ⁢ r o a = k o ⁡ ( θ ) ( 4 ) where r i is the radius from the center of the sphere to the inner surface of the volume , and r o is the radius to the outer surface . from this it is seen that the distance between the two surfaces , along a radius , scales with α : thus all three dimensions of the volume defined by eq . 3 scale with α , resulting in a signal volume that scales as α 3 . since the volume of cells also scales as α 3 , this analysis predicts a linear relationship between the volume of cells and integrated signal . there are several pulse - sequence parameters that can affect the quality of the positive contrast images . the key parameters are : the excitation profiles &# 39 ; shape ( bandwidth , transition width , ripples ), the center - frequency shift , and the echo time . these parameters are linked and the tradeoffs are discussed below . the excitation profiles of the frequency selective rf pulses must be carefully designed to achieve good contrast - to - noise . for a fixed bandwidth of excitation pulses , the largest volume of water will be excited for each cell by minimizing the off - resonance shift , as shown in fig1 . this excites the largest - radius shell of tissue or fluid . however , there is a tradeoff in contrast : if the frequency is set too close to on - resonance water , then excitation of background spins could occur because water could be shifted into the passband by field inhomogeneities . for adequate background suppression , the “ out - of - slice ” ripple of the rf pulses is also a concern . these ripples can be made small at the expense of wider transition widths . for fixed off - resonance frequency , the bandwidth of the rf pulses determines the thickness of the shell excited . for a maximal volume of magnetization , the excitation bandwidth would be set as wide as possible . it is because of this wide bandwidth that the t2 * decay is rapid and a spin - echo sequence is crucial . however , there is a tradeoff because wide bandwidth implies that the t2 * decay of the spin echo will be extremely short , which will limit sensitivity and resolution . hence a different , optimal rf bandwidth for different sized groups of cells is expected . another important challenge is diffusion : the field gradient immediately outside a single , small spio particle is enormous . diffusion of the excited water molecules near the labeled cells could cause significant , irreversible signal dephasing . however , it is known that with conventional pulse sequences , the signal loss in vicinity of sufficiently loaded cells is governed by the “ static dephasing regime ” theory , in which diffusional losses are minor . since the new method images spins which are not visible with conventional methods , the appropriate theoretical model for the relaxation properties of these spins remains unclear . in theory , the effects of diffusion can be reduced by minimizing both the center - frequency shift and the echo time . a potential tradeoff exists because longer rf pulses can excite sharper profiles , and can therefore be moved closer to resonance ( where the gradients are less steep ), but the increase in echo time could increase diffusion losses . although we have identified many potential tradeoffs above , we have not yet attempted to find an optimal combination of parameters . instead , a particular combination of parameters was used that enabled the demonstration of the new method in the experiments described below . spectrally - selective rf pulses were designed using the shinnar - le roux ( slr ) algorithm implemented in matlab ( the mathworks inc ., natick , mass .). by matching the profiles of a 90 - degree excitation and a 180 - degree refocusing pulse , a spin - echo sequence with million - fold ( 120 db ) suppression of on - resonance water was designed as shown in fig2 . fig2 shows a pulse sequence for positive - contrast imaging of magnetically tagged cells . ( a ) the profile for each of the 5 ms rf pulses was designed to excite / refocus a 1 khz passband with 0 . 1 % out - of - slice ripple . ( b ) the profile for the combined 90 - 180 pair gives million - fold suppression of on - resonance water . ( c ) the pulse sequence allows a minimum echo time of 13 ms , with a short ( 4 ms ) readout to minimize the blurring associated with the wideband echo . this pulse sequence was implemented on a ge signa 1 . 5t whole - body mri system ( general electric medical systems , waukesha , wis .). cell labeling solution was prepared by mixing cell culture medium with 25 μg / ml of the spio feridex ( advanced magnetics , cambridge , mass .) and 375 ng / ml of poly - l - lysine ( sigma , st . louis , mo .) at room temperature for 60 minutes . the embryonic stem cell ( esc ) line tl - 1 was derived from 129sv / j mice and cultured in a medium consisting of high - glucose dulbecco &# 39 ; s modified eagles medium with l - glutamate ( specialty media , pillipsburg , n . j . ), 10 % esc qualified fetal bovine serum ( invitrogen , carlsbad , calif . ), and 1 % penicillin / streptomycin solution ( invitrogen , carlsbad , calif .). prior to injection , the cells were incubated with the labeling solution for 12 - 24 hours . the cell cultures were then transferred to centrifuge tubes and subjected to three cycles of centrifuge , each time followed by dilution with phosphate - buffered saline solution to wash away any extra - cellular spio . for initial testing of the sequence , cells were injected into a rectangular block of agar gel . because of concerns about diffusion , groups of cells were injected in the near - solid form resulting from centrifuge spinning without dilution . the cells were injected using a syringe with 5 ml capacity , with an estimation of the number of cells injected made from the volume - measurement markings printed on the syringe . groups of three different cell populations ( 3 × 10 6 , 1 × 10 6 , 0 . 5 × 10 6 ) were injected , and effort was made to avoid inclusion of air pockets . imaging was performed using the sequence illustrated in fig2 with tr = 800 ms , te = 14 ms , fov = 12 cm , and 256 × 128 2dft encoding with an 8 ms readout . the whole - body rf coil was used for transmission and a 5 inch surface coil for reception . to change the frequency range included in the passband of the rf pulses , the center frequency of the scanner ( both excite and receive ) was shifted . projection images were acquired at 0 hz , + 800 hz and − 800 hz shifts . for comparison , standard multislice gradient - echo images were acquired with tr = 100 ms , te = 8 ms , fov = 12 cm , 256 × 192 encoding , and 2 mm slice thickness . to test the new method in the presence of more realistic diffusion parameters , groups of cells were imaged after injection into a section of freshly excised porcine myocardium . the cells were diluted to a concentration of approximately 10 8 cells / ml , and four injections of 1 million cells were performed . the same imaging parameters , sequences , and coils as listed above were used . also , additional images were acquired with the new sequence set at − 800 hz with echo times ranging from 14 ms to 34 ms to investigate diffusion effects . finally , a group of approximately 1 million cells was injected into the hind limb of a live mouse at a concentration of 10 7 cells / ml . the mouse was studied under a protocol approved by the stanford university administrative panel on laboratory animal care . the mouse was anesthetized with an intraperitoneal injection of 12 % ketamine ( wyeth , madison , n . j .) and 4 % xylazine solution ( phoenix pharmaceuticals , st . joseph , mo .) and allowed to breathe spontaneously . the concentration of the anesthetic solution was kept within the 100 - 120 μl / g dosing range . imaging was performed approximately 45 minutes after the injection . the same imaging parameters , sequences , and coils as described above were used , except with an 8 cm fov . the phantom experiment in fig3 shows initial investigations into the minimum detectable number of cells and the correlation between signal and the number of cells injected . fig3 shows a comparison of off - resonance imaging of magnetically labeled cells and conventional gradient - echo images . the phantom was a slab of agar gel with a plastic grid ( 1 cm squares ) included for landmarking . ( a ) the gradient - echo images show voids at the injection sites of 3 million cells ( 1 ), 1 million cells ( 2 ), and 0 . 5 million cells ( 3 ). ( b ) the on - resonance projection also shows voids , but with less contrast due to background signal . ( c ) the off - resonance projection (− 800 hz ) shows excellent contrast . ( d ) plot of the signal shown in ( c ) is computed by summing the signal in a small roi containing each bright spot , vs . the estimated number of cells . the signal at the site of each injection was computed by summing the signal in a rectangular roi containing the injection site , consisting of 230 pixels . a significant linear correlation between the estimated number and the signal was observed ( r = 0 . 87 , p & lt ; 0 . 005 ), which agrees with the theory , supra . injections of 5 × 10 5 cells were easily detected , suggesting that the limit of the method is lower . the shape of bright regions in fig3 ( c ) agrees with theory , with signal emanating from the right and left of the injection ( along an axis perpendicular to the main field ) where the magnetic field is suppressed ( see fig1 ). the potential signal loss due to diffusion was investigated in the experiments shown in fig4 and fig5 . fig4 shows a test of positive - contrast imaging in vitro . a section of porcine myocardium injected with labeled cells is shown . ( a ) gradient - echo images show voids at each injection site of 1 million labeled cells . ( b ) the off - resonance projection at − 800 hz clearly shows the four injections of labeled cells . ( c ) the off - resonance projection at + 800 hz also shows the injections , with the signal located at the top and bottom of each injection as predicted by theory . there is also a region of positive contrast ( arrow ) that is not at an injection site , but does correlate with a small void in ( a ). this was likely due to leakage of labeled cells through a blood vessel . the images are cropped to 7 cm × 7 cm . fig5 illustrates the effect of echo time on the off - resonance signal . the mean signal inside an roi containing an injection of 1 million cells into porcine myocardium is shown . the same roi for the on - resonance and off - resonance (− 800 hz ) was used . the difference in slope between the two curves is possibly due to diffusion losses in the gradient field surrounding the cells . the diffusion coefficient within the excised myocardium can be assumed to be similar to that encountered in vivo . thus , the reasonable signal observed at an echo time of 14 ms indicates that diffusional losses are not a major limitation for this number of cells . the apparent t2 of the off - resonance water surrounding the cells was found to be slightly shorter than that of the on - resonance water ( fig5 ), and this is presumed to be due to diffusion effects . the in vivo experiment shown in fig6 demonstrates that the new method is feasible even when the cells are injected at a fairly low concentration ( 10 7 / ml ), which was feared to increase diffusional signal loss . in fig6 labeled cells were injected into the hind limb of a mouse . the on - resonance spin - echo image shows a slight artifact at the location of the injection ( arrow ). ( b ) the spin - echo image at − 800 hz shows positive contrast at the corresponding location . the spin - echo image at + 800 hz shows signal at a similar location , but with different geometry due to the fact that a different part of the dipole field is being excited / refocused . the images are cropped to 2 . 8 cm × 3 . 0 cm . this is an important result as dilute cell suspensions may be needed to minimize cell damage at the time of delivery . in this experiment , the new method was applied 45 minutes after the cell injection , so it is reasonable to assume that some absorption of the fluid into the surrounding tissue had occurred . the results shown in fig3 to fig6 demonstrate the feasibility of the new method . in all cases , the new method gave positive contrast at the sites where the labeled cells were injected . the imaging of a contiguous group of labeled cells with positive contrast is anticipated to be useful for quickly visualizing and landmarking after an injection . this may be particularly useful when a small receiver coil with a small volume of sensitivity is used , giving a large intensity variation across the image and making voids difficult to detect . conventional , negative - contrast scans could then be prescribed from the positive contrast projection . the correlation between the signal and the number of cells shown in fig3 provides hope that quantification of labeled cell volume will be simpler with the new method in comparison with the conventional , negative contrast methods . based on these results , it seems feasible to estimate the volume of cells with the new method immediately after injection , simply by summing the pixels in an roi . however , if the goal were to follow the volume of cells over time , quantification might not be so simple . in this case , cell division will reduce the concentration of contrast agent within each cell , which will undoubtedly change the signal characteristics . the pulse sequence presented here is simple . one obvious extension to this method is to employ spectral - spatial selective excitation to enable the excitation of the desired frequency band , while also restricting the excitation to a spatial slice . this would reduce the level of background suppression required , because less on - resonance water would be inside the spatial region affected by the rf pulse . also , a better shim can be achieved over a 2 - dimensional slice , with the possibility of shimming each individual slice in a multislice approach . another improvement to the method would be to reduce the echo time . this could be essential for using the method to image a group of labeled cells over a long period after injection . in this case , the cells may divide , reducing the amount of contrast agent in each cell , and migrate so that labeled cells are distributed amongst non - labeled cells . with smaller groups of cells , the magnetic field gradient surrounding the cells becomes larger , and signal dephasing due to diffusional motion becomes more of a concern . we have presented a new method for imaging magnetically labeled cells in vivo with positive contrast . positive contrast has inherent advantages over existing negative contrast techniques , which suffer from partial voluming and hence require high resolution . the experiments described here show the feasibility of the method . the signal from the off - resonance water surrounding labeled cells was shown to correlate with the number of cells . the t2 of the signal from the new method was slightly shorter than that from the on - resonance water in the same location . however , the in vivo experiment demonstrated that this will not be a major limitation , at least for large numbers of cells . the new method is anticipated to be useful for quickly visualizing the location of a cell injection , and for quantifying the volume of labeled cells . while the invention has been described with reference to specific embodiments , the description is illustrative of the invention and is not to be construed as limiting the invention . in one embodiment of the invention , the spin echo created by the sequence is achieved with only one rf pulse , instead of two . this can be accomplished by implementing a “ self - refocusing ” rf pulse , which creates it &# 39 ; s own spin echo . this embodiment will allow shorter echo times than would otherwise be possible , reducing the effects of diffusion and making the method more sensitive . in another embodiment of the invention , the 90 - degree and / or 180 - degree pulse are replaced with spectral - spatial rf pulses , making slice selection with the new method possible . in another embodiment of the invention , the above two embodiments are combined with the envelope of the spectral - spatial rf pulse designed to be self - refocusing . this will enable slice selection as well as shorter echo times than can be achieved with a conventional spin - echo sequence . in another embodiment of the invention , multiple images are acquired with the frequency offset of the sequence varied over a range including both positive and negative shifts relative to water . then , spatial correlation of the image signal is used , either by an automatic algorithm or by a human , to compute the location , volume and spatial configuration of the labeled material . in another embodiment of the invention , the source of the magnetic field inhomogeneity is not a group of labeled cells , but instead any object or material with magnetic susceptibility sufficiently different from water , which can be placed inside the body . for example , a catheter or guidewire with a tip having a susceptibility sufficiently different from water could be visualized using the invention . various modifications and applications may occur to those skilled in the art without departing from the true scope and spirit of the invention as defined by the appended claims .

contrast agents incorporating super - paramagnetic iron - oxide nanoparticles have shown promise as a means to visualize labeled cells using mri . labeled cells cause significant signal dephasing due to the magnetic field inhomogeneity induced in water molecules near the cell . with the resulting signal void as the means for detection , the particles are behaving as a negative contrast agent , which can suffer from partial - volume effects . disclosed is a new method for imaging labeled cells with positive contrast . spectrally - selective rf pulses are used to excite and refocus the off - resonance water surrounding the labeled cells so that only the fluid and tissue immediately adjacent to the labeled cells are visible in the image . phantom , in vitro , and in vivo experiments show the feasibility of the new method . a significant linear correlation between the estimated number of cells and the signal has been observed .

referring to the drawings and initially to the perspective of fig1 , a golf or sports cage system is generally designated by the reference numeral 10 and is seen to be supported in a standard garage door opening and dosing system 11 including a left track 12 , a right track 13 , a torsion spring assembly 14 permitting a segmented door assembly 16 to open and close from its closed position illustrated in fig1 . the tracks 12 and 13 are supported by brackets shown in fig2 and 5 on a door frame 18 . the tie - downs for the golf cage system 10 are permanently affixed to the concrete garage floor 20 , as will be seen from the following views . the golf cage system 10 is supported on the horizontal portion of the side tracks 12 and 13 and is seen to include a forward ball striking double panel 22 , a left side panel 24 , a right side panel 26 , and a top panel 28 . it should he understood that the panels 22 , 24 , 26 and 28 can be constructed of a netting material common in the golf net industry , which applies to other sports industries such as baseball , and can also include panels that are canvas or vinyl reinforced , for example , and possibly other panel materials . the forward double panel 22 , as will be seen in the other views , consists of a rear panel that is preferably a net material and a forward ball striking panel that can be canvas or a nylon reinforced vinyl material . the forward panel 22 is affixed to the floor by tie - down assemblies 30 , and the side panels 24 and 26 are fixed to the floor 20 by tie - down assemblies 31 and 32 below the distal ends of the door side tracks 12 and 13 . referring to fig2 , which is a fragmented perspective view of the left door track 12 , it should be noted that the track is fragmented at 36 and 38 so that fig2 can be shown larger to aid in the clarity of the parts . the track 12 is channel - shaped in cross section as shown in fig3 , and is supported on the door frame by brackets 40 , 41 and 42 that are arranged generally perpendicular to the door frame 18 . the orientation of the double ball striking panel 22 parallel to the door 16 and spaced from but adjacent the door 16 and door frame 18 enables the ball impact forces on the double panel 22 to be transferred axially through the tracks 12 , 13 , through the brackets 40 , 41 , and 42 into the door frame 18 in a direction perpendicular to the door frame 18 to minimize the twisting forces at ball impart imposed by the double wall 22 on the tracks 12 and 13 , which is an important aspect of the present invention . the tracks 12 , 13 have a horizontal portion 45 , a 90 degree bend portion 46 , and a vertical portion 47 . the golf cage system 10 is supported in the horizontal portion of the tracks 12 , 13 so that the double ball striking wall 22 is positioned approximately three feet from the door 16 , but the door spacing can be varied depending upon the integrity of the double wall 22 . note that the double wall 22 includes a forward netting panel 22 a and a rear ball striking panel 22 b that may be canvas or nylon reinforced vinyl for example . as seen in fig2 and 4 , the golf cage system 10 is supported at its forward ball striking end by a double roller linkage assembly 50 that includes a main roller assembly 51 and a link 52 , and a stowage roller 53 . the main roller assembly 51 supports a cross shaft 55 that supports all the forward ends of the netting panels and extends between the tracks 12 and 13 where a mirror image of the roller linkage assembly 50 is supported in the right door track 13 . a rear roller assembly 58 is mounted in the rear end of the side tracks 12 , 13 and supports the upper reaches of the side panels 24 and 26 and the top panel 28 . the sides of the double front panel 22 are fixed on concrete floor 20 by a pair of tie downs 30 that include snap hooks 60 shown in fig7 , and as noted the rear end of the side panels are tied to the floor 20 by the low profile tie - down 31 and an identical snap hooks 62 to snap hooks 60 . the rear ends of the top panel 28 and the side panels 24 and 26 are tied to the rollers 28 by snap hooks 64 and 65 as seen in fig2 . the main roller assembly 51 illustrated in fig3 is shown mounted in the channel - shaped left rail 12 and fixed thereto by a threaded fastener 68 . the channel track 12 is a mirror image of the channel track 13 and is seen to include horizontal wall 70 , top wall 71 , and cup - shaped lower wall 72 in which the roller assembly 51 is locked by bolts 68 , which requires the user to drill holes in the tracks 12 , 13 at the proper locations . viewing fig3 , the roller assembly 51 supports the cross shaft 55 and is seen to include a cylindrical base 74 having a threaded aperture 75 therein that threadedly receives the bolt 68 and as the bolt 68 is threaded into aperture 75 it draws rod portion 74 against the interior of the rail wall 70 firmly locking the roller assembly 51 to the rails 12 , 13 . the roller assembly includes annular outer tread 76 , a race 76 a , a plurality of ball bearings 77 , an inner annular race 78 that rides against the ball bearings 77 , and a side race assembly 80 . the main roller assembly includes a cylindrical rod portion 81 that fits in an elongated bore 82 in the ends of the shaft 55 that with cross rod 83 permits an axial adjustment in the length of the rod 55 to accommodate limited variations in the spacing between the side tracks 12 , 13 . other arrangements besides the bore 82 and cross rods 83 can accommodate the same axial length adjustment for the shaft 55 as will appear to those with engineering skills in the mechanical arts . the roller assemblies 53 are not locked to the tracks 12 , 13 , while the roller assemblies 58 are lacked to the rear end of the rails 12 , 13 in the position illustrated in fig2 with bolt fasteners such as fastener 68 illustrated in fig3 , requiring the customer to drill suitable apertures in the side rails 12 , 13 to accommodate and permit the rollers 58 to be fixed to the rails . the fixation of the roller assemblies 58 keeps the side panels 24 , 26 and the top panel 28 in a taut position as shown in fig1 . viewing fig1 , the golf cage system is stowed by releasing the tie - downs 31 , 32 , 30 and snap hooks 64 , 65 , folding the side panels 24 , 26 against the double wall panel 22 , then folding the top panel downwardly against the folded panels , and then rolling the four panels around the shaft 55 into a bundle 86 illustrated in fig5 which is larger in diameter than illustrated in fig5 for simplicity . this manipulation can be affected by attaching a crank , not shown , to the reduced rod portion 81 of the main bearing assemblies 51 and rotating the crank to facilitate this maneuver . otherwise , it can also be done simply by hand grasping the bundle 86 and rotating it to roll up the panels onto the singular shaft 55 . after the bolt fasteners 68 are removed , the roller assemblies 51 with the linkage assembly 50 are shifted to the rear end of the tracks 12 , 13 and when the roller assemblies reach 53 reach the distal end of the tracks 12 , 13 as seen in fig5 , the linkage assembly is swung downwardly to the position illustrated in fig5 with the linkage assembly vertical and the roller assemblies 51 suspended and supporting the rolled panels 86 as shown . the purpose of the linkage assembly 50 is to locate shaft 55 , roller assemblies 51 , and the material 86 out of the way of door operating linkages 90 commonly found in automatic door openers and closers in today &# 39 ; s technology . the rollers 53 may be locked in the position illustrated in fig5 to prevent the inadvertent misplacement of the golf cage system in its stowed position . an important aspect of the present invention is that the tie - down assemblies 30 are low profile to permit both tire traffic and human traffic on the garage floor 20 without any significant impediment . as seen in fig6 and 7 , the tie - down assembly 30 is circular in configuration and has a major diameter of about 2 to 3 inches and a height of less than 0 . 500 inches and preferably closer to 0 . 250 inches . the snap hook assembly 60 is conventional and used throughout the present golf cage system at the four locations illustrated in fig1 , as well as the upper locations as indicated at 64 and 65 in fig2 . it should be understood that the snap hook assemblies are connected to loops 86 tethered to the panels 24 , 26 , 28 and the double panel 22 . the low profile tie - down assembly 30 includes a one - piece circular annular stamping 92 having a frusto - conical portion 93 with an included angle of about 30 degrees to facilitate tire traffic and to not impede foot traffic . an inner portion of the circular tie down assembly 30 circular portion 94 is recessed from the upper surface of the frusto - conical portion 23 so that a pivoting ring 96 is seated in the recess portion 94 and is flush with the upper surface thereof when the tie down assembly 30 is in its inactive position shown in fig6 . the tie - down assembly 30 includes a looped ring support 97 welded to the upper surface of the recess portion 94 and the assembly includes holes 100 and 101 to receive screws 102 and 103 to affix the tie - downs 30 to the garage floor . the securement of the tie downs 30 to the garage floor may be enhanced by abrading the upper surface of the concrete floor in the area of installation , and applying epoxy to the lower surface of the pleat 92 and at the same time drilling holes for the screws 102 and 103 in the floor and permitting the epoxy to cure overnight . the epoxy is preferably an rt cure epoxy material that is easy for the customer to use . it is also possible that depending upon the loads on the golf cage system to affix the tie - downs 30 to the concrete floor with epoxy only , although it is preferably done in an ambient environment above 50 degrees f . fig8 is a perspective partly segmented view of an economy model golf cage system according to the present invention . this golf cage system is generally designated by the reference numeral 210 and is seen to include a net supporting telescopic metal tube 215 supported on door tracks 212 and 213 . tube 215 has sections 216 and 217 adjustable axially to accommodate limited track spacing variations . the ends of tube 215 are fixed into the hollow end caps 218 and 219 which are fixed into the tracks 213 and 212 by heavy threaded fasteners 221 and 222 that extend through holes 214 in the tracks 212 and 213 into threaded apertures 220 in the caps 218 and 219 . ball striking net 225 is suspended from tube 215 by a plurality of loops and the lower end of the net is tethered to the concrete floor by tie - downs 227 and 228 identical to those in the fig1 to 7 embodiment .

a golf cage system that uses the customer &# 39 ; s garage door tracks as the frame for the cage . the cage is oriented to transfer loads from ball impact through the tracks to the frame of the door in a perpendicular direction to minimize track twisting . the cage has a ball striking drop panel suspended from a shaft mounted on rollers or end caps that ride in the tracks and fastened to the tracks in their active position . side panels and a top panel are also supported on the rollers at their forward ends and supported on another set of rollers in the tracks at the distal ends of the tracks . low profile tie - downs are epoxied to the concrete garage floor to facilitate unobstructed foot and tire traffic .

in reference to the figures , the apparatus of the invention making it possible to clean in particular turfed ground comprises a chassis 1 on which are arranged , in relation to the direction of travel or work f 1 of the apparatus , a front or upstream roller 2 able to roll on the turfed ground to serve as support on the ground for the apparatus and a rear or downstream cylindrical brush 3 parallel to the roller 2 extending transversely to the direction of travel f 1 of the apparatus . the cylindrical brush 3 is rotatably mounted on the chassis 1 in the opposite direction of rotation from the roller 2 . this brush makes it possible to pick up waste present on the turfed ground to project it rearward by the centrifugal force into a recovery or collecting pan for waste 4 integral with the chassis behind the cylindrical brush 3 . the cylindrical brush 3 is in continuous contact with the front roller 2 to constantly clean the perimeter of that roller by ridding it of the waste deposited on the roller and that is projected by the brush 3 into the collecting pan 4 . the cylindrical brush 3 can be adjusted to a working height relative to the ground along a bowed trajectory whereof the center a is situated on the longitudinal axis of the roller 2 as symbolized by the double arrow f 2 in fig3 . this working height of the brush 3 depends on the height relative to the ground of the lawn to be cleaned such that the bristles 3 a of the brush 3 can penetrate the lawn without touching the ground . in operation , the cylindrical brush 3 picks up , by brushing , the waste d present in the lawn between the roller 2 and the brush 3 and , at the same time , the brush 2 continuously cleans the front roller 2 to prevent any deposition of waste on the perimeter of said roller , thereby optimizing the picking up of the waste because the working height of the brush 3 relative to the ground is kept constant . the waste d picked up off the ground and on the roller 2 is projected by the bristles 3 a of the brush 3 upward and rearward by the centrifugal force to be ejected into the collecting pan 4 . the cleaning apparatus can be hitched to the rear of a machine m designed to dethatch the ground , itself hitched to the rear of a driving tractor , not shown , but it is understood that this apparatus can be hitched to the rear of any other machine for working the ground , such as , for example , a ground coring machine , or simply to the rear of a driving tractor by a traditional three - point fastening . the chassis 1 of the cleaning apparatus comprises two rigid side flanges 6 arranged parallel to the direction of travel f 1 of the assembly formed by the machine m and the cleaning apparatus and are fastened respectively to the inner faces of two side walls 7 integral with the chassis of the machine m behind it . one flange 6 and one side wall 7 situated on a same side are twinned in their upper portions to form a rigid arm 8 extending upward behind the cleaning apparatus . the collecting pan 4 is removably fastened to the two side arms 8 . each arm 8 is provided on the outer face of the corresponding side wall 7 with a pneumatic or hydraulic cylinder 9 able to be actuated to tilt the collecting pan 4 in relation to the chassis 1 of the cleaning apparatus in order to empty the waste d collected in that pan . the front roller 2 is mounted freely rotating around its longitudinal axis between the two side flanges 6 . more specifically , each of the ends of the roller 2 is rotatably mounted in at least one ball or needle type bearing , not shown , fastened in a bearing support 10 in the form of a substantially diamond - shaped plate fastened by fastening screws 11 to the inner face of a support plate 12 of the rear cylindrical brush 3 and that can pivot around the longitudinal axis y - y ′ of the roller 2 . the heads 13 of the two fastening screws 11 of the bearing support 10 to the support plate 12 of the cylindrical brush 3 are housed in two bowed lumens 14 , respectively , made through each rigid flange 6 . the centers of the radii of curvature of the two bowed lumens 14 are situated on the longitudinal axis y - y ′ of the roller 2 , which extends perpendicular to the flanges 6 , and are symmetrical to said axis . each bearing support 10 includes a bush 15 coaxial to the longitudinal axis y - y ′ of the roller 2 , passing through the support plate 12 of the brush 3 and the corresponding flange 6 such that the assembly formed by the bearing support 10 and the plate 12 can turn by a determined angular value relative to the flange 6 around the longitudinal axis y - y ′ when the working height of the cylindrical brush 3 is adjusted . each of the support plates 12 of the cylindrical brush 3 is normally fastened to the corresponding flange 6 via two fastening bolts 16 respectively passing through two piercings of the plate 12 and two bowed lumens 17 formed through the corresponding flanges 6 and only one of which is partially visible in fig5 . the two lumens 17 are situated on a same circumference and the centers of their radii of curvature are situated on the axis y - y ′ of the roller 2 . a plate 18 is fastened to the outer face of a portion of each flange 6 , not covered by the corresponding wall 7 , by the two bolts 16 passing respectively through two piercings of the plate 18 that can be blocked with the plate 12 at the flange 6 by tightening the nuts 19 of the bolts 16 in a determined position of the two bowed lumens 17 . a means 20 is fastened to each of the plates 18 and enables the adjustment of the working height of the cylindrical brush 3 . each adjusting means 20 comprises a sleeve 21 with an inner tapping fastened , for example by welding , to the outer face of the corresponding plate 18 , and a screw 22 passing through the sleeve 21 and whereof the end opposite its head 23 bears on a stop plate 24 integral with the chassis 1 of the cleaning apparatus . each plate 18 comprises a plurality of graduations 25 formed by small windows that can be formed selectively opposite a fixed reference point , not shown , integral with the outer face of the corresponding flange 6 and so as to indicate the working height of the cylindrical brush 3 . the two plates 12 include two parallel arms 12 a extending behind the roller 2 toward the collecting pan 4 and between which the cylindrical brush 3 is rotatably mounted , which is thus situated opposite a knife 28 rotor 27 for dethatching the ground of the machine m . the cylindrical brush 3 is driven in rotation by an electric or hydraulic engine 29 fastened by bolts 29 a to the outer face of one of the support arms 12 a of the brush 3 coaxially to the longitudinal axis thereof so as to drive the brush 3 in the opposite direction of rotation from that of the roller 2 during movement of the machine m along the direction f 1 . to adjust the working height of the cylinder brush 3 , an operator first loosens both nuts 19 of the fastening bolts 16 then , using a key , acts on each screw 22 head 23 to drive each of the screws 22 in one direction or the other to move the bolts 16 in their respective curvilinear lumens 17 in the corresponding direction so as to simultaneously move each plate 18 and each support plate 12 of the cylindrical brush 3 around the longitudinal axis y - y ′ of the roller 2 . in this way , the cylindrical brush 3 is moved in relation to the flanges 6 and , as a result , to the roller 2 , along the curved path symbolized by the double arrow f 2 in fig3 and center path situated on the y - y ′ of the roller 2 . it should be noted that during pivoting of the cylindrical brush 3 around the axis y - y ′, the heads 13 of the fastening screws 11 move in their respective curvilinear lumens 14 of the flanges 6 with concomitant pivoting of the bearing supports 10 relative to the flanges 6 via bushes 15 . the pivoting of the cylindrical brush 3 around the axis y - y ′ therefore makes it possible to position that brush at a working height depending on the height of the lawn to be cleaned . once the adjustment is done with the visual indication of the working height of the brush 3 by the graduations 25 , the operator again tightens the two nuts 19 to lock the pairs of plates 18 , 12 to their respective flanges 6 and , as a result , lock the cylindrical brush 3 at its working height . the pivoting of the cylindrical brush 3 around the axis y - y ′ of the roller 2 makes it possible to keep the distance or frictional pressure of the bristles 3 a of the brush 3 constant on the roller 2 to ensure cleaning thereof , regardless of the working height of the brush 3 relative to the ground . the cleaning apparatus also comprises , integral with the chassis 1 , a bowed plate 30 with the concavity thereof facing the cylindrical brush 3 behind the latter part and extending substantially over the entire width of the cylindrical brush 3 . the bowed plate 30 is in the form of a cylindrical cap concentric to the cylindrical brush 3 , i . e . the radius of curvature of the cylindrical cap is centered on the longitudinal axis x - x ′ of the cylindrical brush 3 . the bowed plate 30 has a lower portion 31 that is curved substantially in an elongated or horizontal v whereof one 32 of the walls forming branches is an extension of the bowed plate 30 and the other lower free branch 33 , which extends behind the bowed plate 30 , comprises an upwardly curved end portion 34 such that an outwardly rounded edge 35 , extending transversely to the direction of travel f 1 of the machine m , is defined between the branch 33 and the curved portion 34 . this rounded edge 35 is designed to bear continuously on the ground during the movement of the machine m . the bowed plate 30 has an upper portion opposite the lower branch 33 extended by a wall 36 curved upwardly behind the bowed plate 30 and the assembly formed by the bowed plate 30 and the curved walls 31 , 36 extend from the ground by a height such that the free edge of the curved wall 36 is situated approximately below and overhanging the lower edge 4 a defining the inlet opening of the waste d into the collecting pan 4 . the bowed plate 30 and its curved walls 31 , 36 include two end side walls 37 mounted freely pivoting , at their ends opposite the bowed plate 30 , relative to the chassis 1 around the longitudinal axis x - x ′ of the cylindrical brush 3 so as to rest continuously by gravity on the ground by the rounded connecting edge 35 between the curved walls 33 , 34 . more precisely , and as will better emerge from fig7 , each side wall 37 includes a piercing 37 a concentric to a cylindrical sleeve 38 integral with the inner face of the corresponding support plate 12 of the cylindrical brush 3 such that the side wall 37 can pivot freely around the sleeve 38 . the side plate 37 is axially maintained on the sleeve 38 by an outer stop ring 39 such as a circlips . the bowed plate 30 is arranged relative to the cylindrical brush 3 such that the end of the bristles 3 a of the brush 3 successively sweep , during operation , the bowed inner face facing the brush of the plate 30 . the bowed plate 30 and its curved walls 31 , 36 as well as the side walls 37 can be made of sheet metal . the role of the bowed plate 30 , during successive sweepings by the bristles 3 a of the cylindrical brush 3 , is to pick up waste d not previously ejected by the cylindrical brush 3 in the collecting pan 4 and ensure the transfer of the waste d by the bristles 3 a of the brush 3 toward the bottom of the bowed plate 30 so that it can then be picked up by the bristles 3 a with other waste present on the ground in order to eject the waste as well as that picked up by the bristles 3 of the brush 3 on the roller 2 , into the collecting pan 4 . fig3 thus shows waste d present on a row of bristles 3 a just upstream of the curved wall 36 of the bowed plate 30 considering the clockwise direction of rotation f 3 of the brush 3 and that was not able to be ejected into the collecting pan 4 due to the relatively high speed of said brush . thus , when the row of bristles 3 a including the residual waste d comes into sweeping contact with the bowed plate 30 , the latter part prevents the residual waste d from escaping radially from the row of bristles 3 a to prevent it from being propelled onto the ground behind the brush 3 and said plate from retaining the residual waste d up to its lower edge from which the row of bristles 3 a , through the relatively high rotational speed of the brush 3 , can keep the residual waste d until it is ejected upwardly and rearwardly into the collecting pan 4 by the centrifugal force . the bowed upper wall 36 being situated approximately below the lower edge 4 a of the inlet opening of the waste ejected d by the brush 3 , it prevents the passage of residual waste not ejected into the pan 4 between the upper edge of the wall 36 and the opposite wall 4 b of the pan 4 comprising the lower edge 4 a of the inlet opening of the waste in the pan . the bowed plate 30 thus participates in an effective and complete cleaning of the ground while allowing the bristles 3 a of the brush 3 to pick up all of the waste present on the ground just upstream of the lower portion of the bowed plate 30 . the bristles 3 a of the cylindrical brush 3 , instead of being arranged in a line or row as shown in the figures , can be made up of several circular portions parallel to each other along the longitudinal axis of the cylinder or be arranged helically along that cylinder . the bristles 3 a of the brush 3 can be formed by sections of bristles in lines alternating along the brush 3 , i . e . regularly angularly staggered along the latter . alternatively , the bristles 3 a of the brush 3 can be arranged in a chevron pattern .

a turf cleaning machine includes a bowed plate swept by a cylindrical plate . the bowed plate , when successively swept by a cylindrical brush , catches waste not ejected by the brush into a collecting pan to ensure collection of the waste . the waste is picked up a second time for ejection from the brush into the pan .

fig1 shows a 3d view of a typical ct system 1 in accordance with the invention , which is suitable for performing the method in accordance with the invention . it consists in the familiar way of a gantry housing 5 in which is arranged the gantry , which here cannot be seen , to which are attached an x - ray tube 2 as the radiation source and a large - area multi - row detector 3 . lying on the patient table 6 , the patient 7 to be scanned is pushed along the system axis 4 through the opening 8 in the gantry housing 5 , continuously for a spiral scan or discontinuously for a circular scan , while the x - ray tube 2 attached to the gantry and the detector 3 lying opposite it rotate around the system axis 4 . control of the system is effected by a control and computation unit 9 , which also has a memory 10 in which are stored the control and analysis programs prg 1 - prg n of the ct system 1 , which are called up and executed to operate the system . the computer programs prg x and stored look - up tables which execute the method in accordance with the invention will preferably also be located here . the preferred form of embodiment of an x - ray tomography system , for which the method in accordance with the invention described here is used , is shown in cross - section in fig2 . this shows a c - arm ct device 1 , which is basically familiar , having on its c - arm 5 an x - ray tube 2 , which is arranged opposite a large - area detector 3 . using the c - arm 5 , the x - ray tube 2 and detector 3 can be rotated around a patient 7 , arranged on the patient table 6 in the radiation field and the system axis 4 , whereby tomographic images of the patient can be reconstructed from the detector output data , just as with conventional ct using a gantry . the control , analysis of the detector data and reconstruction of the tomographic views are here again effected in a control and computation unit 9 , which has a memory 10 for storing away familiar computer programs , and programs prg 1 - prg n and data tables in accordance with the invention . c - arm devices of this type are used predominantly for coronary angiography . because the detector 3 happens here to be a very large - area one , and because it is virtually impossible to realize the application of collimators such as are used for the reduction of scattered radiation in conventional ct systems with one to multi - row detectors , additional measures are required to suppress computationally the effect of scattered radiation on the image . however , because there is at the same time a need for rapid image construction , and the computing power is limited or expensive , the method in accordance with the invention for scattered radiation correction , which is once again presented and explained below , is proposed . in order to present the basic idea of the invention , it is necessary first to explain the principle of beam hardening correction . in doing so , the following terms will be used : τ f ( e )= exp (− μ f ( e ) t ): transparency of the spectral filter used ( e . g . copper ), w u ( e )= q u ( e ) τ f ( e ) η d ( e )/ c u : effective standardized spectral distribution , c u = ∫ 0 eu ⁢ q u ⁡ ( e ) ⁢ τ f ⁡ ( e ) ⁢ η d ⁡ ( e ) ⁢ ⅆ e , ⇒ ∫ 0 eu ⁢ w u ⁡ ( e ) ⁢ ⅆ e = 1 ⁢ : for the water correction , the simplifying assumption is made that the attenuation of an x - ray beam in the object ( patient ) is evoked purely by water equivalent material . here , “ water equivalent ” means : the energy - dependence of the mass attenuation coefficient ( μ / ρ )( e ) is identical to that of water , and differences are due solely to local density differences . if one now considers a measurement beam which penetrates through the object , with the coordinate along its path designated by x and the location - dependent linear energy - dependent attenuation coefficient given by μ ( x , e )= ρ ( x ) α ( x , e ), then the mass attenuation coefficient α is calculated from : the projection value for the measurement beam under consideration is then : p a = - log ⁡ ( ∫ 0 eu ⁢ exp ⁡ ( - ∫ μ ⁡ ( x , e ) ⁢ ⅆ x ) ⁢ w u ⁢ ⅆ e ) = - log ⁡ ( ∫ 0 eu ⁢ exp ⁡ ( - ∫ ρ ⁡ ( x ) ⁢ α ⁡ ( x , e ) ⁢ ⅆ x ) ⁢ w u ⁢ ⅆ e ) for this purpose , a “ water equivalent thickness ” b u = b u ( p a ) is determined as follows : let α w ( e ) be the energy - dependent mass attenuation coefficient of water ; the polychromatic logarithmic projection value for a measurement beam which is attenuated along the path length ( effective thickness ) b in water ( ρ = 1 g / cm 3 ) is : this function can be calculated in advance for any voltage u , or can also be determined experimentally . it increases monotonically with b and can be inverted , e . g . by inverse interpolation . it is possible to determine for each measured value p a an equivalent water thickness b u = b u ( p a )= b in such a way that p a = f u ( b ) is true , namely by inversion of the last equation , which gives : using b u it is then possible to convert to the corresponding projection value , which would have been measured in the ideal case with a monochromatic “ spectrum ” with photons of one single reference energy e 0 : using b u = f u − 1 ( p a ) the hardening - corrected projection value becomes p *= α w ( e 0 ) b u = α w ( e 0 ) f u − 1 ( p a )= p a + δa δ a = α w ( e 0 ) f u − 1 ( p a )− p a the term δa represents the explicit form of the hardening correction term , as used below . following this preliminary manipulation , the basic idea of the invention will now be presented . ( y , z ): coordinates on the detector ; i o = i o ( y , z ): “ calibration image ”= measured “ unattenuated ” intensity distribution with no object in the beam path ; i t = i t ( y , z ): measured total intensity distribution , including scattered radiation , with the object in the beam path ; i a = i a ( y , z ): primary intensity distribution with the object in the beam path , with hardening but without scattered radiation ; i s = i s ( y , z ): intensity distribution solely for the scattered radiation generated by the object ; t = i t / i o : standardized total intensity distribution , including scattered radiation , with the object in the beam path ; p a = i a / i o : standardized primary radiation distribution with hardening but with no scattered radiation ; s = i s / i o : standardized scattered radiation distribution . it should be noted here that only the distributions i o and i t or t , as applicable , are from measurements . in order to outline the basic idea , the simplifying assumption is made that s and p a are also known . ct image reconstruction is effected using the negative of the logarithms of standardized intensity data , commonly called “ projection data ” and here denoted by the lowercase letter p . it then follows from equation (# 1 ) that : p t = ⁢ - log ⁡ ( p a + s ) = ⁢ - log ⁡ ( p a ⁡ ( 1 + s / p a ) ) = ⁢ - log ⁡ ( p a ) - log ⁡ ( 1 + s / p a ) p t = p a − δs (# 2 ) where δ s = log ( 1 + s / p a ) (# 3 ) equation (# 3 ) specifies the scattered radiation correction term which must be added to the projection data , p t , which is distorted by scattered radiation , in order to obtain the projection data p a , now only distorted by hardening : the hardening - corrected projection data , to be used for the reconstruction , is denoted by p *. the hardening correction or water correction , as applicable , converts p a to p * as follows : in which δa is the hardening correction term indicated above for the beam hardening correction . if one wishes to formulate the scattered radiation correction as an “ amplification ” of the hardening correction , it then follows from equations (# 4 ) and (# 5 ) that one can see that all the quantities in the preceding equations are location - dependent , i . e . are functions of the location coordinates ( y , z ) on the detector . this applies in particular for the “ amplification factor ” ρ = ρ ( y , z ) in equation (# 6a ). an essential point recognized by the invention is that the two terms in equation (# 6a ), the hardening term δa ( y , z ) and the scattered radiation term δs ( y , z ), have a similar spatial characteristic . for example , if we look at the graph of the two correction terms for a scan of a cylinder , they both initially follow a very flat course out from the middle , and then fall off more steeply towards the edge . this characteristic is illustrated in fig3 and 4 for two different projection angles . fig3 shows the influence of beam hardening correction and scattered radiation correction for a projection angle of 0 ° for an elliptical phantom , where it should be remarked that , as shown in fig2 , for a projection angle of 0 ° the cone of the beam does not completely envelop the phantom or patient , as applicable . along the abscissa are plotted the detector pixels of a central image row , in arbitrary units , while the ordinate scale is the negative of the logarithms of the projection values . curve 11 shows the graph of error - free projection data , with exact hardening and scattered radiation correction . curve 12 shows the measured projection values , with no beam hardening correction and no scattered radiation correction , while curve 13 shows the projection data with no scattered radiation portion but with beam hardening correction . accordingly , difference curves are shown below , curve 14 showing the beam hardening effect alone , and curve 15 containing exclusively the scattered radiation portion . fig4 illustrates the same , but for a projection angle of 90 °, where it is here possible to recognize from the fall - off at the sides of the curve that from the side the beam cone envelops the phantom completely . the reference marks correspond to those used in fig3 . because the most marked effect on the reconstructed image , the cupping , is determined by the large projection values , i . e . the measurement beams with the greatest attenuation in the object , it is possible to replace ρ in equation (# 6a ) by a suitable mean value in the region of pixels in the center of the image , or of pixels with the maximum projection value , as appropriate . if we write ρ = ρ o for this representative constant , then the exact equation (# 6 ) is replaced by the approximation this then means that the scattered radiation correction can be replaced by amplification of the beam hardening correction term δa by a factor ρ o , making it possible to save demanding computational steps . an improvement in accuracy can be achieved without significant increase in the computation time if , instead of a global amplification factor , a specific amplification factor ρ o = ρ o ( z ) is introduced for each row z in the projection image , this remaining constant for each pixel within the row . it has been found that for a typical object with an elliptical cross - section the correction method in accordance with equation (# 7a ) falls off too little towards the edge of the object , leading to a distortive brightening , i . e . although the cupping is reduced a wide bright annulus is produced around the edge of the object . in order to counteract this effect , one can modify the scattered radiation correction term δs o =( ρ o − 1 )· δa in equation (# 7a ) by multiplying it with a suitable shaping function h ( y , z ), which has a value range lying between 0 and 1 and which falls off to 0 towards the edge of the object . for this purpose it is possible to use , for example , the projection function p t itself , standardized and possibly also smoothed . in the notation this is represented by an overscore : p * 1 ( y , z )= p t ( y , z )+( 1 + ρ ′ 1 h ( y , z )) δ a ( y , z ) (# 7b ) this does again increase the computational effort somewhat , and speed is lost , because by comparison with the algorithm (# 7a ) there is for each pixel at least an extra addition , a memory access and a multiplication . however , this modified algorithm once again requires no antilogarithms and logarithms to be determined , and is therefore still faster than the familiar algorithm for scattered radiation correction , which is performed on the measured intensities and not on the projection data . a further improvement in the correction can be achieved by reducing the density excess at the edge of the object , for example the density excess at the edge of an object is really significantly reduced by a generalization of the approach in equation (# 7b ). for this purpose the approach in (# 7b ) can be generalized to amplify the fall - off of the shaping function by raising it to a power with an exponent n & gt ;= 1 . the following then applies : p * 1 ( y , z )= p t ( y , z )+( 1 + ρ ′ 1 h n ( y , z )) δ a ( y , z ) (# 7c ) as mentioned above , in presenting the basic idea of the invention the simplifying assumption was made , for the purpose of estimating ρ o , that s and p a are known , at least for representative pixels . in equations (# 3 ) and (# 6a ) one can see that the only input is the ratio s / p a . this can be estimated with the help of an s / p table database . however , the lookup in the s / p table assumes a knowledge of the equivalent water thickness ( path length ). this is then calculated from the logarithm of the projection value p a =− log ( p a ), using an algorithm which is known per se as part of the water correction . the retrieval from the s / p database , using the algorithm cited , of the quotient s / p a required in equation (# 6a ), is described briefly by this term depends on p a , but p a is for its part only known after estimation of the ratio s / p a of scattered to primary . this implicit problem can be solved iteratively . to simplify the notation , in what follows p a and p t refer only to scalar values , because for the determination of ρ o one can restrict oneself to a mean pixel value . the iteration rule for p a then reads as follows : iteration ( n ≧ 0 ): p a ( n + 1 ) = p t + log ( 1 + g ( p a ( n ) )) (# 9b ) because the correction method operates directly on the projection data , it is independent of the exposure geometry , but nevertheless this must be taken into account in creating the s / p database , and in principle any suitable reconstruction algorithm can be used . now refer again to fig3 and 4 , in which are shown the results of the scattered radiation correction in accordance with the invention , with the reference mark 16 . it can be seen that the differences from the ideal graph of the projection data , in particular at the 90 ° projection angle , are very small , so that scarcely any loss of quality is to be expected in the image display from this scattered radiation correction , which can be performed with very little computational cost . in concrete terms , the scattered radiation correction can be carried out as an amplified water correction , using a constant amplification factor for each projection image , thus corresponding to the following work steps : initially , the appropriate pre - calculated multi - dimensional s / p table , which still depends on the tube voltage and the air gap and on the exposure parameters such as the array size , antiscatter grid , prefiltering etc . used for data acquisition , is read in . after this , for each projection image , which consists of logarithms of the data , a global amplification factor ρ is determined as follows : 1 . extract the s / p sub - table which is specific to the tube voltage , and the air gap which may have to be estimated ; 2 . reduce the projection image ( e . g . by 8 × 8 downsampling or binning ; median or low - pass filtering ); 3 . determine the pixel with the maximum projection value and the mean value from , e . g . 5 × 5 pixels including the maximum ; 4 . use this mean value for p s and by means of an iteration algorithm as shown in equations (# 9a , b ) calculate an estimate of p a ; 5 . determine the hardening correction term δa = α w ( e 0 ) f u − 1 ( p a )− p a 6 . determine the amplification factor ρ as in equation (# 7b ), where value of the term s / p a is to be determined as implied by equation (# 8 ) using the s / p table . then , for each pixel in each projection image , the amplified water correction shown by equation (# 6 ) is applied , using the constant amplification factor ρ previously determined . a possible variant of this approach consists in using in step 3 not the maximum value but instead the mean value in a so - called “ dominant ”. after this , in the modified step 3 , the mean value is calculated for a prescribed dominant , which is a reduced region , generally a prescribed small roi (= region of interest ) in the middle of the detector . in accordance with the invention , the scattered radiation correction can also take place as an amplified water correction , with a constant amplification factor for each image row of each projection image . here , instead of a global amplification factor a specific amplification factor ρ = ρ ( z ) is introduced for each row z in the projection image , but this remains constant for each pixel within the row . this modification of the method , which does somewhat increase the computational effort , achieves an improvement in the accuracy . the sequence of program steps for each projection image then changes as follows : first , as a general preparation , for each projection image of logarithmic data : an s / p sub - table is extracted which is specific to the tube voltage and possibly to the air - gap which must be estimated ; the projection image is reduced , e . g . by 4 × 4 downsampling or binning and median or low - pass filtering ; this is now followed by determination of the row - dependent amplification factor ρ ( z ), with : the determination for each row z ′ in the reduced projection image of an amplification factor ρ ( z ′) by the steps : determination of the pixel with the maximum projection value and determination of the mean value of several pixels including the maximum ; ( alternatively , analogous to the variant 5 . 2 : mean value across 5 cm in the region of the middle of the row ) use this mean value for p s and by means of an iteration algorithm as shown in equations (# 9a , b ) calculate an estimate of p a ; determine the hardening correction term δa = δa ( z ′) from δa = a w ( e 0 ) f u − 1 ( p a )− p a determine the amplification factor ρ = ρ ( z ′) as in equation (# 7b ), where value of the term s / p a is to be determined as implied by equation (# 8 ) using the s / p table . the amplification factor ρ ( z ′) determined on the reduced row grid is now expanded onto the original fine grid by linear interpolation ; beforehand , smoothing can be carried out by 1 - dimensional convolution . finally , the water correction is performed for each row z of the projection image , using the amplification factor ρ ( z ). in sum , therefore , the invention makes available a scattered radiation correction which is based on the hardening correction and is applied to the logarithms of the projection data . this means that it is no longer necessary , before and for the purpose of scattered radiation correction , to take the antilogarithms of the ct data which is being used and then , after the correction has been effected , to take the logarithms again , thus enabling a not inconsiderable computational effort to be saved . it goes without saying that the characteristics of the invention cited above can be used not only in the combination described in each case , but also in other combinations , or separately , without going outside the bounds of the invention .

the invention relates to a method for speeding up the scattered radiation correction in a computed tomography system with a radiation source and a detector constructed in large - area format with a number of rows of detectors , by which an object is scanned from numerous projection angles , uses the measured values for the attenuation of the radiation in generating projection data which is postprocessed for the purpose of reconstructing tomographic views , in doing which a beam hardening correction is applied directly to the projection data , whereby according to the invention the scattered radiation correction is also applied directly to the projection data .

referring to fig1 - 8 of the drawing , there is depicted a particulate dispensing hairbrush with combination bristles denoted generally by reference 10 . the brush 10 may be formed of any suitable lightweight material , preferably a plastic , with polypropylene being useable by example . the brush 10 may be formed of a single - piece , molded body 12 or of multiple pieces joined together by adhesive , double shot molding , heat or sonic welding , etc . by way of example only , the body 12 includes a handle 14 with elongated shaft 16 extending from a first outer end 18 to a second end 20 . an aperture 22 may be formed in the shaft 16 adjacent the first end 18 to provide a convenient means for supporting the brush on a hook or other surface when not in use . the shaft 16 is provided in a convenient hand grip size and may optionally be provided with ergonomic surfaces 24 , such as soft , flexible ribs , which extend along some or substantially all of the exterior surface of the shaft 16 . the body 12 of the brush 10 also includes a head 30 which may be integrally joined to the shaft 16 . the head 30 has a generally cubical , hollow shape , with the illustrated rectangular shape being by way of example only . the head 30 has a first end 32 and an opposed second end 34 . the second end 34 of the head 30 is joined to the second end 20 of the shaft 16 of the handle 14 by a connector 36 . the head 30 is formed with a hollow interior chamber or reservoir 38 which opens to an aperture 40 at the first end 32 of the head 30 . the aperture 40 is releasably closable by a cap 42 . the cap 42 may be affixed to the first end 32 of the head 30 by a snap - on , friction fit , a threaded connection , etc . dispensable materials , i . e ., particulate solids , such as powder , or even fluid materials , may be introduced into the reservoir 38 in the head 30 through the aperture 40 . at least one aperture , with two pairs of spaced apertures 44 being shown by way of example only , are formed in one major surface of the head 30 . the apertures 44 open to the reservoir 38 to allow transfer or migration of the material contained within the reservoir 38 through the apertures 44 and onto the bristles mounted on the head 30 as described hereafter for dispensing to human or pet hair . a cover 50 is in the form of an elongated , generally flat rod having a first end 52 and an opposed second end 54 . the second end 54 is enlarged , such as by a bent flange 58 , to provide a finger engageable edge for moving the cover 50 between a first position shown in fig1 wherein apertures 56 , which are provided in substantially the same size and the same number as the aperture ( s ) 44 in the head 30 , are spaced from the apertures 44 in the head 30 by solid portions of the cover 50 to close off the apertures 44 to the transfer of the material within the reservoir 38 to the bristles on the head 30 and a second position , shown in fig7 and 8 , wherein the apertures 56 in the cover 50 are aligned with the apertures 44 and the head 30 allowing dispending of material from the reservoir 38 to the brush bristles . the cover 50 may be mounted interiorally or exteriorally on the major surface 31 of the head 30 and may slide within a groove formed in the major surface 31 of the head 30 . the groove 60 slidably captures the cover 50 in the head 30 . a plurality of bristles are mounted on the major surface 31 of the head 30 . although all of the bristles can be of the same type of material and substantially the same height , by way of example only , a first group of bristles 70 are fixedly mounted on the major surface 31 of the head 30 by suitable mounting means , such as molding in the major surface 31 , adhesive , staples , etc . the first group of bristles 70 may be formed of soft , densely arranged , boars hair bristles . a second group of bristles 74 are arranged about substantially the entire outer periphery of the first group of bristles 70 , as shown in fig1 and 7 . the bristles 74 forming the second outer peripheral group of bristles generally have a more rigid construction that the softer bristles 70 in the first group of bristles 70 . the outer peripheral bristles 74 , which are illustrated as being disposed only along the two longitudinal sides of the inner bristles 70 , may comprise individual , flexible nylon or polypropylene bristles which are joined by means of molding , hooking or other fastening means such as molding to the major surface 31 of the head 30 . the bristles 74 , as shown in detail in fig4 , have a shaft 76 , a spherical ball - shaped end 78 , and an attachment end 80 which is illustrated by example only as being in the form of a bent hook for mounting in the first major surface 31 of the head 30 . fig3 depicts an alternate construction for the outer bristles in which the outer bristles are formed of clumps or groups 84 of a plurality of flexible plastic , such as nylon , bristles . the bristles 84 are flexible , but more rigid than the inner disposed , softer bristles 70 . although not shown , the outer bristles may also be formed of metal , joined at one end to the head 30 for used with brushing pet undercoats . the height of the inner bristles 70 may be of the same height as the outer peripheral bristles 74 . as shown in fig2 and 8 , the outer peripheral bristles 74 may also be provided in different heights , one set of which may be of the same height as the inner bristle 70 or both sets may be shorter in height than the overall height of the inner bristles 70 . in use , the brush 10 may be used as a conventional brush on human or pet hair or undercoats when the cover 50 is in the first closed position shown in fig1 and 2 . the more rigid outer peripheral bristles 74 , 84 , etc ., gently stroke hair , and , in particular , braids , without detangling or untwisting the braids . in loose , unbraided or untied hair , the outer peripheral bristles separate and detangle the hair as the brush 10 is drawn through the hair in a sideways direction of the brush 10 . that is , the brush 10 is urged through human or pet hair or pet undercoats in a sideways motion from left to right or right to left in the brush orientation shown in fig1 . when it is desired to dispense the particulate or other material stored in the reservoir 38 , the cover 50 is urged to the second open position . while the brush 10 is moved through the human or pet hair or pet undercoat , gravity causes the particulate material or other material stored within the reservoir 38 in to migrate or transfer from the reservoir 38 to the soft , inner bristles 70 and then onto the human or pet hair . the brush 10 may be vibrated by shaking the brush during each brushing stroke to promote or enhance migration of material from the reservoir 38 to the inner bristles 70 . alternately , a vibratory means , such as a small battery powered motor , may be mounted in the brush 10 , such as in the handle 14 , to provide vibration of the head 30 during brush strokes . it is also contemplated that the brush 10 may be constructed without the slidable cover 50 . in this aspect , the apertures 44 in head 30 remain open at all times . due to the slightly clinging nature of powder or other particulate material typically applied to human hair , or pet hair or fur , while a small amount of the particulate material may migrate from the interior reservoir 38 through the apertures 44 onto the bristles 70 when the major surface 31 is oriented in a downward facing position , substantial transfer of the particulate material is achieved during a brush stroke by means of vibration , i . e ., by either manual shaking of the brush or a motor aided vibration as described above . referring to fig9 - 14 of the drawings , there is depicted a second embodiment of a particulate dispensing hairbrush with combination bristles denoted generally by reference 110 . brush 110 may also be formed of any suitable lightweight material , preferably a plastic , with polypropylene being useable by example . brush 110 may be formed of a single - piece , molded body 112 or of multiple pieces joined together by adhesive , double shot molding , heat or sonic welding , etc . body 112 includes a handle 114 with an aperture 122 which may be formed in handle 114 adjacent to one end to provide a convenient means for supporting the brush on a hook or other surface when not in use . handle 114 is provided with an over - grip having an ergonomic surface 124 , such as soft , flexible ribs , which extend along some or substantially all of the exterior surface of handle 114 . body 112 of the brush 110 also includes a head 130 which is joined to handle 114 . head 130 includes a top 144 and a bottom 146 and has a first end and an opposed second end . the second end of the head 130 is joined to the other end of handle 114 by means of fingers 148 a , 148 b extending from top 144 and bottom 146 , respectively . head 130 is formed with a hollow interior chamber or reservoir 138 ( defined by reservoir top 154 and reservoir bottom 156 ) which opens to an access aperture at the end of the head 130 ( see fig1 and 14 ). the aperture is releasably closable by a cap 142 . as in the first embodiment , dispensable materials , i . e ., particulate solids , such as powder , or even fluid materials , may be introduced into reservoir 138 in head 130 through the aperture . apertures 151 are shown in fig1 along one surface of the head 130 . apertures 151 open to reservoir 138 to allow transfer or migration of the material contained within the reservoir 138 through the apertures 151 and onto the bristles mounted on the head 130 , as described hereafter , for dispensing to human or pet hair . a plurality of bristles are mounted along said one surface of the head 130 . particularly , a first group of bristles ( not shown ) may be fixedly mounted along the surface of head 130 at location 161 comprising soft , densely arranged , boar or horse hair bristles . a second group of bristles 141 are arranged about substantially the entire outer periphery of location 161 . bristles 141 forming the second outer peripheral group of bristles are typically made of a plastic material and generally have a more rigid construction than the softer bristles of the first group . in use , brush 110 may be used as a conventional brush on human or pet hair or undercoats . as shown in fig1 and 14 , a load dial 131 is provided along the neck region of head 130 in order to turn a shaft 133 to which the load dial is connected , which subsequently turns a load dial fin 135 connected to shaft 133 and located within brush head 130 . when fin 135 turns or moves , it engages and depresses an internal piston / plunger unit 137 . piston / plunger unit 137 includes a plurality of pistons 139 and urges the material held in reservoir 138 through apertures 151 where the material is ultimately trapped by the soft , densely arranged horse or boar hair bristles for subsequent transfer . piston / plunger unit 137 then springs back into its original position ( by means of springs 159 ) so that it is ready for additional dispensing of said material . when it is desired to dispense the particulate or other material stored in the reservoir 138 , brush 110 is moved through the human or pet hair or pet undercoat , with gravity causing the particulate or other material stored within reservoir 138 to migrate or transfer from reservoir 138 to the brush and then onto the human or pet hair .

a brush having a head with a reservoir formed therein and at least one aperture formed in the head for opening the reservoir to the exterior of the head is provided . the inventive brush also includes a plurality of bristles mounted on the head for transferring material dispensed from the reservoir through the at least one aperture in the head as the brush is drawn through human or animal hair . the inventive brush includes a refill aperture formed in the head and a cap releasably engageable with the refill aperture . the brush may also include a cover movably mounted on the head for closing an aperture in the head with the cover movable between a first position for closing the aperture , and a second position for opening the aperture .

the triblock copolymers employed in the present invention have the more general configuration a - b - a wherein each a is a crystalline polymer end block segment of polystyrene ; and b is a elastomeric polymer center block segment of poly ( ethylene - butylene ). the poly ( ethylene - butylene ) and polystyrene portions are incompatible and form a two - phase system consisting of sub - micron domains of glassy polystyrene interconnected by flexible poly ( ethylene - butylene ) chains . these domains serve to crosslink and reinforce the structure . this physical elastomeric network structure is reversible , and either heating the polymer above the softening point of polystyrene temporarily disrupt the structure , which can be restored by lowering the temperature . plasticizers particularly preferred for use in practicing the present invention are well known in the art , they include rubber processing oils such as paraffinic and naphthenic petroleum oils , highly refined aromatic - free paraffinic and naphthenic food and technical grade white petroleum mineral oils , and synthetic liquid oligomers of polybutene , polypropene , and polyterpene . the synthetic series process oils are high molecular weight oligomers which are permanently fluid liquid monoolefins , isoparaffins or paraffins of moderate to high viscosity . many such oils are known and commercially available . the composition of this invention can also contain small amounts of conventionally employed additives such as stabilizers , antioxidants , antiblocking agents , colorants , fragrances , flame retardants , and the like to an extend not affecting or decreasing the desired properties of the present invention . the triblock copolymer component by itself lacks the desired contemplated properties ; whereas , when the triblock copolymer ( having styrene to ethylene and butylene ratio within the range contemplated in the instant invention ) is combined with selected plasticizing oils with an average molecular weight of between about 200 to about 700 , as determined by ebulliscopic methods , wherein , for most purposes , the oil constitutes about 300 to about 1 , 600 parts and more preferably about 350 to about 1 , 600 parts by weight of the triblock copolymer , that an extremely soft and highly elastic material is obtained . this transformation of the triblock copolymer structure in heated oil resulting in a composition having a gel rigidity of about 20 gram to about 700 gram bloom and substantially without oil bleedout along with high tensile strength and elongation and other desirable combination of physical properties is unexpected . as used herein , the term &# 34 ; gel rigidity &# 34 ; in gram bloom is determined by the gram weight required to depress a gel a distance of 4 mm with a piston having a cross - sectional area of 1 square centimeter at 23 ° c . the gelatinous elastomer compositions of the present invention are prepared by blending together the components including other additatives as desired at about 23 ° c . to about 100 ° c . forming a paste like mixture and further heating said mixture uniformly to about 150 ° c . to 200 ° c . until a homogeneous molten blend is obtained . these components blend easily in the melt and a heated vessel equipped with a stirrer is all that is required . the instant composition is excellent for cast moulding and the moulded products have various excellent characteristics which cannot be anticipated from the properties of the raw components . the basis of this invention resides in the fact that a poly ( styrene - ethylene - butylene - styrene ) triblock copolymer having styrene end block to ethylene and butylene center block ratio within the contemplated range of from between 31 : 69 to 40 : 60 when blended in the melt with an appropriate amount of plasticizing oil makes possible the attainment of gelatinous elastomer compositions having a desirable combination of physical and mechanical properties , notably high elongation at break of at least 1 , 600 %, ultimate tensile strength of about at least 8 × 10 5 dyne / cm 2 , low elongation set at break of substantially not greater than about 2 %, tear resistance of at least 5 × 10 5 dyne / cm 2 , substantially about 100 % snap back when extended to 1 , 200 % elongation , and a gel rigidity of substantially not greater than about 700 gram bloom . more specifically , the gelatinous compositions of the present invention , as hereinbefore defined , exhibit at least seven measurable properties . they are : ( 1 ) tensile strength of about 8 × 10 5 dyne / cm 2 to about 10 7 dyne / cm 2 as measured with crosshead separation speed of 25 cm per minute at 23 ° c . ; ( 2 ) elongation of about 1 , 600 % to about 3 , 000 % as measured with crosshead separation speed of 25 cm per minute at 23 ° c . ; ( 3 ) elasticity modulus of about 10 4 dyne / cm 2 to about 10 6 dyne / cm 2 as measured with crosshead separation speed of 25 cm per minute at 23 ° c . ; ( 4 ) shear modulus of about 10 4 dyne / cm 2 to about 10 6 dyne / cm 2 as measured with a 1 , 2 , and 3 kilogram load at 23 ° c . ; ( 5 ) gel rigidity of about 20 gram bloom to about 700 gram bloom as measured by the gram weight required to depress a gel a distance of 4 mm with a piston having a cross - sectional area of 1 square cm at 23 ° c . ; ( 6 ) tear propagation resistance of at least 5 × 10 . sup . 5 dyne / cm 2 as measured at a crosshead separation speed of 25 cm / minute at 23 ° c . ; ( 7 ) and substantially 100 % snap back recovery when extended at a crosshead separation speed of 25 cm / minute to 1 , 200 % at 23 ° c . the gelatinous elastomer articles moulded from the instant compositions have various additional important advantages in that they do not craze , creep , tear , crack , or rupture in flextural , extension , compression , or other deforming conditions of normal use ; but rather the moulded articles made from the instant composition possess the intrinsic properties of elastic memory enabling the articles to recover and retain its original moulded shape after many extreme deformation cycles as compared to prior art triblock copolymer oil - extended compositions . in applications where low rigidity , high elongation , good compression set and excellent tensile strength are important , the instant compositions would be preferred . the gelatinous elastomer compositions of the present invention are useful in low frequency vibration applications , such as viscoelastic layers in constrained - layer damping of mechanical structures and goods , as viscoelastic layers used in laminates for isolation of acoustical and mechanical noise , as viscoelastic layers used in wrappings , enclosures and linings to control sound , as compositions for use in shock and dielectric encapsulations of electrical and electronic components , as moulded shape articles for use as therapeutic hand exercising grips , as articles for use as novel amusement toys and novel re - useable lint removers . the invention is further illustrated by means of the following illustrative embodiments , which are given for purpose of illustration only and are not meant to limit the invention to the particular reactants and amounts disclosed . a comparison is made between poly ( styrene - ethylene - butylene - styrene ) triblock copolymers having styrene end block to ethylene and butylene center block ratio below the range between 31 : 69 to 40 : 60 and ratio within the range between 31 : 69 to 40 : 60 . three different triblock copolymers were melt blended separately with a paraffinic white petroleum oil . table i below shows the physical properties obtained with respect to each of the different styrene to ethylene and butylene ratio triblock copolymer oil - blends tested . table i______________________________________ weight partsformulation s / eb ratio . sup . ( 1 ) a b c______________________________________s - e - b - s . sup . ( 2 ) 28 : 72 100s - e - b - s . sup . ( 3 ) 29 : 71 100s - e - b - s . sup . ( 4 ) 33 : 67 100paraffinic oil . sup . ( 5 ) 400 400 400stabilizer . sup . ( 6 ) 2 . 5 2 . 5 2 . 5breaking strength ,. sup . ( 7 ) dyne / cm . sup . 2 4 × 10 . sup . 5 4 × 10 . sup . 5 4 × 10 . sup . 6tear propagation ,. sup . ( 8 ) dyne / cm . sup . 2 8 × 10 . sup . 4 7 × 10 . sup . 4 1 × 10 . sup . 6elongation at break ,. sup . ( 9 ) % 180 168 1 , 700compression set . sup . ( 10 ) at 24 hours 81 %. sup . ( r ) 77 %. sup . ( r ) 0 . 0 % rigidity , gram bloom 1 , 536 1 , 520 360______________________________________ . sup . ( 1 ) styrene to ethylene and butylene . sup . ( 2 ) shell kraton g 1650 . sup . ( 3 ) shell kraton g 1652 . sup . ( 4 ) shell kraton g 1651 . sup . ( 5 ) arcoprime 200 . sup . ( 6 ) irganox 1010 . sup . ( 7 ) astm d 412 modified . sup . ( 8 ) astm d 1938 modified . sup . ( 9 ) astm d 412 modified . sup . ( 10 ) astm d 395 modified . sup . ( r ) ruptured completely the results of table i show drastically un - acceptable poor properties of triblock copolymers having styrene to ethylene and butylene ratios below ( not within ) the contemplated range of the instant invention . one hundred parts by weight of a poly ( styrene - ethylene - butylene - styrene ) triblock copolymer ( shell kraton g 1651 ) having a styrene end block to ethylene and butylene center block ratio of about 33 . 67 with 0 . 1 parts by weight of a stabilizer ( irganox 1010 ) was melt blended with various quantities of a naphthenic oil ( arco tufflo 6024 ). samples having the dimensions of 5 cm by 5 cm by 3 cm were cut and measured for gel rigidity on a modified bloom gelometer as determined by the gram weight required to depress the gel a distance of 4 mm with a piston having a cross - sectional area of 1 cm 2 . the average gel rigidity values with respect to various oil concentrations are set forth in table ii below . table ii______________________________________oil per 100 parts of gel rigidity , triblock copolymer gram bloom______________________________________360 500463 348520 280615 240635 220710 172838 1351 , 587 54______________________________________ example ii is repeated except about 980 parts oil is used and the gel rigidity found to be about 101 gram bloom . other properties measured are : tensile strength at break about 4 . 4 × 10 6 dyne / cm 2 , elongation at break about 2 , 470 %, elasticity modulus about 3 . 5 × 10 4 dyne / cm 2 , and shear modulus about 3 . 7 × 10 4 dyne / cm 2 . the tensile strength , elongation , elasticity modulus were measured with cross - head separation speed of 25 cm / minute at room temperature . the shear modulus was measured with a 1 , 2 , and 3 kilogram load at room temperature . example ii is repeated except about 520 parts of a polybutene ( amoco indopol h - 300 ) is used and the gel rigidity found to be about substantially unchanged with respect to use of naphthenic oil alone . example ii is repeated except about 520 parts of a polypropene ( amoco c - 60 ) is used and the gel rigidity found to be about substantially unchanged with respect to use of naphthenic oil alone . example ii is repeated except about 520 parts of a polyterpene ( hercules piccolyte s 10 ) is used and the gel rigidity found to be about substantially unchanged with respect to use of naphthenic oil alone . example ii is repeated except about 360 parts of a combined mixture of : 72 parts of a paraffinic oil ( arco prime 200 ), 72 parts of a naphthenic oil ( arco tufflo 6014 ), 72 parts of a polybutene oligomer ( amoco indopol h - 200 ), 72 parts of a polypropene oligomer ( amoco polypropene c - 60 ), and 72 parts of a polyterpene oligomer ( hercules piccolyte s 10 ) is used and the gel rigidity found to be about substantially unchanged with respect to the use of naphthenic oil alone . example iii was repeated except 933 parts oil with 147 parts by weight of a poly ( styrene - ethylene - butylene - styrene ) triblock copolymer containing 47 parts of a naphthenic process oil ( shell kraton g 4609 ) having a styrene to ethylene and butylene ratio of about 33 : 67 was used and the physical properties found to be about substantially unchanged with respect to the components used in example iii . example iii was repeated except 933 parts oil with 147 parts by weight of a poly ( styrene - ethylene - butylene - styrene ) triblock copolymer containing 47 parts of a paraffinic white petroleum oil ( shell kraton g 4609 ) having a styrene to ethylene and butylene block ratio of about 33 : 67 is used and the physical properties found to be substantially unchanged with respect to the components used in example iii . example ii was repeated except about 400 parts of oil was used and the properties measured were : tear propagation about 1 . 4 × 10 6 dyne / cm 2 , no crack growth in 180 ° bend under 50 gram load for 5 , 000 hours at room temperature , tensile strength about 4 × 10 6 dyne / cm 2 , elongation at break about 1 , 700 %, tensile set about 0 % at 1 , 200 % elongation , compression set about 0 % when tested under 5 , 000 gram load for 24 hours , and 100 % snap back recovery after extension to 1 , 200 %.

a novel gelatinous composition is disclosed which contains an intimate melt blend admixture of poly triblock copolymer having said styrene end block to ethylene and butylene center block ratio within the range of from between 31 : 69 to 40 : 60 , and high levels of an plasticizing oil . the gelatinous composition is transparent and have a novel combination of properties including unexpectedly high elongation and tensile strength and excellent shape retention after extreme deformation under high - velocity impact and stress conditions . the gelatinous products of this invention are soft , flexible , and have elastic memory , characterized by a gel rigidity of from about 20 gram to about 700 gram bloom . these and other properties are particularly essential for the gelatinous composition to have utility as toys , therapeutic hand exercising grips , shock absorbers , acoustical isolators , and other uses .

in the method of the subject invention , metabolizable carbohydrates such as sucrose , glucose , lactose , dextrins , pre - gelatinized starches , fructose , maltose and other mono , di , oligo , and polysaccharides which are normally absorbed and metabolized in the digestive tract may be coated with a food or pharmaceutical grade coating such as stearic acid , hydrogenated or partially hydrogenated oils , such as cottonseed , soybean or rape seed oil , calcium stearate , stearyl alcohol and the like . the coating may be from any of various processes , including coating in a coating pan , spraying , fluidized bed , or utilizing the rotating disc method such as disclosed in u . s . pat . nos . 5 , 100 , 592 and 4 , 675 , 140 . in the method of the subject invention , the carbohydrate core is coated so as to experience controlled , delayed absorption when ingested into the human body . the coated product should result in a shelf - stable powder with particle size range of 30 to 1 , 000 μm . the actual size of the particle would depend both on dissolution rates desired and organoleptic characteristics of the food system in which it is administered . in general , where a smoother textured food is required , such as beverages , a finer particle size range ( 75 - 150 μm ) would be utilized . for food systems where the food is masticated , larger sized particles could be used (+ 150 μm ). because the active component is encapsulated by the method of the subject invention , the resulting coated particles would be relatively inert and bland in both aroma and taste . this would allow the coated particle of the subject invention to be incorporated in a variety of foods without affecting the characteristic properties and flavors of the food . the coating set forth above could be selected to be compatible with the components and preparation of the food . for instance , ethyl cellulose , a non - food ingredient , could be selected for foods containing free fats or oils and elevated preparation temperatures of up to 100 ° c . hydrogenated tallow and stearic acid coatings would be suitable where temperatures do not exceed 60 ° c . and significant quantities of free lipids are not present . in the following example , several methods of coating carbohydrates are set forth where the in vitro release rates of some of the products which have been obtained by such coating , are shown . d - glucose was sieved to obtain 250 g of a fraction which passed through a 300 μm sieve but was retained by a 177 μm sieve . this was placed into the coating pan such as is commonly used in the pharmaceutical industry to coat tablets . in order to have a sufficient amount of material in the pan for proper mixing and coating , it was found necessary to add another solid which was of a larger size so that after coating , it could be separated from the glucose . approximately 500 g table salt of about 420 to 500 μm was used for this purpose . stearic acid , 375 g , was dissolved in 1875 ml of hot ( 75 ° c .) ethanol . the pan was set to rotate 50 to 55 rpm . a two - fluid nozzle was connected to a hot air supply which was regulated between 15 to 22 psi . the ethanol solution was supplied to the liquid side of the nozzle at a rate of about 10 ml / min . room temperature air was blown into the pan to help evaporate the ethanol . samples were removed from the pan after 20 , 30 , 40 and 50 parts of stearic acid had been sprayed per 100 parts of solids being coated in the pan . after 50 parts were sprayed , the solids were separated by sieving . the fraction 75 to 420 μm was tested except for the highest level of coating where the fraction of 180 to 300 μm was also tested . to test the release , 2 g of the coated sample was shaken in 100 ml of water in a 250 ml plastic bottle ( approximately 1 inch travel 60 cycles / min ). periodically , approximately 3 ml of the solution was withdrawn and the concentration determined by measuring the refractive index of the solution relative to that of pure water ( differential refractive index ). after the measurement , the solution was returned to the bottle . after 1 day , the particles were filtered out of the solution and crushed with a mortar and pestle . the crushed particles were combined with the solution and concentration was measured again . this represents the concentration corresponding to 100 % of the glucose released . to obtain the percent glucose release , the glucose concentration in the solution at any time was divided by the concentration corresponding to 100 % released . the loading was calculated by dividing the concentration corresponding to the 100 % of the glucose released by the concentration corresponding to 2 g uncoated glucose in 100 ml . fig1 shows the percentage of glucose released from the particles of example 1 versus time . it may be seen that when the amount of coating increases , the rate of release is decreased . and that the time scale may be adjusted to release the glucose in a time corresponding to the residence time in the gastro - intestinal tract by suitable adjustments in the process . the rotating disc allows rapid coating of particles . approximately 100 g glucose passing a 125 μm sieve but being retained by a 75 μm sieve were slurried into 200 ml solution of acetone 4 parts to 1 part of ethanol containing 7 . 5 % w / v ethyl cellulose and immediately poured into the central opening of a rotating vaned disc ( 8 inches in diameter with 24 vanes ) rotating at 10 , 000 rpm . the particles were dry and were immediately collected . when tested for release , the 75 to 300 μm fraction which had a payload of 89 % ( 11 % coating ) corresponding to an average wall thickness of 9 . 6 μm released 82 % of its glucose concentration in 5 minutes and 97 % in 20 minutes . this coating thus shows only slight protection and would not be sufficient on its own but may serve as a prime coat . a second coat is a hot melt coat containing tristearin , which is applied by spraying from solution . other fats and fat - like substances , including triglycerides such as tristearin , tripalmitin , trilaurin or glyceryl behenate or mixtures thereof , diglycerides and monoglycerides as well as free paraffin wax , bees wax , carnauba wax , and microcrystalline waxes allowed as part of food or drug components . proteins may also be utilized as a second coating and may be egg albumin , casein , zein , or soy proteins . semi - synthetic polymers may also be used and include ethyl cellulose , cellulose acetate phthalate , hydroxypropyl methyl cellulose phthalate . synthetic polymers also are possible for use as a second coating and include acrylate copolymers approved for coating of medical forms for oral ingestion . application of these materials may generally be accomplished by spraying from solution , dispersion or emulsion , as appropriate . a hot melt was prepared as follows : 26 g stearic acid was melted and heated to 150 ° c . 10 . 5 g ethyl cellulose ( 7 cps ) was dissolved in it . 103 g hydrogenated tallow was added and the liquid brought to about 85 ° c . 70 g of the product from example 2 passing a 150 μm sieve but being retained by a 75 μm sieve was added to the melt and stirred in to make a homogeneous mixture . the rotating disc used in example 2 was heated to 80 ° c . and turned on to rotate at 10 , 000 rpm and the slurry poured into the opening of the disc at the rate of about 300 ml / min . two fractions which represented together 83 % of the product were tested 75 to 150 μm and 150 to 300 μm . the payload was 34 and 44 % respectively . in 5 minutes , the release rate was 51 . 4 and 20 . 5 %, in 20 minutes 61 . 2 and 34 . 7 % was released , in 80 minutes , 74 . 3 and 65 . 6 % was released . after 5 hours , 81 % of both fractions were released . coating of glucose in a fluidized bed with a solution of ethyl cellulose 750 g anhydrous glucose , passing a 300 μm screen but being retained by a 177 μm screen was placed in a fluidized bed ( 6 inch diameter ) where it was fluidized with air from below . ethyl cellulose was dissolved in acetone ethanol 4 / 1 by volume to make a 3 % w / v solution . the solution was sprayed with a two - fluid nozzle using air at an air pressure of 25 psi and a liquid rate of about 8 ml / min . it was sprayed on until 5 . 4 % of coating was deposited . the 75 to 300 μm fraction was tested . 46 . 8 % was released in 5 minutes , 72 . 6 % was released in 20 minutes , 91 % was released in 80 minutes . fructose was sieved to remove particles smaller than 420 μm . 650 g of this was placed in the apparatus described in example 1 and coated with stearic acid by spraying a 20 % w / v solution in ethanol as in example 1 . a sample removed from the run had a payload or glucose content of 75 . 9 %. in the standard release test , it released 45 . 1 % in 10 minutes , 48 . 2 % in 1 hour , 64 % in 3 hours , 91 % in 19 hours . 40 g stearic acid ( witco hystrene 9718 ) was melted and heated to 135 ° c . 20 g ethyl cellulose ( dow , ethocel of 7 ) was dissolved in it . then 140 g of hydrogenated tallow ( kraft ) was added and dissolved . 100 g corn starch mira - gel 463 ( staley ) was dispersed in the melt and sprayed with an 8 - inch diameter vaned disc at 10 , 000 rpm . 245 g of product was collected . the particles of product ranged from about 30 to 300 μm in size . the original starch granules are about 15 μm ; therefore , several of the granules make up a product particle glued together by the hot melt . to determine the active content , the product was ground with a mortar and pestle and 1 g placed into cellophane tubing with a 6000 molecular cut - off . also into the tube was placed 30 ml water 0 . 05 ml ban 120l amylase , 6 units ( novo nordisk ) and 2 ml agm 200 l amyloglucosidase 400 units ( novo nordisk ). 1 unit of amylase breaks down 5 . 25 g of soluble starch per hour at 37 ° c . and ph 5 . 6 . 1 unit of amyloglucosidases hydrolyses 1 micromole of maltose per minute at 25 ° c . and ph 4 . 3 . the ends of the cellophane were tied , and formed into a u - shape and immersed into 300 ml of acetate buffer of ph 4 . 5 . the buffer was stirred with a magnetic stirrer and thermostatted at 37 ° c . 5 ml samples were taken from the buffer after 12 , 24 , and 48 hours , frozen and analyzed with the hitachi 747 glucose hexokinase method . a calibration with glucose in the presence of the enzyme is necessary . the amount of glucose liberated from this sample was 49 % of that of the uncoated mira - gel and did not change appreciably after 12 hours . to determine the rate of available glucose in a simple simulated digestion , we proceeded as above , except 821 mg of unground product containing 403 mg of starch was used . the buffer was sampled at 20 minutes , 1 hour , 4 hours and 8 hours after the start of the experiment . the samples were frozen and later analyzed . the coated mira - gel starch showed the following release : controlled release of carbohydrates from pre - gelatinized starch granules obtained from other starchy foods would also be achievable by the above encapsulation methods . this would include starches obtained from cereals , such as wheat and rice , and froth starches obtained from root crops , such as potato and tapioca . diabetes patients who are taking insulin or oral hypoglycemic drugs are prone to low blood sugar reactions especially during or after exercise or increased activity . low blood sugar or hypoglycemia is defined as a blood glucose level below 50 mg / dl and is potentially a very serious , acute complication of diabetes . a normal blood sugar range is generally 70 to 120 mg / dl . symptoms of hypoglycemia range from shakiness , light - headedness and tachycardia to headache , blurred vision , poor coordination and eventually to loss of consciousness and death . there are two main counter - regulatory hormones that help the body recover from hypoglycemia : glucagon and epinephrine . decreased hormone secretion in people who have had diabetes for several years can cause more frequent low blood sugar reactions and more difficulty in noticing that blood sugar is low . to exercise safely , diabetics often have to increase food intake either before , during or after exercise . exercise of moderate intensity ( doubles tennis , leisurely biking , golfing ) requires about 10 to 15 grams of carbohydrates per hour of exercise . one to two hours of strenuous activity may require 25 to 50 grams of additional carbohydrates . a beverage or snack bar with controlled release carbohydrates lends itself to preventing low blood sugar during and after exercise . controlled release carbohydrates ( crc ) may be described as a shelf - stable powder with a particle size range of 30 - 1000 μm . products in which a smooth , non - gritty texture was desired would utilize the finer particle size range . products which are granular or have large particles could utilize the larger particle size range . when the active components are encapsulated according to the subject invention , crc powders are relatively inert and bland in both aroma and taste . this will allow crc to be incorporated in a variety of foods without affecting the characteristic properties and flavor of food . alternatively , colorants and flavors can be added to coatings to improve consumer acceptance . emulsifiers can be incorporated as part of coating to aid in dispersion in the food system . crc powders in which the coated carbohydrate is readily water soluble releases its load by a diffusion process as it transits the digestive system . therefore , these products would have to be prepared by mixing in a liquid system or a viscous food system , e . g ., yogurt , and consumed 5 - 15 minutes after preparation . crc powders may be prepared in which the coated carbohydrate is a pre - gelatinized starch . the carbohydrate load would be released by hydration , swelling and reaction with the digestive amylases . hence , crc powders based on starch granules would have extended stability in liquid systems . this would extend the food application to rte foods ( puddings , yogurts , frozen novelties ) and ready to drink beverages . crc powders could be added to food products which are low in water activity - dry beverages , nutritional beverage powders , dessert mixes . product would be prepared according to recipe and consumed . crc powders could be used as a sole source of carbohydrates in the food or in combination with uncoated rapidly absorbed carbohydrates . crc powders are designed to release the bulk of their carbohydrate payload within approximately four hours after ingesting . release times significantly longer than four hours would incur the release of excessive carbohydrates in to the large intestine . this would affect the osmotic water balance and increase the risk of bacterial fermentation leading to increased gas formation and laxation . crc products are produced by coating glucose granules with stearic acid as in example 1 . glucose payload would be approximately 75 % and coating thickness would be adjusted to give 80 % release within 1 - 4 hours after ingestion . based on the above parameters , each 100 kcal of energy from glucose released would require 41 . 7 g of material . the carbohydrate load and release rate can be adjusted to individual nutritional needs and product application . examples of different caloric deliveries using the above example are listed below : 1 . 25 . 0 g crc delivers 15 g cho and 60 kcal energy . 2 . 41 . 7 g crc delivers 25 g cho and 100 kcal energy . 3 . 50 . 0 g crc delivers 30 g cho and 120 kcal energy . nine ounces of prepared beverage is formulated to provide 22 g of readily absorbable , uncoated carbohydrates plus 30 g of controlled release carbohydrates . the crc material is encapsulated to release as follows : ______________________________________time cho released calories total calories______________________________________start exercise 22 g 88 8860 minutes 15 g 60 148120 minutes 15 g 60 208______________________________________ this controlled release beverage would support two hours of strenuous exercise . if a diabetic wants to support three hours of moderate exercise , such as a round of golf , he or she would only drink 6 ounces of beverage . this would provide : ______________________________________time cho released calories total calories______________________________________start exercise 15 g 60 6060 minutes 10 g 40 100120 minutes 10 g 40 140______________________________________ while there will always be individual differences between people , this product would generally enable the diabetic exerciser to maintain a blood sugar level between 100 and 180 mg / dl , providing they start in this range . by incorporating crc into a snack bar similar to an &# 34 ; energy bar &# 34 ; or &# 34 ; granola bar ,&# 34 ; similar release rates could be obtained . although there may be a limited amount of crc granules crushed through chewing , the bulk will be ingested intact as part of the swallowed bolus . the quantity of readily absorbable carbohydrate released by chewing would be factored into the requirements for the calories required at the start of exercise . the caloric load in the above 9 oz . beverage sample could be incorporated in a single bar scored into 3 parts . for two hours of strenuous exercise , the subject eats the whole bar . for three hours of moderate exercise , the subject eats two of the three parts , with additional carbohydrate left for future consumption . alternatively , the carbohydrate load might be delivered in 3 separate smaller bars . hypoglycemia can be a serious problem for a diabetic during the night -- usually around 3 a . m . a bedtime beverage which is taken 1 / 2 hour before sleep is formulated to provide 15 g of uncoated carbohydrates for normal absorption and 15 grams of crc for slow release . ______________________________________time cho released calories total calories______________________________________start sleep 15 g 60 6060 minutes 5 g 20 80120 minutes 5 g 20 100180 minutes 5 g 20 120______________________________________ this will prevent a significant fall in blood glucose during the night for those who have exercised vigorously during the day and are at risk of hypoglycemia for up to 30 hours after the exercise . if the blood sugar is well controlled , the overnight blood sugar will remain within the acceptable range of 70 - 140 mg / dl . individual variations exist and release curves and levels would be adjusted based on individual medical needs . the product made with crc may contain other nutrients , e . g ., fiber , vitamins , and minerals to provide additional nutritional benefits . artificially sweetened powdered soft drink with 42 grams coated glucose in 8 oz of beverage . ______________________________________coated glucose from example 1 42 . 00 g * guar gum . 40 (. 10 -. 60 ) aspartame . 04 (. 02 -. 10 ) citric acid . 30 (. 10 -. 60 ) trisodium citrate . 26 (. 15 -. 40 ) dried citrus flavor . 24 (. 05 - 4 . 0 ) red # 40 . 01 (. 005 -. 15 ) polysorbate . 01 (. 005 -. 03 ) 43 . 26 g______________________________________ * 100 kcal from glucose 25 grams glucose add powder to 8 fl . oz . of cold water and shake or stir thoroughly and drink . using the above example , uncoated sugars such as fructose , glucose or sucrose could be added to deliver a portion ( 10 - 50 %) of the caloric requirements and the level of coated glucose decreased correspondingly . ______________________________________coated glucose of example 1 21 . 00 g * fine granular glucose 22 . 00 ( 5 . 0 - 50 . ) guar gum . 40 (. 10 -. 60 ) aspartame . 04 (. 02 -. 10 ) citric acid . 30 (. 10 -. 60 ) trisodium citrate . 26 (. 15 -. 40 ) dried citrus flavor . 24 (. 05 - 4 . 0 ) red # 40 . 01 (. 005 -. 15 ) polysorbate . 01 (. 005 - 0 . 3 ) 44 . 26 g______________________________________ formula delivers 12 . 6 g of carbohydrate from crc and 22 g of carbohydrate from glucose . ______________________________________instant chocolate pudding______________________________________coated fructose of example 5 42 . 00 gpregel . corn starch 18 . 35 ( 12 - 24 ) monopotassium phosphate 1 . 80 ( 1 . 4 - 2 . 2 ) tetrapotassium pyrophosphate 1 . 80 ( 1 . 4 - 2 . 2 ) mono and diglycerides . 70 (. 4 - 1 . 0 ) cocoa powder 12 . 00 ( 8 . 0 - 16 . 0 ) aspartame . 28 (. 2 -. 4 ) vanilla flavor . 07 (. 01 - 1 . 4 ) 77 . 00 g______________________________________ pour mix into bowl . add 2 cups cold skim milk and blend for 2 - 3 minutes with beater . pour into serving cups . chill . makes four 1 / 2 cup servings . ______________________________________snack bar______________________________________crc example 1 25 . 00 g ( 5 . 0 - 50 . ) glucose 7 . 00 ( 4 . 0 - 10 . ) granola cereal 8 . 75 ( 4 . 0 - 10 . ) vegetable 2 . 00 ( 1 . 0 - 4 . 0 ) glycerine 1 . 50 ( 0 . 5 - 3 . 0 ) water 1 . 00 ( 0 . 5 - 3 . 0 ) sweet whey 1 . 00 ( 0 . 2 - 2 . 0 ) lecithin . 15 ( 0 . 5 -. 30 ) cinnamon . 15 ( 0 . 5 -. 30 ) flavoring . 10 (. 02 -. 20 ) 46 . 65 g______________________________________ formula delivers 15 g carbohydrate from crc and 15 g untreated carbohydrates from glucose and the granola cereal blend ( rolled oats , wheat , glucose syrup ). ______________________________________dark chocolate bar______________________________________crc ( ethyl cellulose coating 25 . 00 g ( 5 - 40 ) 15 g carbohydrate ) sucrose 25 . 00 ( 15 - 35 ) chocolate liquor 28 . 20 ( 10 - 35 ) cocoa butter 21 . 00 ( 10 - 35 ) lecithin . 50 ( 0 . 2 - 1 . 0 ) natural flavor . 30 ( 0 . 1 - 0 . 6 ) 100 . 00 g______________________________________ formula delivers 15 g carbohydrate from crc and 33 g carbohydrate from sucrose and chocolate liquor . while the invention has been described with reference to a preferred embodiment , it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention . in addition , many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof . therefore , it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention , but that the invention will include all embodiments and equivalents falling within the scope of the appended claims . various features of the invention are set forth in the following claims .

a composition of carbohydrates having an edible coating is disclosed , whereby the coated carbohydrate , when orally ingested , causes a time delay release of the carbohydrate into the digestive system . the method of administering carbohydrates in this manner may be useful in the treatment of diseases such as diabetes and exercise programs calling for sustained effort .

in more detail , the instant invention relates to the unexpected finding that when one combines methomyl and oxamyl in a designated solvent , unexpected solubility synergism is observed . that is to say , when one adds both methomyl and oxamyl , in the designated ratio , to a designated solvent , one is able to dissolve an unexpectedly large amount of total , mixed active ingredient in the solvent . depending upon the lowest temperature which the solution must withstand without crystallization , one can obtain a concentration of 1 to 5 lbs . of total active ingredient per u . s . gallon of solution . the weight ratio of methomyl to oxamyl is about 2 : 1 to about 1 : 2 . 5 , preferably about 1 . 5 : 1 to 1 : 1 . 5 and most preferably about 1 : 1 to 1 : 1 . 5 . the solvents may be a system of methanol / water containing from about 0 - 70 weight percent water ; acetone / water containing from about 0 - 70 weight percent water ; or cyclohexanone / cyclohexanol / methanol / water containing from about 20 - 92 weight percent cyclohexanone and cyclohexanol provided at least about 35 % of this component is cyclohexanone , about 3 - 25 weight percent methanol and at least about 5 % water . the preferred solvent is a system of methanol / water containing from about 0 - 70 percent water , most preferably about 20 - 50 percent . the ph may vary from about 2 . 8 to 3 . 2 ; the most preferred acid to be utilized is phosphoric acid , but other acids such as acetic , citric and sulfuric acid are also acceptable so long as the desired ph is obtained . in a preferred embodiment , phosphoric acid in the amount of about 0 . 4 to 0 . 6 weight percent is utilized . if desired , warning agents may be added such as dyes , colorants , or odor - producing chemicals . typically , a coloring agent would be added in an amount from about 0 . 01 - 0 . 10 percent . suitable coloring agents would be &# 34 ; marasperse &# 34 ;, a product of the american can company , &# 34 ; lignosols &# 34 ;, sold by lignosol chemicals company , or organic dyes such as fd & amp ; c blue no . 1 , fd & amp ; c red no . 3 ( 773 erythrosine ) or fd & amp ; c yellow no . 5 ( 640 tartrazine ). in fact , any coloring agents that do not react chemically with the other formulation ingredients may be utilized . combinations of coloring agents are also suitable . &# 34 ; marasperse &# 34 ; cb , or fd & amp ; c blue no . 1 are the preferred coloring agent . the preparation of both methomyl and oxamyl is well known to one skilled in the art . for instance , the preparation of methomyl and its various uses as an insecticide , nematocide etc . are included in u . s . pat . no . 3 , 639 , 633 to james b . buchanan , the disclosure of which is herein incorporated by reference . the preparation of oxamyl and its uses for various purposes such as an insecticide , miticide , or nematocide are taught in u . s . pat . no . 3 , 530 , 220 to buchanan , the disclosure of which is herein incorporated by reference . as would be expected , the concentrates of the instant invention are useful for controlling insects , other arthropod pests and pestiferous mollusks and nematodes . the methomyl , oxamyl , acid and any other ingredients such as coloring agents may be mixed in conventional equipment by conventional means . for instance , they may be mixed as follows : the solvent system and acid are added to a glass - lined or stainless steel kettle equipped with a stirring mechanism and facilities for blanketing the kettle with nitrogen or other inert gas to reduce the fire hazard of the flammable solvents . the active ingredients and the warning agent such as a coloring agent are added to the kettle while stirring ; stirring is continued until the active ingredients and coloring agent are dissolved . the solution can then be filtered by techniques known in the art . a &# 34 ; sparkler &# 34 ; filter may be used . formulations of the following compositions are prepared by dissolving the methomyl , oxamyl and coloring agent , where applicable , in the solvent system and acid at ambient temperature . the solution is clarified by filtration techniques known in the art . ______________________________________a . methomyl 22 lb . oxamyl 22 lb . &# 34 ; marasperse &# 34 ; cb . sup . ( 1 ) 0 . 025 lb . ch . sub . 3 oh 33 . 3 lb . h . sub . 2 o 22 . 1 lb . 85 % h . sub . 3 po . sub . 4 0 . 33 lb . b . methomyl 20 lb . oxamyl 10 lb . f . d . & amp ; c . blue no . 1 . sup . ( 2 ) 0 . 01 lb . ch . sub . 3 oh 62 . 7 lb . h . sub . 2 o 6 . 9 lb . 85 % h . sub . 3 po . sub . 4 0 . 33 lb . c . methomyl 15 lb . oxamyl 15 lb . acetone 52 lb . water 13 lb . 85 % h . sub . 3 po . sub . 4 5 lb . d . methomyl 20 lb . oxamyl 30 lb . cyclohexanone 27 lb . ch . sub . 3 oh 4 . 5 lb . water 13 . 5 lb . 85 % h . sub . 3 po . sub . 4 5 lb . e . methomyl 15 lb . oxamyl 15 lb . cyclohexanone 15 . 6 lb . cyclohexanol 19 . 5 lb . ch . sub . 3 oh 9 . 75 lb . water 20 . 15 lb . 85 % h . sub . 3 po . sub . 4 5 lb . ______________________________________ . sup . ( 1 ) available from american can co . . sup . ( 2 ) available from h . kohnstamm & amp ; co . inc ., new york or chicago . methomyl and oxamyl were added to various methanol : water solvent systems ranging from 100 % ch 3 oh to 40 % ch 3 oh : 60 % h 2 o . the methomyl and oxamyl were dissolved separately or combined on a 1 : 1 weight ratio in the solvent systems at room temperature at a concentration exceeding the solubility limit at - 6 ° c . each sample was seeded with methomyl and / or oxamyl at - 6 ° c . and allowed to crystallize until equilibrium was established . the supernatant liquid of each sample was assayed for methomyl and / or oxamyl by liquid chromatography . the following results were obtained . __________________________________________________________________________solubility of methomyl and oxamyl ( 1 : 1 wt . ratio ) in ch . sub . 3 oh / h . sub . 2 o at - 6 ° c . in gms / 100 gms__________________________________________________________________________solvent both actives in solvent methomyl methomyl oxamylsolvent methomyl oxamyl & amp ; oxamyl alone in alone in % ch . sub . 3 oh /% h . sub . 2 o gms gms gms solvent gms solvent gms__________________________________________________________________________100 / 0 63 . 9 80 143 . 9 30 . 7 33 . 390 / 10 66 . 4 92 . 0 158 . 4 29 . 9 40 . 680 / 20 58 . 1 87 . 0 145 . 1 26 . 3 44 . 770 / 30 43 . 8 52 . 7 96 . 5 20 . 8 42 . 260 / 40 35 . 5 53 . 2 88 . 7 15 . 5 39 . 750 / 50 23 . 7 33 . 3 57 . 0 10 . 5 29 . 040 / 60 18 . 8 33 . 7 52 . 5 6 . 2 20 . 9__________________________________________________________________________ the table illustrates that in a common solution , both the total combined amount of actives as well as the amount of each individual component has been increased over what a solution of each active ingredient alone in that solvent could contain . the following figures plot the solubility data of example 2 . curve 1 of fig1 plots the solubility of methomyl alone in the various methanol / water solvents . curve 2 of fig1 plots the solubility of methomyl in the presence of oxamyl . curve 3 of fig2 plots the solubility of oxamyl alone in the various methanol / water solvents . curve 4 of fig2 plots the solubility of oxamyl in the presence of methomyl . the shaded areas between curves 1 and 2 and between curves 3 and 4 represent the increase in solubility derived from having both methomyl and oxamyl present . solubility of methomyl and oxamyl ( 2 : 1 wt . ratio ) in ch 3 oh / h 2 o at - 6 ° c . methomyl and oxamyl were added to various methanol : water solvent systems ranging from 100 wt . % ch 3 oh to 30 wt . % ch 3 oh : 70 wt . % h 2 o . the methomyl and oxamyl were dissolved in a 2 : 1 weight ratio of 50 wt . % methomyl to 25 wt . % oxamyl in the solvent systems . the samples were equilibrated at - 6 ° c . in a constant temperature freezer after which they were seeded with methomyl and oxamyl crystals to ensure crystallization of both materials . after crystal - liquid equilibrium was assured , liquid was removed at - 6 ° c . and assayed for methomyl and oxamyl . solids were also removed at - 6 ° c ., washed with hexane and dried . the solids were then dissolved in methanol to yield a 10 wt . % solution . this solution was evaluated by thin layer chromatography ( tlc ) to ensure the solids consisted of both methomyl and oxamyl . all solids were composed of the mixture . the following assays were obtained on the liquids . __________________________________________________________________________solubility of methomyl and oxamyl ( 2 : 1 wt . ratio ) in ch . sub . 3 oh / h . sub . 2 o at - 6 ° c . in gms / 100 gms__________________________________________________________________________solvent both actives in solvent methomyl methomyl oxamylsolvent methomyl oxamyl & amp ; oxamyl alone in alone % ch . sub . 3 oh /% h . sub . 2 o gms gms gms solvent gms solvent gms__________________________________________________________________________100 / 0 82 . 5 113 195 . 5 30 . 7 33 . 390 / 10 / 73 . 7 106 179 . 7 29 . 9 40 . 680 / 20 59 . 8 94 . 7 154 . 5 26 . 3 44 . 770 / 30 34 . 2 89 . 1 123 . 3 20 . 8 42 . 260 / 40 55 . 2 99 . 2 154 . 4 15 . 5 39 . 750 / 50 46 . 1 96 . 6 142 . 7 10 . 5 29 . 040 / 60 42 . 2 100 142 . 2 6 . 2 20 . 930 / 70 24 . 1 57 . 4 81 . 5 -- -- __________________________________________________________________________ the above data illustrate that the solubility of both methomyl and oxamyl is increased in methanol : water solvent systems when a 2 : 1 wt . ratio of methomyl to oxamyl is dissolved initially . furthermore , the total amount of active ingredient in a given solution , when both oxamyl and methomyl are present in combination in solution is much greater than the sum of the individual components dissolved in separate solutions . in addition , the quantity of solvent needed to dissolve given quantities of oxamyl and methomyl when in mixture is less than 1 / 3 the quantity of solvent needed to dissolve the oxamyl and methomyl individually . solubility of methomyl and oxamyl 1 : 2 . 5 wt . ratio in ch 3 oh : h 2 o at - 6 ° c . example 3 was repeated by dissolving methomyl and oxamyl in a 1 : 2 . 5 weight ratio in the same solvent systems under the same conditions . the following methomyl and oxamyl solubilities at - 6 ° c . were found . tlc indicated the solids in each sample contained both materials . __________________________________________________________________________solubility of methomyl and oxamyl ( 1 : 2 . 5 wt . ratio ) in ch . sub . 3 oh / h . sub . 2 o at - 6 ° c . in gms / 100 gms__________________________________________________________________________solvent both actives in solvent methomyl methomyl oxamylsolvent methomyl oxamyl & amp ; oxamyl alone in alone in % ch . sub . 3 oh /% h . sub . 2 o gms gms gms solvent gms solvent gms__________________________________________________________________________100 / 0 71 . 1 72 . 3 143 . 4 30 . 7 33 . 390 / 10 69 . 9 76 . 4 146 . 3 29 . 9 40 . 480 / 20 57 . 3 73 . 7 131 . 0 26 . 3 44 . 870 / 30 22 . 0 46 . 1 68 . 1 20 . 6 42 . 360 / 40 44 . 0 74 . 8 118 . 8 15 . 5 39 . 650 / 50 41 . 1 74 . 0 115 . 1 10 . 5 29 . 140 / 60 28 . 8 51 . 6 80 . 4 6 . 2 20 . 930 / 70 15 . 6 34 . 7 50 . 3 -- -- __________________________________________________________________________ methomyl and / or oxamyl were added to a solvent system consisting of 60 % cyclohexanone , 10 % methanol and 30 % water at room temperature at a concentration higher than the solubility limit at - 6 ° c . the methomyl and oxamyl were added together , at weight ratios of 2 : 1 , 1 : 1 and 1 : 2 . 5 . the solutions were cooled to - 6 ° c . and seeded with methomyl and / or oxamyl to initiate crystallization . the solutions remained at - 6 ° c . until equilibrium was assured . the supernatant liquid in each sample was analyzed for methomyl and oxamyl by liquid chromatography . the following results were obtained . __________________________________________________________________________solubility of methomyl and oxamyl ( 2 : 1 , 1 : 1 and 1 : 2 . 5 wt . ratios ) in cyclohexanone , ch . sub . 3 ohand h . sub . 2 o at - 6 ° c . in gms / 100 gms solvent__________________________________________________________________________ both actives in solvent methomyl methomyl oxamylmethomyl / oxamyl methomyl oxamyl & amp ; oxamyl alone in alone inratio gms gms gms solvent gms solvent gms__________________________________________________________________________2 : 1 64 . 8 84 . 8 149 . 6 29 . 5 48 . 41 : 1 46 . 2 80 . 1 126 . 3 29 . 5 48 . 41 : 2 . 5 66 . 6 82 . 7 149 . 3 29 . 5 48 . 4__________________________________________________________________________ methomyl and oxamyl solubility in cyclohexanone , cyclohexanol , ch 3 oh and h 2 o at - 6 ° c . methomyl and oxamyl were dissolved separately and in weight ratios of 1 : 1 , 2 : 1 and 1 : 2 . 5 methomyl to oxamyl in a solvent system consisting of 30 wt . % cyclohexanone , 30 wt . % cyclohexanol , 30 wt . % water and 10 wt . % methanol . these solutions were equilibrated at - 6 ° c . and seeded with methomyl and / or oxamyl crystals . the samples of liquid and solids remained at - 6 ° c . until solid - liquid equilibrium was assured . a liquid sample was removed from each at - 6 ° c . and assayed for methomyl and / or oxamyl . solids were also isolated at - 6 ° c ., washed , dried and dissolved in ch 3 oh to yield a 10 % solution which was analyzed by tlc to ensure both methomyl and oxamyl crystals were present in the solids of the combination sample . all such solids contained both oxamyl and methomyl . __________________________________________________________________________solubility of methomyl and oxamyl ( 2 : 1 , 1 : 1 and 1 : 2 . 5 wt . ratios ) in cyclohexanone , cyclohexanol , ch . sub . 3 oh and h . sub . 2 oat - 6 ° c . in gms / 100 gms solvent__________________________________________________________________________ both actives in solvent methomyl methomyl oxamylmethomyl / oxamyl methomyl oxamyl & amp ; oxamyl alone in alone inratio gms gms gms solvent gms solvent gms__________________________________________________________________________2 : 1 42 . 7 83 . 0 125 . 7 24 . 5 41 . 51 : 1 39 . 6 63 . 7 103 . 3 24 . 5 41 . 51 : 2 . 5 40 . 2 61 . 8 102 . 0 24 . 5 41 . 5__________________________________________________________________________ solubility of methomyl and oxamyl 80 : 20 wt . ratio acetone : h 2 o methomyl and oxamyl were dissolved in a solvent system consisting of 80 wt . % acetone and 20 wt . % water separately and in 1 : 1 , 2 : 1 and 1 : 2 . 5 wt . ratios of methomyl and oxamyl . these solutions were equilibrated at - 6 ° c . and were seeded with methomyl and / or oxamyl . they remained at - 6 ° c . until solid - liquid equilibrium was assured . liquid was removed from each sample at - 6 ° c . and assayed for methomyl and oxamyl . solids were also removed at - 6 ° c ., washed , dried and dissolved in methanol to yield a 10 wt . % solution which was evaluated by tlc for oxamyl and methomyl . both were present in the solids from combination samples . the following results were obtained on the liquids removed from the samples . __________________________________________________________________________solubility of methomyl and oxamyl 2 : 1 , 1 : 1 and 1 : 2 . 5 wt . ratiosin 80 : 20 wt acetone and h . sub . 2 o in gms / 100 gms solvent__________________________________________________________________________ both actives in solvent methomyl methomyl oxamylmethomyl / oxamyl methomyl oxamyl & amp ; oxamyl alone in alone inratio gms gms gms solvent gms solvent gms__________________________________________________________________________2 : 1 64 . 8 84 . 6 149 . 4 41 . 4 52 . 01 : 1 67 . 0 79 . 3 146 . 3 41 . 4 52 . 01 : 2 . 5 66 . 6 82 . 8 149 . 4 41 . 4 52 . 0__________________________________________________________________________ the data in examples 2 - 7 show that increases in solubility occur when oxamyl and methonyl , both active insecticides and nematocides , are dissolved together in the solvents taught . the increases allow significant economies of solvent cost , packaging and shipping by greatly reducing the solvent necessary . the magnitude of these increases is unexpected .

chemically and physically stable insecticidal , nematocidal , water - soluble , liquid concentrates of s - methyl - oxy ]- thioacetimidate , and methyl n &# 39 ;, n &# 39 ;- dimethyl - n - oxy ]- 1 - thiooxamimidate when dissolved in an appropriate solvent , preferably methanol and water , in the presence of a small amount of acid , display solubility synergism .

turning now to the drawings , fig1 shows a golf club 10 . broadly speaking , the golf club 10 includes a lower shaft 12 , a midsection 14 , and an upper shaft 16 . upper shaft 16 of golf club 10 has a lower end 18 fitted with a first collar 20 . first collar 20 terminates in a threaded male projection 22 ( shown in fig2 ) which has a pin hole 23 . fig1 illustrates an upper end 24 of upper shaft 16 covered with a handle 26 . lower shaft 12 has an upper end 28 which terminates in a second collar 30 . second collar 30 has a pin hole 31 and a threaded female opening 32 ( shown in fig2 ). fig1 illustrates the club head 34 which is attached to a lower end 36 of the lower shaft 12 . midsection 14 is composed of spacer segment 38 ( a ) in fig1 . in fig2 midsection 14 contains spacer segment 38 ( a ) and spacer segment 38 ( b ). referring to fig4 the midsection 14 has spacer segments 38 ( a ) through 38 ( h ). turning to fig2 spacer segment 38 ( a ) has a threaded female opening 40 and a threaded male projection ( not shown ). spacer segment 38 ( b ) has a threaded female opening ( not shown ) and a threaded male projection 42 . each spacer segment added to the golf club 10 has a similar structure and further includes a pin hole 44 on its threaded male projection , a pin hole 46 on its barrel 48 , and a wrench flat 49 . referring to fig2 spacer segment 38 ( a ) has a threaded female opening 40 which threadably receives threaded male projection 22 . a roll pin 50 is inserted through pin hole 46 of spacer segment 38 ( a ) and pin hole 23 of the threaded male projection 22 , thus reinforcing the connection . still referring to fig2 second collar 30 has a threaded female opening 32 for threadably receiving the threaded male projection 42 of second spacer segment 38 ( b ). threaded male projection 42 has a pin hole 44 through its entire diameter , and second collar 30 has a pin hole 31 which is reflected across the threaded female opening 32 ( shown in breakaway ) thus permitting a removable roll pin 52 to be inserted when threaded male projection 42 is threadably received by threaded female opening 32 . this secures second spacer segment 38 ( b ) to second collar 30 of lower shaft 12 . in a preferred embodiment , each threaded male projection is about ¾ of an inch in length , and the barrel 48 has a length ( j ) of about 1 inch . the spacer segments can be of varying sizes and lengths , but preferably they are substantially similar to one another . [ 0020 ] fig2 also illustrates how the spacer segments look when connected to one another . spacer segment 38 ( b ) has a threaded female opening ( not shown ) which receives the threaded male projection ( not shown ) of spacer segment 38 ( a ). a roll pin 54 is inserted through spacer segment 38 ( b ) and the male projection ( not shown ) of spacer segment 38 ( a ) resulting in a secure connection between the two spacer segments . this connection can be repeated numerous times between many spacer segments . flat 49 is provides a gripping surface for tightening the connections . in a preferred embodiment of this invention , the golf club length can be potentially increased by up to eight spacer segments as shown in fig4 where spacer segments 38 ( a )- 38 ( h ) are interconnected by the same male / female and roll pin connection described above . spacer segment 38 ( a ) is secured to a first collar 20 by a roll pin 50 . eighth spacer segment 38 ( h ) is secured to a second collar 30 by a removable pin 52 . [ 0022 ] fig3 shows a sectional view of the connections when the golf club is lengthened by only one spacer segment . an upper shaft 16 is covered by a handle 14 . a lower end 18 of upper shaft 16 ends in a first collar 20 . an upper end 28 of lower shaft 12 is fitted with a second collar 30 . a spacer segment 38 ( a ) has a threaded female opening 40 which threadably receives a threaded male projection 22 of first collar 20 . this connection is secured by a roll pin 50 . second collar 30 has a threaded female opening 32 which threadably receives a threaded male projection 56 of spacer segment 38 ( a ). this connection is secured by a removable roll pin 52 . each time a user wishes to lengthen the golf club , he or she can withdraw removable roll pin 52 and add another spacer segment by putting the new spacer segment &# 39 ; s threaded female opening over the threaded male projection of the most recently attached spacer segments . the user then connects the new spacer segment &# 39 ; s threaded male projection to second collar 30 by way of the above described male / female connection followed by reinsertion of removable roll pin 52 . it will be appreciated that this unusual feature of adding segments permits a child to use the same golf club for quite some time . furthermore , club head 34 ( fig1 ) could be any golf head that the user desires , not just the one shown . placing an amount of epoxy on the male / female connection and inserting a roll pin through that connection provides the same strong , rigid shaft of a one piece golf club . these features save money for the families of children who play golf and give children from a wide range of economic backgrounds the ability to afford quality equipment .

a golf club which includes interconnected segments which can be added to extend the length thus providing an inexpensive alternative to buying new golf clubs . the segments are securely connected to achieve a rigid and sturdy golf club which can grow longer as a child grows taller . the segments preferably have a threaded male / female connection with epoxy applied to the threads followed by the added security of a roll pin inserted into the connection .

the following definitions are used herein . halo is fluoro , chloro , bromo , or iodo . alkyl includes both straight - or branched - chain alkyl , as well as cycloalkyl and ( cycloalkyl ) alkyl . aryl denotes a phenyl radical or an ortho - fused bicyclic carbocyclic radical in which at least one ring is aromatic . aryl includes aralkyl , alkaryl and alkaralkyl . heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non - peroxide oxygen , sulfur , and n ( y ) wherein each y is absent or is h , o , ( c 1 - c 4 ) alkyl , phenyl or benzyl , as well as a radical of an ortho - fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom , particularly a benz - derivative or one derived by fusing a propylene , trimethylene , or tetramethylene diradical thereto . as used herein , the term “ glutathione derivative ” means a compound of the formula : specific and preferred values listed below for radicals , substituents , and ranges , are for illustration only and they do not exclude other defined values or other values within defined ranges for the radicals and substituents . specifically , ( c 1 - c 8 ) alkyl can be methyl , ethyl , propyl , isopropyl , butyl , iso - butyl , sec - butyl , pentyl , 3 - pentyl , hexyl , heptyl , octyl , cyclopropylmethyl , cyclopropyl , cyclopentyl , or cyclohexyl ; ( c 1 - c 8 ) alkoxy can be methoxy , ethoxy , propoxy , isopropoxy , butoxy , iso - butoxy , sec - butoxy , pentoxy , 3 - pentoxy , hexyloxy , heptyloxy , or octyloxy ; ( c 1 - c 8 ) alkanoyl can be acetyl , propanoyl , butanoyl , isobutanoyl , pentanoyl , hexanoyl , heptanoyl , or octanoyl ; and ( c 2 - c 8 ) alkanoyloxy can be acetoxy , propanoyloxy , butanoyloxy , isobutanoyloxy , pentanoyloxy , hexanoyloxy , heptanoyloxy , or octanoyloxy . aryl can be phenyl , indenyl , benzyl , or naphthyl . heteroaryl can be furyl , imidazolyl , triazolyl , triazinyl , oxazoyl , isoxazoyl , thiazolyl , isothiazoyl , pyrazolyl , pyrrolyl , pyrazinyl , tetrazolyl , pyridyl , ( or its n - oxide ), thienyl , pyrimidinyl ( or its n - oxide ), indolyl , isoquinolyl ( or its n - oxide ) or quinolyl ( or its n - oxide ). preferably , alkyl is ( c 1 - c 4 ) alkyl and aryl is phenyl or benzyl . a specific group of compounds are compounds of formula i wherein r 1 and r 2 together with the nitrogen to which they are attached are a ring selected from the group consisting of azetidino , pyrrolidino , piperidino , hexamethyleneimin - 1 - yl , and heptamethyleneimin - 1 - yl . another specific group of compounds are compounds of formula i wherein r 1 and r 3 together are a divalent ethylene or propylene chain and r 2 is ( c 1 - c 8 ) alkyl , ( c 6 - c 12 ) aryl , or heteroaryl . a third specific group of compounds are compounds of formula i wherein r 1 and r 2 together with the nitrogen to which they are attached are an azetidino , pyrrolidino , piperidino , hexamethyleneimin - 1 - yl , or heptamethyleneimin - 1 - yl ring , said ring being substituted on carbon by a substituent r b ; wherein r b and r 3 taken together are a divalent ethylene or propylene chain . a preferred group of compounds are compounds of formula i wherein r 1 and r 2 are individually ( c 1 - c 8 ) alkyl , or ( c 6 - c 12 ) aryl ; r 3 is ( c 1 - c 8 ) alkyl , hydrogen , sc (═ s ) n ( r 1 )( r 2 ) or a glutathione derivative ; x is o or s ; n is 0 or 1 or a pharmaceutically acceptable salt thereof . another preferred group of compounds are compounds of formula i wherein r 3 is ( c 6 - c 12 ) aryl or heteroaryl and n is 0 . as used herein , the term “ glutamate - related disorder ” comprises : a ) neurodegenerative diseases associated with elevated levels of extracellular glutamate , including huntington &# 39 ; s disease , alzheimer &# 39 ; s disease , parkinson &# 39 ; s disease , aquired immunodeficiency syndrome ( aids ), epilepsy , nicotine addiction , cerebral ischemia ( stroke ), and familial amyotrophic lateral sclerosis ( als ); as well as neurodegenerative diseases associated with thiamine deficiency , such as wernicke - korsakoff syndrome , cerebral beriberi , machado - joseph disease , soshin disease , and related diseases such as those disclosed by thomas et al ., j . am . geriatr . soc ., 43 , 1279 ( 1995 ); and b ) other diseases or conditions wherein glutamate activity is implicated , such as anxiety , glutamate related convulsions , hepatic encephalopathy , neuropathic pain , domoic acid poisoning , hypoxia , anoxia , mechanical trauma to the nervous system , hypertension , alcohol withdrawal seizures , alcohol addiction , alcohol craving , cardiovascular ischemia , oxygen convulsions , and hypoglycemia . some compounds of formula ( i ) have been shown to be potent inhibitors of rat liver mitochondrial low km aldehyde dehydrogenase ( see u . s . pat . no . 5 , 153 , 219 , the examples of which are described hereinbelow in examples 1 - 6 ). for example , preferred compounds for use in the practice of the invention include those wherein x is o , r 1 and r 2 are individually ethyl or methyl and r 3 is methyl . more preferably , r 1 ═ r 2 = methyl or ethyl , e . g ., the compound is s - methyl - n , n - diethylthiolcarbamate sulfoxide ( detc - me sulfoxide ) or s - methyl - n , n - diethyldithiocarbamate sulfoxide ( ddtc - me sulfoxide ). preferred compounds for use in the practice of the invention are substantially more bioactive than disulfiram , less toxic than the parent compounds and do not require bioactivation by the p450 liver enzyme system as do the metabolic precursors . pharmaceutically acceptable salts of the compounds of formula ( i ) include the nontoxic addition salts with organic and inorganic acids , such as the citrates , bicarbonates , malonates , tartrates , gluconates , hydrochlorides , sulfates , phosphates , and the like . all percentages are weight percentages unless otherwise indicated . the compounds of formula i , wherein n = 1 or 2 , may be readily prepared by oxidation of the corresponding thiol esters of formula ii : wherein x , r 1 , r 2 , and r 3 are as described hereinabove . thiol esters of formula ( ii ) wherein x ═ o and r 1 and r 2 are individually ( c 1 - c 8 ) alkyl , ( c 6 - c 12 ) aryl , or heteroaryl ; or wherein r 1 and r 2 together with the nitrogen to which they are attached are a 4 - 8 membered ring as described hereinabove , may be prepared by the bubbling carbonylsulfide into a mixture of triethylamine and the requsite amine of formula ( r 1 )( r 2 ) nh , in a suitable solvent , such as t - butanol . in situ alkylation with the requsite iodide of formula r 3 i , yields the corresponding thiol ester of formula ii . dithiocarbamates of formula ii ( x ═ s ) can be prepared using techniques that are well known in the art , for example , as disclosed by m . faiman et al ., alcoholism , 7 , 307 ( 1983 ). the final products can be purified by chromatography on silica gel . useful methods for preparing compounds of the invention are also disclosed in u . s . pat . no . 5 , 035 , 878 , issued jul . 30 , 1991 . compounds of formula ( i ), wherein r 1 and r 3 together are a divalent ethylene or propylene chain and r 2 is ( c 1 - c 8 ) alkyl , ( c 6 - c 12 ) aryl , or heteroaryl ; or compounds of formula ( i ) wherein r 1 and r 2 together with the nitrogen to which they are attached are an azetidino , pyrrolidino , piperidino , hexamethyleneimin - 1 - yl , or heptamethylene - imin - 1 - yl ring , said ring being substituted on carbon by a substituent r b ; wherein r b and r 3 taken together are methylene (— ch 2 —), ethylene (— ch 2 ch 2 —), or a direct bond ; and wherein the ring comprising r b and r 3 is a five - or a six - membered ring ; can be prepared by condensing carbonyl chloride with the requsite precursor comprising an amine and a mercaptan . conversion of the carbamoyl thioester to a sulfoxide can be carried out using techniques that are well known in the art , for example , as disclosed by m . faiman et al ., alcoholism , 7 , 307 ( 1983 ). in clinical practice , one or more of the compounds of formula i , or the salts thereof , will normally be administered orally in the form of a pharmaceutical unit dosage form comprising the active ingredient in combination with a pharmaceutically acceptable carrier which may be a solid , gelled or liquid diluent or an ingestible capsule . a unit dosage to the compound or its salt may also be administered without a carrier material . as examples of pharmaceutical preparations may be mentioned tablets , hard or soft gelatin capsules , aqueous solutions , suspensions , and liposomes and other slow - release formulations , such as shaped polymeric gels . oral liquid preparations may be in the form of , for example , aqueous or oily suspensions , solutions , emulsions , syrups or elixirs , or may be presented as a dry product for constitution with water or other suitable vehicle before use . such liquid preparations may contain conventional additives such as suspending agents , emulsifying agents , non - aqueous vehicles ( which may include edible oils ), or preservatives . the compounds according to the invention may also be formulated for parenteral administration ( e . g ., by injection , for example , bolus injection or continuous infusion ) and may be presented in unit dosage form in ampules , prefilled syringes , small volume infusion containers or multi - dose containers with an added preservative . the compositions may take such forms as suspensions , solutions , or emulsions in oily or aqueous vehicles , and may contain formulatory agents such as suspending , stabilizing and / or dispersing agents . alternatively , the active ingredient may be in powder form , obtained by aseptic isolation of sterile solid or by lyophilization from solution , for constitution with a suitable vehicle , e . g ., sterile , pyrogen - free water , before use . for topical administration to the epidermis , the compounds may be formulated as ointments , creams or lotions , or as the active ingredient of a transdermal patch . suitable transdermal delivery systems are disclosed , for example , in a . fisher et al . ( u . s . pat . no . 4 , 788 , 603 ), or r . bawa et al . ( u . s . pat . nos . 4 , 931 , 279 ; 4 , 668 , 506 ; and 4 , 713 , 224 ). ointments and creams may , for example , be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents . lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents , stabilizing agents , dispersing agents , suspending agents , thickening agents , or coloring agents . the active ingredient can also be delivered via iontophoresis , e . g ., as disclosed in u . s . pat . nos . 4 , 140 , 122 ; 4 , 383 , 529 ; or 4 , 051 , 842 . formulations suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base , usually sucrose and acadia or tragacanth ; pastilles comprising the active ingredient in an inert base such as gelating and glycerin or sucrose and acacia ; mucoadherent gels , and mouthwashes comprising the active ingredient in a suitable liquid carrier . when desired , the above - described formulations can be adapted to give sustained release of the active ingredient employed , e . g ., by combination with certain hydrophilic polymer matrices , e . g ., comprising natural gels , synthetic polymer gels or mixtures thereof . pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories . suitable carriers include cocoa butter and other materials commonly used in the art , and the suppositories may be conveniently formed by admixture of the active compound with the softened of melted carrier ( s ) followed by chilling and shaping in molds . formulations suitable for vaginal administration may be presented as pessaries , tampons , creams , gels , pastes , foams or sprays containing , in addition to the active ingredient , such carriers as are known in the art to be appropriate . for administration by inhalation , the compounds according to the invention are conveniently delivered from an insufflator , nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray . pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane , trichlorofluoromethane , dichlorotetrafluoromethane , carbon dioxide or other suitable gas . in the case of a pressurized aerosol , the dosage unit may be determined by providing a valve to deliver a metered amount . alternatively , for administration by inhalation or insufflation , the compounds according to the invention may take the form of a dry powder composition , for example , a powder mix of the compound and a suitable powder base such as lactose or starch . the powder composition may be presented in unit dosage form in , for example , capsules or cartridges or , e . g ., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator . for intra - nasal administration , the compounds of the invention may be administered via a liquid spray , such as via a plastic bottle atomizer . typical of these are the mistometer ® ( wintrop ) and the medihaler ® ( riker ). for topical administration to the eye , the compounds can be administered as drops , gels ( see , s . chrai et al ., u . s . pat . no . 4 , 255 , 415 ), gums ( see s . l . lin et al ., u . s . pat . no . 4 , 136 , 177 ) or via a prolonged - release ocular insert ( see a . s . michaels , u . s . pat . no . 3 , 867 , 519 ) and h . m . haddad et al ., u . s . pat . no . 3 , 870 , 791 ). pharmaceutical compositions of the invention may also contain other adjuvants such as flavorings , colorings , antimicrobial agents , or preservatives . it will be further appreciated that the amount of the present compound ( s ), or an active salt or derivative thereof , required for use in treatment will vary not only with the particular salt selected but also with the route of administration , the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician . usually the active substance will comprise between about 0 . 005 and 99 %, or between 0 . 1 and 95 % by weight of the unit dosage form , for example , between about 0 . 1 and 50 % of preparations intended for oral administration . the amount of the compound of formula i that is administered and the frequency of administration to a given human patient will depend upon a variety of variables related to the patient &# 39 ; s psychological profile and physical condition . for evaluations of these factors , see j . f . brien et al ., europ . j . clin . pharmacol ., 14 , 133 ( 1978 ); and physicians &# 39 ; desk reference , charles e . baker , jr ., pub ., medical economics co ., oradell , n . j . ( 41st ed ., 1987 ). generally , the dosages of the present compounds will be smaller than that administered in the case of disulfiram which is presently administered at 4 - 8 mg / kg orally , or than putative dosages of detc - me . disulfiram has been used in the treatment of alcoholism for almost 50 years ( j . hald et al ., lancet , 2 1001 - 1004 ( 1948 ); m . d . faiman , biochemistry and pharmacology of ethanol , volt 2 ., eds . majchrowicz , e . and novel , e . p ., pp . 325 - 348 , plenum press , new york ). it has recently been demonstrated that disulfiram exerts its anti - alcohol effect in vivo only after bioactivation to the active metabolite s - methyl - n , n - diethylthiocarbamate sulfoxide ( detc - meso ) ( a . madan et al ., drug metab . dispos ., 23 , 1153 - 1162 ( 1995 )), that is a potent and selective carbamoylating agent for sulfhydryl groups ( l . jin et al ., chem . res . toxicol . 7 , 526 - 533 ( 1994 ). however , disulfiram is known to produce a number of unwanted neurological side - effects . not all of the adverse neurological effects of disulfiram can be attributed to modification of glutamate receptors . disulfiram is metabolized to carbon disulfide , a known neurotoxin , and potently inhibits copper enzymes , such as superoxide dismutase and dopamine β - hydroxylase , through the action of another disulfiram metabolite , diethyldithiocarbamate ( t . j . haley , drug metab . rev ., 9 , 319 - 335 ( 1979 ); d . i . eneanya et al ., ann . rev . pharmacol . toxicol ., 21 , 575 - 596 ( 1981 )). detc - meso does not share any of these latter effects with disulfiram , such as carbon disulfide formation or copper - enzyme inhibition , so it would be expected to more selectively affect glutamate receptors in vivo . in particular , detc - meso is not likely to cause the seizures , optic neuritis and peripheral neuropathy linked to higher doses (& gt ; 500 mg / day ) of disulfiram , that are most probably a consequence of cs 2 formation ( c . m . fisher , arch . neurol ., 46 , 798 - 804 ( 1989 ); b . mokri et al ., neurology , 31 , 73 - 735 ( 1981 ); h . r . hotson et al ., arch . neurol ., 33 , 141 - 142 ( 1976 )). the invention will be further described by reference to the following detailed examples . detc - me was synthesized employing a modification of the method of p . klason , j . prak . chemie , 36 , 67 ( 1887 ). carbonyl sulfide , produced by dripping saturated kscn into 48 % sulfuric acid , was bubbled into a mixture of 11 . 3 ml of triethylamine and 7 . 7 ml of diethylamine in 100 ml of t - butyl alcohol in a 250 ml round bottom flask . the solution was stirred as the gas bubbled through the amine solution , with the reaction proceeding for 15 to 20 hours . the reaction was terminated by adding 5 ml of methyl iodide to form the final methylated product . the reaction mixture turned yellow and 15 to 20 minutes later a white precipitate formed . after 45 minutes , the reaction mixture was filtered and the alcohol and other volatile materials were evaporated . the remaining oil phase was dissolved in methylene chloride and extracted with 10 % hcl , saturated nahco 3 and brine . the resulting organic phase was dried over sodium sulfate , and evaporated in vacuo . the resulting product was purified by medium pressure liquid chromatography ( c - 18 sepralite ® 40 μm , mobile phase 60 : 40 acetonitrile ( fisher scientific , hplc grade ): water ). fractions containing the detc - me were extracted with methylene chloride . the organic phase was dried with sodium sulfate and solvent removed under reduced pressure . the product ( about 4 g ) was a pale yellow oil . the structure verified by tlc , nmr [ 1 h nmr ( 80 mhz , cdcl 3 ), δ3 . 35 ( q , j = 7 hz , 2h ), δ2 . 50 ( s , 3h ), δ1 . 15 ( t , j = 8 hz , 3h )], and mass spectroscopy [ eims m / z ( relative intensity ) 147 ( m + , 13 ), 100 ( 75 ), 75 ( 24 ), 72 ( 100 ), 44 ( 69 )]. detc - me ( 600 mg ) was added to a suspension of 0 . 865 g of sodium metaperiodate ( aldrich chem . co .) in 8 ml of 1 : 1 methanol - water at 25 ° c . after 48 hours of stirring at 25 ° c ., the reaction mixture was extracted with ch 2 cl 2 . the organic layer was dried with sodium sulfate and the solvent removed under reduced pressure . the crude product was dissolved in a minimum amount of 1 : 1 acetonitrile - h 2 o and purified by medium pressure chromatography ( c - 18 sepralite ® 40 μm mobile phase 1 : 1 acetonitrile - h 2 o . fractions containing detc - me sulfoxide were pooled and extracted with methylene chloride . the solvent was dried with sodium sulfate and removed under reduced pressure to yield 0 . 46 g of detc - me sulfoxide as a yellowish oil ; [ 1 h nmr ( 500 mhz , cdcl 3 ) 3 . 5696 - 3 . 4661 ( m , 2h ), 3 . 4428 - 3 . 3850 ( m , 2h ), 2 . 7082 ( s , 3h ), 1 . 2257 ( t , 3h , j = 7 . 12 hz ), 1 . 1698 ( t , 3h , j = 7 . 09 hz ); mass spectroscopy : cims ( nh 3 ) m / z ( relative intensity ), 164 ( m + 1 , 13 ), 148 ( 3 ), 100 ( 100 ), 72 ( 86 ), 44 ( 82 ); ir ( neat ): 2980 , 1690 , 1420 , 1255 , 1210 , 1065 , 1035 cm − 1 ]. s - methyl - n , n - diethyldithiocarbamate sulfoxide ( ddtc - meso ) was prepared from s - methyl - n , n - diethyldithiocarbamate ( ddtc - me ). the synthesis of ddtc - me was carried out as described by m . d . faiman et al ., alcoholism , 7 , 307 ( 1983 ), sodium metaperiodate ( 200 mg ) ( sigma chemical co .) was dissolved in 25 ml of 50 : 50 meoh : h 2 o at 0 ° c . ddtc - me ( 200 mg ) was separately dissolved in 2 ml of methanol , and was then cooled to 0 ° c . before addition to a constantly stirring solution of sodium metaperiodate in meoh : h 2 o . the reaction mixture was stirred for 24 hr at 0 ° c . and then was diluted to 100 ml with cold 0 . 1 m potassium phosphate buffer ( ph 7 . 4 ). the resulting colorless solution was then extracted with methylene chloride . the organic layer was treated with activated charcoal , and the charcoal was removed by filtration through a celite bed . the solvent was removed under reduced pressure to obtain the crude product which was then purified by preparative hplc ( c - 18 , 5 micron , 150 mm × 10 mm column , alltech ) using 30 : 70 acetonitrile : h 2 o ( acetonitrile , fisher scientific , hplc grade ) at a flow rate of 2 . 5 ml / min . the fractions containing the ddtc - meso were pooled and diluted with four times the original volume with water . the diluted pooled fractions were extracted with methylene chloride . the solvent was dried with sodium sulfate and removed under reduced pressure to yield 50 mg of product a colorless oil : 1 h nmr ( 300 mhz , cdcl 3 ) 3 . 25 - 3 . 42 ( m , 4h ), 2 . 72 ( s , 3h ), 1 . 23 ( t , 3h ), 1 . 17 ( t , 3h ); mass spectroscopy : cims ( nh 3 ) m / z , 180 ( m + 1 ); ir ( neat ): 2954 , 1668 , 1436 , 1400 , 1317 , 1136 , 1113 , 747 cm − 1 . evaluation of detc - me sulfoxide and ddtc - me sulfoxide as in vitro inhibitors of rat liver low km aldehyde dehydrogenase . to determine whether a compound of formula ( i ) can inhibit low km aldehyde dehydrogenase , an amount of the compound is added to isolated mitochondria . to prepare isolated mitochondria , male sprague - dawley derived rats weighing 200 - 400 g were anesthetized with carbon dioxide and then decapitated . the livers from untreated rats were homogenized in 0 . 25 m sucrose and differential centrifugation carried out to isolate the mitochondrial fraction . the mitochondria were solubilized with sodium deoxycholate , and mitochondrial low km aldh activity determined by the method of s . o . c . tottmar et al ., biochem . j ., 135 , 577 ( 1973 ). mitochondria were isolated from the liver of untreated rats and resuspended in 0 . 1 m phosphate buffer ( ph = 7 . 4 ). incubations contained 2 mg of mitochondrial protein , to which was added detc - meso at 0 . 2 μm , 2 . 0 μm , 20 μm or 200 μm , or ddtc - meso at 0 . 5 μm , 2 . 5 μm , 10 μm , 25 μm , 50 μm or 100 μm . the detc - meso or ddtc - meso was dissolved in ethanol and the incubations carried out for one hour . control incubations contained ethanol alone . at the end of the incubation , the mitochondria were isolated by centrifugation , resuspended in 0 . 25 m sucrose buffer and solubilized with deoxycholate . low km aldh activity was determined by the method of s . o . c . tottmar et al ., cited above . as the concentration of the detc - meso is increased , inhibition of rat liver mitochondrial low km aldh also was increased until maximal inhibition of aldh was reached . the concentration of detc - meso required for 50 % inhibition of the rat liver mitochondrial low km aldh was approximately 750 nm . for comparative purposes , 200 μm s - methyl - n , n - diethylthiocarbamate produced only an 8 % inhibition . in both experiments , incubations were carried out for one hour . the concentration of ddtc - meso required for 50 % inhibition is about 15 μm . it is concluded that detc - meso is an extremely potent inhibitor of rat liver mitochondrial low km aldh in vitro . to determine if a compound of formula ( i ) can inhibit aldehyde dehydrogenase activity in vivo , doses of detc - meso ( 1 . 3 mg / kg , 2 . 6 mg / kg , 5 . 2 mg / kg , 10 . 3 mg / kg and 20 . 6 mg / kg ), were administered to male sprague dawley derived rats weighing 200 - 400 g . the rats were bred from a resident colony maintained in the animal care unit at the university of kansas . rats were maintained on a 12 - hour light - dark cycle with access to food and water ad lib until the night before an experiment , at which time food was removed . animals were fasted for 12 hours prior to drug administration . all experiments were carried out in the morning . rats were treated with the doses of detc - meso or detc - me described above , which were dissolved in polyethylene glycol 200 . eight hours later , the rats were anesthetized with carbon dioxide and then decapitated . the liver was quickly removed and the low km aldehyde dehydrogenase determined . control rats were treated with corn oil vehicle only , and each control data point also represents an average of four rats . the liver from drug - treated and control rats was homogenized in 0 . 25 m sucrose and differential centrifugation was carried out to isolate the mitochondrial fraction . the mitochondria were solubilized with sodium deoxycholate , and mitochondrial low km and total ( high and low ) aldehyde dehydrogenase activity determined by the method of s . o . c . tottmar et al ., cited above . as the administered dose of detc - meso is increased , there was a greater degree of rat liver mitochondrial low km aldh inhibition . the dose of detc - meso required to inhibit 50 % of the low km aldh is 3 . 6 mg / kg intraperitoneal ( ip ). for comparative purposes , detc - me required a dose of 6 . 5 mg / kg ip to produce a comparable degree of low km aldh inhibition . furthermore , the dose of disulfiram which inhibited 50 % of the rat liver mitochondrial low km aldh is 56 . 2 mg / kg ip . therefore , detc - meso is substantially more potent as a rat liver mitochondrial low km aldh inhibitor than disulfiram . rats maintained as described in ex . 4 , fasted for 18 hours , were given 10 . 3 mg / kg of the detc - meso intraperitoneally , dissolved in polythylene glycol 200 and then challenged eight hours later with a dose of ethanol ( 1 g / kg ; 20 % v / v ) also administered intraperitoneally . the rats were anesthetized with phenobarbital 30 minutes after alcohol administration and blood was taken by aortic puncture , being drawn into a heparinized syringe . plasma acetaldehyde was determined by the method of c . o . p . eriksson er al ., anal . biochem ., 80 , 116 ( 1977 ). plasma concentrations were determined based on a standard curve obtained with known concentrations of acetaldehyde . control rats were treated with 1 ml / kg of polyethylene glycol 200 . a large increase in plasma acetaldehyde was detected after the ip administration of 10 . 3 mg / kg of s - methyl - n , n - diethylthiolcarbamate sulfoxide dissolved in polyethylene glycol 200 , to male rats which were then challenged with 1 g / kg ethanol ( 20 % v / v ) ip 30 minutes later . plasma acetaldehyde increased to approximately 900 μm . control rats received polyethylene glycol 200 only , and were then challenged with 1 g / kg ethanol ip . in these controls , plasma acetaldehyde was barely detectable . it is concluded that detc - meso can markedly increase plasma acetaldehyde after an ethanol challenge . the increase in acetaldehyde is believed to be responsible for initiating the disulfiram - ethanol reaction , which deters further alcohol consumption . to test whether the protective effect of detc - meso in hyperbaric o 2 - induced convulsions in mice could be due to inhibition of succinic semi - aldehyde dehydrogenase ( ssa dh ), mechanistically related to aldh 2 , the sensitivity of ssa dh to inactivation by detc - meso was determined . potentially , inhibition of ssa dh in brain could offset the build up of ammonia known to occur and produce more gaba . in vitro both aldh 2 and ssa dh are inactivated by detc - meso at 47 m − 1 s − 1 and 300 m − 1 s − 1 , respectively . however , in vivo , only aldh is sensitive to inactivation by detc - meso ( 84 % inhibition of mouse liver enzyme by 2 . 6 mg / kg detc - meso i . p . ); with no effect on the levels of brain or liver ssa dh ( up to 100 mg / kg i . p .). detc - meso has a highly selective and rapid carbamoylating agent for free thiol groups . under physiological conditions ( 37 ° c . ; ph 7 ) it carbamoylates the sulfhydryl group of glutathione ( gsh ) at a rate of 10 m − 1 s − 1 . this rate of reaction was approximately an order of magnitude faster than that of the more familiar α - haloketone functionality . moreover , the carbamoylated glutathione was relatively stable under physiological conditions and was not itself a reactive molecule without oxidative activation . the sulfenic acid of methyl mercaptan , also produced in the reaction of detc - meso with gsh , can be reduced to methyl mercaptan and water by the combined action of glutathione , nadh , glutathione peroxidase , and glutathione reductase , at the expense of reduced pyridine nucleotide . inactivation of aldehyde dehydrogenase ( aldh ) has indicated that only approximately 0 . 5 moles of carbamoylation per mole of active sites is required for inactivation (“ half - of - sites ” reactivity ). at a dose of 5 . 2 mg / kg i . p . in mice , detc - meso achieved 80 % inactivation of aldh in 1 hour . since the rate for enzyme inactivation is 40 m − 1 s − 1 under physiological conditions , the effective concentration of detc - meso at its site of action in vivo is about 11 μm . if the detc - meso were simply evenly dispersed throughout the animal , its concentration would be approximately 32 μm . this would imply a very effective delivery and utilization of detc - meso , however , it ignores the rather high concentrations of gsh that are present in blood , 1 mm , less than 5 % of detc - meso would remain after 5 minutes . in liver , less than 3 % of detc - meso would remain after only one minute . gsh actually mediates the effect of detc - meso . carbamoylated gsh inactivates aldh and / or blocks glutamate binding to synaptic membranes nearly as effectively as detc - meso ( in vivo , but not in vitro ), when the former is injected i . v . or i . p . in mice . however , to complete this cycle the carbamoylated gsh must be activated by oxidation . this may be accomplished via glutathione peroxidase at the expense of intracellular hydrogen peroxide . to separate the effect of carbamoylating agents on aldh and the glutamate receptors , the size of the substituents on the nitrogen of the carbamoyl group is varied . initially the methyl sulfoxide part of the molecule is maintained and the effectiveness of derivatives is tested in vitro for potential intrinsic differences , prior to testing their effectiveness in vivo . different results in the relative effectiveness of these agents in vitro and in vivo against the aldh and glutamate receptors are not unexpected due to potential differences in transport and metabolism of these compounds before or after carbamoylation of gsh . initially a series of symmetrically substituted compounds are examined in which the nitrogen is n , n - dimethyl , di - n - propyl , or di - n - butyl . the synthetic scheme currently employed for detc - meso readily lends itself to preparation of these derivatives and many others , in that the amine can be condensed with carbon oxysulfide and methyl iodide , followed by oxidation of the thio ester with sodium metaperiodate . the following test could be used to test the anti - craving effect of detc - meso and other compounds of the invention . syrian hamsters are employed in methods similar to those of keung and valee , biochemistry , 90 , 10008 ( 1993 ). dose response studies for detc - meso on liver low km mitochondrial aldehyde dehydrogenase ( aldh ) are conducted first to establish a dose for detc - meso . the doses of detc - meso to be used in these studies are , for example , 2 . 6 , 5 . 2 , 10 . 4 and 20 . 8 mg / kg given ip in peg 200 . hamsters ( 20 adult hamsters weighing 130 - 135 g ) are preconditioned to drink 25 % alcohol v / v by placing them in metabolic cages individually with free access to 25 % alcohol v / v . those hamsters that consume more than 8 ml / day are selected for the study . it is anticipated approximately 70 - 90 % of the hamsters will be preconditioned to consume alcohol . from this preconditioned group , selected hamsters are divided in two groups . a control group , which receives peg 200 and a detc - meso - treated group . the dose of drug to be administered is determined from the dose - response studies . each hamster is placed in a metabolic cage . two drinking fluids are supplied for each hamster . one being filtered water and the other 25 % v / v alcohol . the position of each the two drinking bottles on each cage is alternated daily to prevent development of positional preference . fluid intake is measured at 9 : 00 a . m . each day . total alcohol consumed will be calculated and drug efficacy determined . to determine if the drugs of interest are useful inhibiting alcohol withdrawal - induced seizures , male c57bl mice ( 20 - 24 g ) are employed . the mice are housed individually with wood bedding . lighting is on a 12 - hr cycle . mice ( n = 20 ) are given liquid diet containing 7 % ( v / v ) ethanol and vitamin c supplement for 7 days . every 24 - hr the amount of ethanol consumed is measured and replaced with fresh ethanol - containing diet . withdrawal is initiated at 7 : 00 a . m . of 8th day by replacing the ethanol - containing diet with ethanol - free diet . mice are divided into two groups of ten each . one group ( n = 10 ) is treated with detc - meso . the other group ( n = 10 ) which serve as controls is given peg - 200 . two doses of detc - meso are used , 2 mg / kg or 10 . 4 g / kg , which are administered ( intraperitoneally ) daily for three days during the course of alcohol withdrawal . handling - induced withdrawal seizures are rated on a 0 - 4 scale as described by grant et al . ( 1994 ). the mice are picked up by the tail and are rated as follows : 0 , corresponds to little or no reaction ; 1 , corresponds to a mild reaction ; 2 , corresponds to initial hyperactivity escalating into a clonic - tonic seizure upon handling ; 4 , corresponds to death as a result of seizure . two investigators , blind to the drug conditions rate the mice for seizure severity at 2 - hr intervals for the first 6 - hr of withdrawal ( 2 , 4 , and 6 hr into withdrawal ), then every hour until 11 hr of withdrawal ( 7 , 8 , 9 , 10 and 11 hr of withdrawal ). detc - meso is then evaluated for its effect in preventing alcohol - withdrawal seizures . general procedure for preparation of compounds of formula ( r 1 )( r 2 ) nc (═ o ) sch 3 . equimolar amounts of amine [( r 1 )( r 2 ) nh ] and triethyl amine are combined in methylene chloride so that the concentration of each amine is approximately 0 . 3m . the solution is cooled to − 78 ° c . under an inert atmosphere , and carbonyl sulfide ( g ) is bubbled through the mixture . after carbonyl sulfide addition is terminated , the resulting solution is stirred for 30 minutes . two equivalents of methyl iodide are added dropwise from an addition funnel at approximately 1 drop / second . after approximately 1 . 2 hours , the solution is condensed using a rotary evaporator until a precipitate appears . diethyl ether is added to precipitate the salt and the mixture is filtered [ caution : the precipate should be redissolved in water and disposed of as hazardous waste ]. the combined ether washes are condensed using a rotary evaporator to give the compound of formula ( r 1 )( r 2 ) nc (═ o ) sch 3 . general procedure for preparation of compounds of formula ( r 1 )( r 2 ) nc (═ o ) s (═ o ) ch 3 . sodium periodate ( 8 . 3 g ) is dissolved in 180 ml of water and added to the compound from example 10 ( 5 g ) in a 1 l round - bottom flask , and the solution is cooled to 4 ° c . under an inert atmosphere . the flask is wrapped in aluminum foil to shield light . when trace amounts of the sulfone are apparent by hplc or tlc ( 24 - 72 hours ), the reaction mixture is subjected to reverse phase medium pressure liquid chromatography ( c - 18 , see example 1 and 2 )) or flash chromatography ( silica gel ), with acetonitrile as the eluent to , give the compound of formula ( r 1 )( r 2 ) nc (═ o ) s (═ o ) ch 3 . using the general procedures of examples 10 and 11 , the following compounds were prepared : s - methyl n , n - dimethylthiolcarbamate sulfoxide ( dmtc - so ); s - methyl n , n - diethylthiolcarbamate sulfoxide ( detc - so ); s - methyl n , n - dipropylthiolcarbamate sulfoxide ( dptc - so ); and s - methyl n , n - dibutylthiolcarbamate sulfoxide ( dbtc - so ). animals — male swiss webster mice ( 20 - 30 g ) or male sprague - dawley rats ( 250 - 300 g ) were used . all experiments that employed animals were conducted in strict compliance with the nih guidelines on animal use and institutional regulations concerning animal experimentation . animals were exposed to hyperbaric oxygen in a specially designed pressure chamber as previously describe ( m . d . faiman et al ., biochem . pharmacol ., 20 , 3049 - 3067 ( 1971 ); m . d . faiman et al ., aerosp . med ., 45 , 29032 ( 1974 )). the time to first clonic - tonic seizure after brining animals to a final pressure of five atmospheres of 100 % oxygen or after intraperitoneal injection of convulsants was noted by criteria outlined previously ( m . d . faiman et al . ( 1971 ), supra ; m . d . faiman et al . ( 1974 ), supra ). unless otherwise specified , the ability of detc - meso to prevent seizures was tested by intraperitoneal injection of 5 . 2 mg / kg of detc - meso 1 - 2 hours prior to bringing the animal to a final pressure of 5 atmospheres of 100 % oxygen or intraperitoneal injection of n - methyl - d - aspartate ( nmda ) ( 125 mg / kg ) or l - methionine sulfoximine ( metsox ) ( 250 mg / kg ). evaluation of the statistics for whole animal experiments or for changes in brain glutamate binding after administration of detc - meso was conducted by use of the program graphpad instat from graph pad software ( san diego , calif .). binding studies — synaptic membranes ( 100 pg protein ) were isolated ( y . h . lee et al ., j . neurosci . res ., 40 , 797 - 806 ( 1995 )) form whole brain homogenate of male swiss webster mice and were incubated in 0 . 1 mm l - glutamate for 30 minutes at 25 ° c . after addition of 50 nm of [ 3 h ] glutamate , incubation was continued for an additional 45 minutes . reactions were terminated by centrifugation at 4 ° c . to separate membrane - bound from free radioactivity . nonspecific binding ( radioactivity bound in the presence of 0 . 5 mm unlabeled glutamate ) averages 20 - 30 % of total radioactivity bound . the rate ( k ) and maximum percent blockage of glutamate binding ( m ) by detc - meso ( i ) during the incubation time ( t ) was determined by fitting the equation [% inhibition ]= m ( 1 − e − kit ) to these day by use of the program grafit ( erithicus software ltd .). this equation was derived for first - order inactivation by a group specific reagent that gives a partial effect . if “ a ” is the percent of binding activity that remains after extensive exposure ( t =∞) of the receptor to excess detc - meso , then m = 100 − a ) e − kit + a ; substituting ( 100 − m ) for “ a ” and [ 100 −% inhibition ] for “ a ” in this equation gives the one employed for purposes of data analyses . the maximum percent blockage of glutamate binding ( m ) observed did not depend on the concentration of glutamate employed in binding experiments , such that the modified receptors appeared to be “ non - competitively ” inhibited ( independent of whether detc - meso was still present or absent at the time that glutamate binding was assayed ). a second equation was employed in the analysis of binding data that defines partial , irreversible inactivation of two distinct groups of receptors : [% inhibition ]= m 1 ( 1 − e − k 1 i t )+ m 2 ( 1 − e − k 2 i t ), where m 1 and m 2 are the maximum amount of inhibition obtained for complete modification of each receptor population and k 1 and k 2 are the rate constants for these modifications , respectively . reagents — detc - meso was synthesized by the method of hart and faiman ( b . w . hart et al ., biochem . pharmacol ., 3 , 403 - 406 ( 1992 ). carbamoylated glutathione , s -( n , n - diethylcarbamoyl ) glutathione ( detc - gs ), was prepared essentially as described by jin et al . ( l . jin , supra ). the structures and purity of detc - meso and detc - gs were confirmed by 300 mhz nmr and fab - tandem mass spectrometry . a qe300 nmr spectrometer ( general electric , fremont , calif .) and autospec - q tandem hybrid mass spectrometer ( fiscons / vg analytical limited , manchester , england ) were employed for these analyses . liver aldehyde dehydrogenase was extracted and assayed as previously described ( b . w . hart et al ., supra ). metsox , monosodium l - glutamate , glycine , glutathione , and nmda were purchased from sigma chemical company ( st . louis , mo .). l -[ 3 - 3 h ] glutamate ( 46 ci / mmol ) was obtained from amersham life science ( buckinghamshire , england ). treatment of synaptic membrane preparations ( y . - h . lee et al ., supra ) from the brains of mice with detc - meso , resulted in a time - dependent , partial , and irreversible loss of their ability to bind glutamate ( fig2 ). six determinations of the effect of detc - meso were made at each concentration tested ( 1 , 5 , 10 , 50 , 100 , 200 , and 1000 μm ) and the average value is shown with error bars for one standard deviation . the values for m and k obtained when a single exponential was fit to data were 58 ± 7 % and 25 ± 10 m − 1 s − 1 , respectively , and the line calculated by use of these values is shown (−). a dashed line (− − −) that was calculated for a double exponential equation fit to data with nominal values of m 1 = 15 %, m 2 = 43 %, k 1 = 900 m − 1 s − 1 , and k 2 = 8 m − 1 s − 1 is also shown . inhibition of glutamate binding appears to depend on modification of more than one population of glutamate receptor , each with distinct kinetics . although a better fit of these data could be obtained by use of a double exponential equation , a unique fit of this equation to these data could not be obtained , due to the larger number of independent parameters involved . however , a nominal fit of these data indicated that about one - fourth of the total inhibition ( m 1 = 15 %) occurs at a much faster rate ( k 1 = 900 m − 1 s − 1 ), than the rate ( k 2 = 8 m − 1 s − 1 ) associated with inhibition of the remainder ( m 2 = 43 %) ( fig2 ). since the effect of detc - meso on either receptor population is irreversible , glutamate receptor blockage in vivo can be easily determined . synaptic membranes were prepared from the brains of mice injected with detc - meso ( 5 . 2 mg / kg , i . p .). the ability of synaptic membrane preparations isolated from detc - meso - treated mice to bind glutamate was compared with similar preparations isolated from control animals . fig3 ( a ) illustrates the results obtained from synaptic membranes prepared from brains of mice killed two hours after a single dose of detc - meso , or two hours after the last injection of multiple consecutive doses ( 5 . 2 mg / kg , i . p ., daily for seven days ). either single or multiple dosing with detc - meso reduced the capacity of synaptic membranes to bind glutamate by approximately 50 %, the maximum effect obtained in vitro ( fig3 ). each bar represents the average of results obtained from four animals and the error bars are for one standard deviation . for brain synaptic membrane preparations isolated from mice killed 24 hours after a single dose of detc - meso , less inhibition of glutamate binding was found ( fig3 b ). by contrast , for brain synaptic membrane preparations isolated from mice killed 24 hours after the last dose of seven daily consecutive doses , similar inhibition of glutamate binding to that seen 2 hours post - injection of detc - meso ( fig3 ). the results obtained for the group that received a single dose of detc - meso and were sacrificed after 2 hours were significantly different from the group that received a single dose and were sacrificed after 24 hours ( bonferroni &# 39 ; s p & lt ; 0 . 01 determined by anova ). comparison of the singly dosed group that was sacrificed after 2 hours with the multiple dosed groups that were sacrificed after 2 hours or 24 hours did not show statistical significance from each other by the same criteria . it is hard to reconcile the ability of detc - meso to carbamoylate brain glutamate receptors with its extreme lability in vivo . detc - meso rapidly and selectively carbamoylates and the sulfhydryl of glutathione ( gsh ) in vitro ( 10 m − 1 s − 1 at 37 ° c ., ph 7 ), and since the concentration of gsh in vitro is high ( 1 - 6 mm ) ( d . w . potter et al ., toxicol . appl . pharmacol ., 120 , 186 - 192 ( 1993 )), detc - meso will rapidly be converted (& gt ; 95 % within 5 minutes ) to n , n - diethyl - s - carbamoyl - glutathione ( detc - gs , fig4 ). detc - gs has been detected in the bile of mice treated with disulfiram ( l . jin , supra ). unlike detc - meso , detc - gs is not reactive and does not carbamoylate sulfhydryl groups ( l . jin , supra ). although detc - gs reversibly blocked glutamate binding to synaptic membrane preparations from mouse brain ( data not shown ), a time - dependent , irreversible blockage of the glutamate receptor , like that observed with detc - meso , was not obtained . if the effect of detc - meso on glutamate receptors in vivo is mediated by glutathione , then the carbamoylated glutathione requires activation . glutathione ( gsh ), oxidized glutathione ( gssg ), and detc - gs reversibly blocked glutamate binding to mouse synaptic membrane preparations ( data not shown ). however , when the membranes were washed after exposure to gsh , gssg , or detc - gs , inhibition was reversed , unlike the effect by detc - meso . oxidation of the sulfur of detc - gs to a sulfoxide would make it reactive toward sulfhydryl groups ( a . madan et al ., supra ), similar in chemistry to detc - meso , and potentially capable of irreversible inhibition of glutamate receptors in vivo . carbamoylated glutathione and detc - meso had the same effect in vivo , despite the fact that they had different effects on glutamate receptors in vitro . intravenous administration of an equimolar concentration of detc - gs or detc - meso ( 30 μmol / kg ) to mice resulted in a comparable degree of irreversible brain glutamate receptor blockage ( 26 . 9 ± 4 . 3 and 38 . 2 ± 1 . 6 %, respectively ) or liver aldehyde dehydrogenase inhibition ( 30 . 1 ± 1 . 0 or 44 . 9 ± 1 . 0 %, respectively ). since detc - gs reversibly blocked glutamate binding to synaptic membranes in vitro ( i . e ., the inhibition can be reversed by washing the membranes to remove detc - gs ), but in vivo both detc - meso and detc - gs irreversibly blocked glutamate binding , and detc - gs has no effect on aldehyde dehydrogenase in vitro ( reversible or irreversible ), it is suggested that detc - gs is activated by oxidation in vivo ( detc - gso , fig4 ). to test whether carbamoylation of glutamate receptors might prevent seizures caused by glutamate agonists , the effect of detc - meso on seizures induced by glutamate analogs was examined . treatment of mice with detc - meso prior to administration of the glutamate analog n - methyl - d - aspartate ( nmda ) ( 125 mg / kg , i . p .) prevented seizures that result from nmda administration alone ( table 1 ). similarly , detc - meso administered to mice or rats prior to injection of the glutamate analog methionine sulfoximine ( metsox ) more than doubled the time that the animals remain free of seizures ( table 1 ). it has been shown that glutamate is released by rat hippocampal ( brain ) slices subjected to oxidative stress ( d . e . pellegrini - giampietro et al ., j . neurosci ., 10 , 1035 - 1041 ( 1990 )). therefore , the effect of detc - meso on oxygen - induced seizures was investigated . administration of detc - meso ( 5 . 2 mg / kg , i . p .) to mice 2 hours before exposure to 5 atmospheres of 100 % oxygen , prevented the seizures that occurred after 24 minutes in control animals ( table 1 ). effect of detc - meso on nmda and non - nmda subtypes of brain glutamate receptors . nmda is a selective agonist for a major subtype of ionotropic ( calcium ion channel - linked ) glutamate receptor ( n . burnashev , cell . physiol . biochem ., 3 , 318 - 331 ( 1993 )). as determined in the results illustrated in fig2 and 3 , the effect of detc - meso on glutamate binding to synaptic membrane preparations is not a measure of detc - meso &# 39 ; s modification of this receptor subtype . although up to 34 % of the total glutamate binding capacity of synaptic membranes is attributable to nmda receptors ( m . cincotta et al ., anal . biochem ., 177 , 150 - 155 ( 1989 )), the effect of glutamate on these receptors is dependent on glycine ( d . w . bonhaus , mol . pharmacol ., 36 , 273 - 279 ( 1989 )), that was not included in the studies presented in fig2 and 3 . under the conditions of these experiments , nmda does not block glutamate binding to synaptic membrane preparations . when these binding experiments were repeated in the presence of glycine ( 0 . 1 mm ), reversible blockage of glutamate binding to mouse brain synaptic membrane preparations by nmda ( 0 . 5 mm , 32 ± 2 % blockage ) and irreversible blockage by detc - meso ( 0 . 1 mm , 48 ± 3 % blockage ) was observed . the similar degree of inhibition observed by detc - meso in the presence and absence of glycine [ 48 and 53 % ( fig2 ), respectively ] indicates that both nmda and non - nmda glutamate receptor subtypes are affected to a similar extent by carbamoylation . using a protocol similar to that described in example 12 , the [ 3 h ] glutamate binding to mouse brain p - 2 pellet preparation was determined , following treatment with disulfiram ( dsf ), detc - meso , or a combination of n - butyl imidazole ( nbi ) and disulfiram . as shown in fig5 the effects of disulfiram can be blocked by nbi , which is known to inhibit the conversion of disulfiram to detc - meso . this shows that formation of detc - meso by metabolism of disulfiram is required for activity in vivo . using a protocol similar to that described in example 13 , the [ 3 h ] glutamate binding to mouse brain synaptic membrane , and the low liver km aldh activity was determined following treatment with 30 micromolar solutions of representative compounds . results are shown in fig6 . this shows that the effects on aldehyde dehydrogenase and the glutamate receptor can be distinguished from one another . using a protocol similar to that described in example 13 , the mouse liver low km aldh inhibition by detc - meso and detc - gs ( 30 micromolar , i . v .) was determined . results are shown in fig7 . this shows that detc - gs has the same effect as detc - meso in vivo , and is an intermediate in this effect . the invention has been described with reference to various specific preferred embodiments and techniques . however , it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention .

disclosed are novel compounds and novel pharmaceutical compositions for use in medical therapy , as well as intermediates and processes for preparing such compounds . therapeutic methods for preventing or treating glutamate - related disorders in a mammal and methods to inhibit or prevent glutamate binding in mammalian tissue are also disclosed .

the present invention provides an improved distraction screw and a method for its use . fig1 shows an embodiment of the present invention , as represented by a distraction screw 10 , which comprises a distal segment 120 and a removable proximal 130 segment . the distal segment 120 is implantable on a vertebral bone as part of the surgical procedure . the distal segment 120 has a head portion 122 , and a threaded shank portion 124 which can be securely fastened unto the bone structure and which may be self - tapping and / or self - drilling . as shown in fig1 and 2 , the proximal segment 130 has an elongated body 132 with an internal bore 134 extending through its length from its proximal end portion 135 to its distal end portion 137 . the elongated body 132 houses a deployable member 136 , which is disposed within the internal bore 134 . the deployable member 136 is adapted to be retractably deployed beyond the opening 138 of the internal bore 134 at the distal end portion 137 of the elongated body 132 . along the wall 140 of the interior bore 134 of the elongated body 132 are cooperating threads 142 , which complement threads 144 of the deployable member 136 such that rotation of the deployable member 136 relative to the elongated body 132 in one direction extends it beyond the opening 138 of the internal bore 134 in a deployed position , as shown in fig1 and 2 . conversely , rotation of the deployable member 136 in the opposite direction effects its retraction from the deployed position . thus the deployable member 136 can be rotated independently of the elongated member 130 . for the embodiment shown in fig1 , the threads are made as right - hand thread , that is , viewing from the proximal end portion 135 of the elongated body 132 , a clockwise rotation of deployable member 136 causes it to extend beyond the opening 138 of the internal bore 134 . conversely , a counter - clock wise rotation of the deployable member 136 effects its retraction into the internal bore 134 . the proximal segment 130 is adapted to be attached to the distal segment 120 . as shown in fig1 and 2 , the deployable member 136 has a threaded end portion 138 , with threads 150 , which are adaptably securable to interfit and interlock with complemental threads 162 of the threaded well 158 of the distal segment 120 . threads 150 and 162 are oriented in the same turn direction and have the same pitch ( number of threads per unit length ) as those of threads 142 and 144 . this enables the threaded portion 138 to advance into the threaded well 158 when turned clockwise . construction of the threads 142 and 150 , and their respective counterpart complemental threads 144 and 162 can be accomplished by various means . for example , threads 142 and 144 can be constructed as a screw drive arrangement to facilitate the relative movement between the elongated body 132 and the deployable member 136 in deployment or retraction . likewise , threads 150 and 162 can be constructed for effective mutual engagement . as a matter of design preference , threads 142 and 144 may be of any length and may be placed at any point throughout the internal bore of the elongated member . in addition , though not necessary , threads 150 of the deployable member 136 can be an extension of its threads 144 . at its proximal end portion 152 , the deployable member 136 is adapted to be manipulated to effect its extension beyond the opening 138 of the internal bore 134 in a deployed position or retraction . for the embodiment as shown in fig1 and 2 , the rotational movement of the deployable member 136 can be effected by tools such as a wrench , socket wrench , screwdriver , or the like . in one embodiment of the present invention as shown in fig1 , the proximal end portion 152 of the deployable member 136 has a hex - shaped configuration , which is engageable by a socket or a wrench to effect a rotational action . in alternative embodiments , proximal end portion 152 has an intersecting depression ( not shown ) adapted to accommodate the driving tip of a “ phillips ” screwdriver to effect a rotational action . any alternative means and arrangements for engaging and rotating the deployable member 136 can be employed including , but not limited to , a driver or “ allen ” wrench configuration . as referenced above , rotation of the deployable member 136 relative to the elongated body 130 extends the deployable member for its threads 150 to engage the threads 162 of the head portion 160 of the distal segment 120 . once threads 150 are engaged with threads 162 , both the proximal and the distal segments are coupled as a unit . the deployable member 136 can be removed from the elongated body 132 , allowing for different sizes , threads and / or shapes for the head portion and / or tool attachment portions . thus , the attachment and / or arrangement of the elongated body 132 and the deployable member 136 can be a screw - fit , or snap - fit arrangement , which does not interfere with the rotation of the deployable member 136 . the proximal segment 130 is provided with a tool attachment end portion 180 that is adaptable to receive a rotational torque to effect a rotational action of the elongated body 132 . as shown in fig1 , a “ hex - head ” end configuration is provided , on which a socket 187 can be fitted to effect the rotational action of the elongated body 132 . optionally , the proximal end can incorporate a flange 154 to limit the extension of the deployable member 136 beyond the distal end of the proximal segment . the coupled proximal and distal segments employing the above - described means of engagement provide a detachably coupled distraction screw , which functions as a unitary device . in a surgical application , a socket ( coupled to a wrench , not shown ) 187 is attached to the tool attachment portion 180 , and the distraction screw is positioned at a site of a bone structure 20 . by applying a rotational torque to the elongated body 132 in a clockwise direction , both the proximal and distal segments rotate in unison so that thread 110 of the distal segment 120 may engage opening 22 of the underlying bone . shank 124 is advanced and secured onto the bone structure as shown in fig2 . as shown in fig1 and 2 , the distal segment 120 comprises a threaded shank portion 124 and a head portion 160 . as referenced above , threads 110 of the shank portion 124 would preferably , but not necessarily , be self - tapping and / or self - drilling . the threads 110 would also follow the same turn direction as those of threads 150 and 144 . depending on the particular application , the shank portion 124 can be of variable lengths and threads 110 may be of any known configurations . one of ordinary skill in the art would understand that the threads can be of any design that is understood and well known to be applicable for screwing and inserting into mammalian bone . in the embodiment shown in fig1 , 2 and 3 , the internal diameter of the threaded shank portion is progressively tapered from the head portion to the distal tip . the shape of the head portion 160 may be of any geometric design , including but not limited to , rectangular , trapezoidal , cylindrical , circular , spherical , hybrid configurations and the like . further , the head may be absent altogether , placing the engagement adapter directly into the body of the screw shank ( fig7 c ). in the embodiment as shown in fig1 , 2 and 3 , the head portion 160 is mono - axial , remaining in a fixed plane relative to the threaded shank . as used herein , “ mono - axial ” refers to rotation of the head portion and shank along a common arbitrary axis . this is defined by the placement of the head portion in a fixed geometric relationship to the threaded shank such that when the shank is rotated , the head portion also rotates along the same axis . thus , in the embodiment as shown in fig1 , 2 and 3 , the head portion is arranged with its diameter perpendicular to the length of the shank , which defines a common mono - axial relationship . the distal segment 120 can be made of any biologically adaptable or compatible materials . materials considered acceptable for biological implantation are well known and include , but are not limited to , stainless steel , titanium , combination metallic alloys and the like , various plastics , ceramics , biologically absorbable materials and the like . it would be understood by one of ordinary skill in the art that the distal segment 120 can be made of any materials acceptable for biological implantation and capable of withstanding the torque required for insertion and the load encountered during use . any components may be further coated / made with osteo - conductive ( such as deminerized bone matrix , hydroxyapatite , and the like ) and / or osteo - inductive ( such as transforming growth factor “ tgf - b ,” platelet - derived growth factor “ pdgf ,” bone - morphogenic protein “ bmp ,” and the like ) bio - active materials that promote bone formation . the proximal segment 130 may be made from any non - toxic material capable of withstanding the torque required for insertion and the load encountered during use . materials used in the proximal segment 130 need not be limited to those acceptable for implantation , since it functions to deliver the implatable distal segment 120 but is not , itself , implanted . as shown in fig2 , the distraction screw 10 is placed at a predefined location of the vertebral bone . as rotational torque is applied to the distal segment 120 by the tool attachment , both the segments rotate in unison , which inserts the threaded portion 110 of the distal segment into the bone opening 22 . the coupling of the proximal and distal segments provides the longitudinal stability and the structural integrity of the coupled segments as a distraction device . in another embodiment of the present invention as shown in fig5 , 6 a and 6 b , in addition to coupling the deployable member 136 with the distal segment 120 , the elongated body 132 of the proximal segment 130 is also engageable to the distal segment 120 to prevent their relative rotational movement by a rotation locking means . as shown in fig5 , at the distal end portion 137 of the proximal segment 130 , a key 170 is provided . the key 170 is fitted to be inserted into a receptacle 172 as defined by a depression located at the head portion 160 of the distal segment 120 . when the key 170 is inserted into receptacle 172 , the elongated body 132 of the proximal segment 130 is engaged with the distal segment 120 , which prevents the relative rotational movement between the two segments . fig6 a and 6 b show another embodiment of the present invention in which a variation in the design of the rotation locking means is presented . the distal end portion 137 of the proximal segment 130 incorporates a hex extension 190 , which can be fitted into the well 158 of the head portion 160 with a complemental hex socket receptacle 194 . when so fitted , rotation of the distal segment 120 proximal segment 130 relative to each other is inhibited . as shown in fig6 a and 6 b , hex extension 190 has an internal bore 192 through which the deployable member 150 passes for engagement with the distal segment by way of their cooperating threads 150 and 162 . while the rotation locking means is illustrated in a key - receptacle arrangement and hex extension - socket configuration , it is not limited to these examples . it is understood that any engageable arrangement can be used as a rotational locking means . these include , but are not limited to , one or more extended protuberances of the elongated body 132 to seat within complemental bored depressions on the head portion of the distal segment 120 . similarly , square - jaw or spinal jaw clutch arrangements , and serrated or saw tooth edges can be incorporated to mate or interlock with similar features on the head portion ( not shown ). in embodiments that incorporate such rotation locking means , assembly of the proximal and distal segments can be easily accomplished . the deployable member 136 is fitted within the internal bore 134 of the elongated body 132 in a retracted configuration by effecting a relative rotational movement between elongated body and the deployable member along their cooperating threads . the proximal segment 130 is then held adjacent to the head portion 160 of the distal segment 120 to insert key 170 into the receptacle 172 . for the embodiment shown in fig6 a and 6 b , the hex extension 190 is seated within the socket 194 of the head portion 160 . a suitable tool such as a screw driver , wrench , pliers , or the like is used to engage the proximal end portion 152 of the deployable member 136 in a rotating action to extend the threaded end portion 152 beyond the end opening 138 of the bore 134 ( or bore 192 of the hex extension ) to engage the internal threads 162 of the head 160 of the distal segment 120 . their actions secure the proximal and distal segments in a coupled relationship and inhibits any relative longitudinal and rotational movements between the segments . as discussed above , the proximal segment 130 is securably coupled to the distal segment 120 as a distraction device while being anchored onto the bone structure . after the need for the distraction has been met , the proximal segment 130 is detached from the distal segment 120 . from the coupled configuration , the elongated body 132 is held stationary and , using segment 152 , the deployable member 136 is rotated in a direction opposite to that which was used to effect its coupling to the internal threads 162 of the head 160 . this rotation disengages threads 150 from threads 162 of the distal segment 120 . the rotation also releases the friction between the distal portion of the elongated body and the head portion of the distal segment . detachment of the proximal and the distal segment is thus effected , leaving the latter securely implanted onto the vertebral structure , as shown in fig3 . the deployable member can be retracted and stowed into the internal bore 134 of the proximal segment . for the embodiment as shown in fig5 , once the complemental threads 150 and 162 are disengaged , the proximal segment 130 can be dislodged with the key 170 disengaged from the receptacle 172 to separate from the distal segment 120 . in a similar manner , for the embodiment shown in fig6 a and 6 b , once threads 150 and 162 are de - coupled , the hex extension 190 can be withdrawn from hex socket 194 of the distal segment . in this way , the use of the rotation locking means further ensures that the distal segment 120 would not be inadvertently rotated and de - coupled from the skeletal bone while rotating the deployable member 136 during detachment of the proximal and distal segments . fig7 a - 7 c , 8 a - 8 c , 9 a , 9 b , 10 a , 10 b , 11 , 12 a , 12 b illustrate other embodiments of the modular distraction screw . since a thorough description of the device has been presented above , only the relevant design differences of the other embodiments will be described in detail . fig7 a demonstrates another embodiment of the proximal segment . this embodiment employs an elongated proximal segment 130 with a smooth internal bore 134 and no internal threads . a deployable member 133 has a threaded tip 150 on its distal end and proximal segment 152 which is adapted so as to be engaged by a screw driver , wrench or the like in order effect its rotation . a flange 154 is placed immediately distal to the engageable proximal end . fig7 b demonstrates the assembled proximal segment wherein the outer elongated body and the deployable member are each independently rotatable from the other . fig7 c shows the proximal segment 130 , distal segment 160 and the wrench 187 . as threads 150 of the proximal segment are engaged with threads 162 of the distal segment , flange 154 limits the extension of the deployable member and applies a compressive force across the elongated element 130 , thus forming a rigid distraction screw . as before , the screw is inserted into bone by application of a rotational force onto element 180 using wrench 187 . rotation may be achieved by any engageable means and is in no way limited to the hex - wrench arrangement illustrated . after completion of the bone work , the distal segment is disengaged from the proximal segment by rotation of element 152 in the direction opposite to that used for engagement while segment 130 is held stationary using element 180 . optionally , a rotation locking means can be incorporated as part of the distal tip of the proximal segment in order to ensure that the distal segment 120 does not inadvertently rotate and de - couple from the skeletal bone during distraction screw disassembly . fig8 a - 8 c shows another embodiment of the present invention in which a proximal / distal interface is defined by a threaded extension 157 disposed on the head portion of the distal segment . the threaded extension 157 is fitted within the complmental threaded female receptacle 156 of the proximal segment . it is understood that the head of the distal segment beneath extension member 157 may be of any geometric configuration . further , in these or any of the other embodiments presented herein , the proximal / distal interface is not limited to the screw and screw receptacle arrangement depicted . thus , for example , fig9 a and 9 b demonstrate a sprocket arrangement 159 ( male member ) and a complementary receptacle 143 ( female member ), and fig1 a and 10 b show a smooth male member 161 with a key which is used to engage the complementary receptacle 145 . these two design arrangements demonstrate the adaptation that any engageable means can be used . fig1 a , 11 b , 12 a and 12 b demonstrate a sprocket arrangement which permits a locking engagement with the complementary receptacle . as illustrated in fig1 a and 12 b , the cylindrical head 163 , which is a smaller - diameter continuation of the screw shank 124 , is fitted with engageable teeth 167 in the parallel plane ( along the long axis of shank 124 ) and engageable teeth 165 in the perpendicular plane . the distal end portion of the elongated body 132 is provided with a receptacle 147 which is complimentary to the cylindrical head 163 of the distal segment 120 . receptacle 147 has a central bore and engageable teeth in both the parallel and perpendicular planes relative to the long axis of the proximal segment to accommodate and engage teeth 163 and 165 of the distal element 120 . the elongated body 132 of the proximal segment 130 has an engageable proximal end portion 181 , which is adapted to be rotated , as for example , by means of a wrench 191 . similarly , the proximal segment 130 is rotatable by means of a wrench 189 . with rotation , the proximal segment 130 advances along threads 119 to the receptacle 147 of the proximal segment around the cylindrical head 163 of the distal segment to produce a rigid distraction screw . wrench 191 is used to engage the end portion 181 of the proximal segment 132 to effect its rotation . the teeth within receptacle 147 of the proximal segment engage the complimentary teeth 165 and 167 of the distal segment , which rotates the distal segment and drive threads 111 into the underlying bone . once the bone work has been completed , wrench 189 is used to rotate the proximal segment 130 in the direction opposite to that used during engagement causing it to retreat along threads 119 . in this way , the head portion 163 can be disengaged from the receptacle 147 thus leaving the distal segment 120 attached to the bone . one of ordinary skill in the art will understand that the engageable arrangements described herein are illustrative and not restrictive , and that any engageable means may be alternatively used at any of these points of contact . the distal segment 120 of the distraction screw 10 , which remains securely affixed onto the vertebral bone , provides enhanced structural integrity of the bone by reducing the stress concentration generally expected of an empty opening in a structural member . leaving the distal segment 120 in place further eliminates the robust bone bleeding encountered after removal of current , commercially - available distraction screws and obviates the need to fill the holes with a hemostatic agent . the distal segment 120 can also provide a point of anchoring for a skeletal plate 30 or other prosthetic devices to adjust , align and maintain the spatial relationship ( s ) of adjacent bones or bony fragments during healing and fusion after surgical reconstruction , as shown in fig4 . since placement of the distraction screws is performed as the first step in the surgical procedure , the anatomical landmarks required to ensure proper alignment of the plate or other prosthetic device in the desired anatomical plane are still intact . plate fixation using the affixed distal segment is largely similar for the many mono - axial embodiments illustrated . for simplicity , it will be described in detail for the first embodiment alone . as shown in fig4 , a skeletal plate 30 is mounted onto the distal segment , where head portion 160 is adapted with peripheral surface contour to fit an opening 32 of the skeletal plate . a mounting plate 212 having a tapered opening 214 centers the screw 210 in alignment and engagement with the threads 162 of the head portion . the mounting plate 212 also serves as a washer to assert the necessary force onto the skeletal plate 30 to be secured onto the bone substrate 20 . in this way , the distal segment guides the placement of the plate and maximize the likelihood of correct anatomical alignment . it will also provide an additional point of attachment for the plate or device and enhances the structural integrity of bone / plate interface . it is accepted that fusion of a specific spinal level will increase the load on the disc space immediately above and below the fused segment . over time , the increased load will promote degeneration of the adjacent discs and may ultimately require that they be removed and the fusion extended to the adjacent bony level . in that event , the mounting plate 212 can be removed , permitting access to the distal segment 120 . the proximal segment 130 and the elongated member 136 can be reattached to the distal segment 120 and , thus , reconstitute the distraction screw without removal . a second distraction screw is placed into the bone of the new operative level and the surgical reconstruction is performed . after the necessary work , the proximal segments 130 are removed from each distraction screw , leaving distal segments 120 securely affixed to the vertebral bodies . a bone plate or device is affixed to maintain the spatial relationships of the new operative level while bone healing and fusion progress . again , each distal segment 120 so affixed provides an additional point of attachment for the plate or device . in other embodiments of the present invention , the distal segment incorporates a poly - axial design feature , which further facilitates the mounting of the skeletal plate 30 onto the vertebral bone . as used herein , “ poly - axial ” refers to the ability for the head portion of the distal segment to rotate about an axis that is other than that of the longitudinal axis of the threaded shank . this design provides a ready mechanism through which a skeletal plate maybe affixed onto an implantable distal segment that has been placed into the skeletal bone at an angle other than the perpendicular . this situation arises when the degenerated bony elements have suffered significant mal - alignment , requiring that the distraction screws be placed at an angle to the bone surface in order to achieve the trajectory needed to realign the bones . examples of the poly - axial head design are illustrated in fig1 , 14 , 15 a - c , 16 a , 16 b , 17 and 18 . with such a feature , a poly - axial distal segment 220 incorporates a head portion 222 , which generally assumes the geometric shape of a spherical segment , or cup shape , and a neck portion 224 with a narrower cross - sectional profile that tapers to the shank portion 226 . a poly - axial head adapter 230 is swivelably fitted over the head portion 222 . the poly - axial head adapter 230 has a ring body 232 , which has an internal ring opening with a smaller internal diameter at its lower portion 234 than its upper portion thus forming a socket arrangement . the lower portion 234 also has a smooth concave external contour 236 . poly - axial head adapter 230 is installed over the head portion 222 by way of the opening at its lower ring portion . a rotational space between the poly - axial head adapter 230 and the head portion 222 is provided to allow the poly - axial head adapter to move . this type of connection can be considered a ball joint , or socket connection , though other means for providing a connecting relationship between the poly - axial head adapter and the head portion while permitting varying degrees of rotational flexibility ( swivelability ) can also be adapted . a flange 228 is located between the neck portion 224 and the shank portion 226 , on which the poly - axial head adapter 230 can be rested . flange 228 also provides as a stop when the shank 226 is inserted onto the bone structure , as well as a measure of the depth of the shank implant . a concave curvature in the lower portion of the flange 228 allows the maximum thread / bone contact and support when the distal segment 220 is affixed in an inclined angle relative to the surface of the bone 20 . coupling of the proximal segment 130 and the distal segment 220 in this embodiment can employ any of the coupling designs described in detail for the mono - axial distal segment . these methods include , but are not limited to , the design illustrated in fig1 and 14 . once coupled , the segments will function as a unitary device . by applying a rotational force to the proximal segment 130 , the threaded shank of the distal segment 226 can be advanced and secured into the underlying bone , as described for the mono - axial design . following the distraction work and detachment of the proximal segment from the implantable distal segment , the skeletal plate 30 can be mounted onto the implantable distal segment . as shown in fig1 , the adapter ring 230 is peripherally contoured for it to be fitted within an opening 32 of the skeletal plate 30 . poly - axial head adapter 230 has an open top with internal circumferential thread 238 for receiving a mounting plate 242 with complemental threads 244 . as shown in fig1 , 15 a and 15 b , mounting plate 242 has a circular - shaped top flange 246 , which is seated on the rim 34 of the opening 32 of the skeletal plate 30 . after the skeletal plate 30 is mounted onto the adapter ring 230 , the mounting plate 242 is threaded onto its internal thread 238 , thus forming a unitary piece . before the treads 242 and 238 are completely engaged , the skeletal plate can be tilted or rotated for it to be aligned in proper placement . since the adapter ring 30 is swivelable in relation to the head portion 222 , skeletal plate 30 can be easily manipulated to assume the desired position in relation to the bone structure despite the other than normal or vertical entry of the distal segment onto the bone structure . after placement of the bone plate 30 , the mounting plate 242 is tightened against the thread 238 . the force asserted by the thread engagement draws the head adapter close to the mounting plate , which in turn closes the space between the lower portion 234 of the adapter ring and the head portion 222 and to firmly secure the head adapter onto the distal segment as well as the skeletal plate . as shown in fig1 a , the mounting plate has a central opening 250 into which a turning devise can be inserted to facilitate its turning . although illustrated as a hexagonal opening into which an “ allen ” wrench driver may be deployed , any engagement method consisting of a driver and complimentary receptacle can be employed . fig1 a , 16 b , 17 and 18 show another variation in the poly - axial design feature . the poly - axial head adapter 310 is provided with a cap 312 , which is coupled to the head adapter by means of threads 318 . in assembly , screw 274 is fitted into the poly - axial head adapter 310 and cap 312 is used to engage threads 318 . the screw 274 has a head portion 276 and a flat top 278 . the cap 312 has a central opening 316 with internal threads 320 , which is adapted to receive the threaded , rounded distal end 402 of the deployable member 136 . cap 312 may be further adapted to receive an optional rotation locking means . while the key design ( opening 314 ) is illustrated for simplicity , it is understood that the rotation locking means may be of any engageable configuration . after key 170 is fitted into the key opening 314 , the deployable member is extended to pass through the threaded opening 316 and to push against the top surface 278 of the screw 274 . as the threaded distal portion is rotated further in relation to threads 320 , the force exerted by the rounded end 402 on surface 278 causes the under surface of the screw head 276 to firmly engage portion 322 of head adapter 310 , forming a unitary distraction screw . with distraction screw assembly , its important that the long axis of the proximal segment 130 be the same as the long axis of screw 274 , permitting uniform rotation of both segments along a common axis . in use , a rotational torque is applied to the proximal segment 130 , which is translated by the key 170 to the head adapter 310 and , in turn , to screw 274 . the shank rotates and engages the underling bone . following distraction and bony realignment , the proximal portion is detached from the poly - axial head adapter , leaving the implantable distal segment affixed to bone . the skeletal plate 30 is mounted with its opening 32 to fit over the peripherally contour of the distal segment and is manipulated to assume the desired position . the swivel action of the poly - axial head adapter permits proper placement of the skeletal plate even with angled placement of bone screw 274 . a mounting plate 324 is seated on the stepped rim 34 of the opening 32 of the skeletal plate 30 . it has a central opening 326 though which a mounting screw 328 can be passed to engage threads 320 of screw cap 312 . as the threads are tightened , force is exerted onto surface 278 by the rounded end of screw 328 causing the under surface of the screw head 276 to firmly engage portion 322 of head adapter 310 , and locking the poly - axial head portion to screw 274 . the same action also effects a force on the mounting plate , bearing against the step rim 34 of the skeletal plate 30 for it to be securely anchored . for this embodiment , it is understood that a space is provided between the screw cap and the mounting plate to provide for the engagement of the poly - axial head adapter and the head portion . from the above , it is apparent that the poly - axial design will produce a highly versatile distraction screw and can be used even with significantly mal - aligned bony structures . the ability of adapter ring 310 to rotate and swivel permit it to accommodate and orient the skeletal plate 30 , thus ensuring proper alignment and correct plate fixation . as described above , the present invention is that of a distraction screw and its use . it provides a significant design advantage over existing art by decreasing the bone stress encountered at the empty bone holes and reducing the extent of operative bleeding . the present design also provides an additional point of fixation for the implantable plate / prosthesis , maximizes the likelihood of proper plate / prosthesis alignment , and provides a ready mechanism for modular extension of the surgical reconstruction to adjacent levels at a future date . while the different embodiments of the present invention have been illustrated as consisting of a proximal and distal segment , it is understood that a modular distraction screw may be constructed from more than two components . the preceding descriptions and accompanying drawings are to be considered as illustrative and not restrictive in character . further understanding of the present invention , and other embodiments as described herein can be obtained through a review of the claims :

an improved distraction bone screw and a method for its use are described . the distraction screw is comprised of an implantable distal segment and a detachably secured proximal segment . the distal segment includes a head portion and a threaded shank portion . the proximal segment is represented as an elongated body having an internal bore that extends through its length . a deployable member is disposed within the bore , which is extendible outside the internal bore to securely couple to the distal segment . as an assembly , the distraction screw is used to affix and realign bone during surgical reconstruction . upon completion of the surgical work , the proximal segment is removed and the distal segment is left attached to the reconstructed bone . securely affixed , the distal segment provides an additional point of fixation for the skeletal plates that are used to preserve the bony alignment while bone healing occurs . the affixed distal segment will also provide a ready mechanism for distraction screw replacement at the time of surgical revision without obligatory plate removal . different embodiments of the proximal segment , distal segment and the rotational locking mechanisms which inhibit the rotation of one segment relative to the other during deployment were also described . in addition , in cases where the distraction screw must be placed into the bone at an inclined angle , poly - axial heads were provided so that proper skeletal plate placement can still be accomplished .

before describing the present invention in detail , it should be understood that the invention as described is not to be limited in its application to the process details described herein . the invention as such , embraces other embodiments and various ways for being applied . it is also should be understood that the phraseology or terminology used herein is for the purpose of description and it is not intended for any type of limitation . the present invention provides systems and processes for processing a marine biomass . as a preferred embodiment , the marine biomass is krill , preferably the antarctic krill euphasia superba . other krill species or crustacean can also be processed using the systems and processes of the present invention . examples of such species are e . crystallorophias , e . frigida , e . tricantha , e . vellantini , e . lougirostris , e . lucens , e . similis , e . spinifera , e . recurva , e . pacifica , thysanoessa macrura , t . vicinia , t . gregaria , t . raschii , t . inermis , pandalus borealis , cervimunida johni , heterocarpus reedi or pleuroncodes monodom . the krill is preferably processed in a fresh state as defined herein . frozen krill is not preferred to be used with the process of the present invention , as ice crystals formed during krill freezing which can disrupt anatomical structures of the crustacean . destruction of tissues by freezing is a well established subject in the state of art ( whittaker d k . 1984 . mechanisms of tissue destruction following cryosurgery . ann r coll surg engl . 66 : 313 - 318 ). tissue disruption could favor oil emulsification during processing and also phospholipids &# 39 ; deterioration during frozen storage . as a preferred embodiment , the krill is processed fresh on board a fishing vessel either factory trawler , mother factory vessels , or intermediate processor or similar or whatever other ship suitable to carry out the process of this invention within a term of 14 , 12 , 10 , 8 , 6 , 5 , 4 , 3 , or preferably 2 hours of catching krill . in some embodiments , the krill is processed on board a ship within 1 hour or preferably 0 . 5 hours or more preferably within 20 minutes after catching the krill . within the embodiments of the present invention , it is included that the ship tows a trawl that is configured to catch the krill and / or that the ship receives its krill or other species from fishing vessels or other factory trawlers . the krill is then transferred from the trawl to the ship and processed , preferably immediately after krill catching . the trawl comprises ( either a regular fishing gear composed of trawls and / or purse seining system and / or ) a pumping system to pump the freshly caught krill from the trawl to the ship so the krill can be processed in a fresh state . in some embodiments the catch system , be it regular trawl or pump system , it is designed in such a manner that substantially no damage , ( deterioration ) grinding or mincing is done to the krill during the pumping from the trawl to the ship . in a preferred embodiment , the fresh whole krill or fraction is transported to the cooker using belt conveyor , or screw conveyor or screw pumping or another transport system avoiding krill agitation to avoid the oil emulsification with protein and water . the whole krill is cooked ( i . e ., heated ) in a cooker with indirect and / or direct steam heating or another heating system , but at a low rotation speed of about 1 - 100 rpm , preferably 2 - 20 rpm , and more preferably 5 - 10 rpm , without agitation to avoid the oil emulsification . the krill temperature at the exit of the cooker is about 20 - 100 ° c ., preferably 50 - 100 ° c ., more preferably 75 - 100 ° c . and even more preferably 93 - 95 ° c ., or whatever other temperatures not disclosed here but that are necessary to reach complete protein denaturation . the cooker type is not particularly restricted but as preferred embodiment this cooker must operate without agitation for avoiding the emulsification state . in some embodiments the cooked krill is transported to the two - phase decanter using a screw conveyor or a screw pumping , or another transporting system without krill agitation for avoiding oil emulsification . the cooked krill is passed through a two phase decanter with high torque of about 1 - 10 knn , preferably 1 . 2 - 5 knn , more preferably 1 . 5 - 3 knm , even more preferably 1 . 8 - 2 . 5 knm , and a speed of about 100 - 10 , 000 rpm , preferably 1000 - 8000 rpm , more preferably 2 , 000 - 5 , 000 rpm , even more preferably 3 , 000 - 4 , 600 rpm , for partial de - watering and partial de - fatting , separating it into a decanter solids phase and a decanter liquid phase . in some embodiments , a decanter type is not particularly restricted . the moisture content of decanter solid is about 40 - 80 %, preferably , 50 - 70 %, more preferably 55 - 67 %, even more preferably 58 - 65 %. table no 1 shows the lipid and moisture content of decanter solids and decanter liquids , obtained with krill catch during fatty period using a previous cooker with indirect and direct steam heating with screw conveyor at low rotation speed . the decanter solid has a lipid content range of 19 . 8 % to 22 . 4 % wt dry base , so the resulting hill meal with 8 % of moisture from this solid will have a lipid content of about 18 . 2 % to 20 . 6 %. these results show that a two - phase decanter alone is not enough to reach a good de - fatting of the cooked krill for obtaining more krill oil and krill meal with a fat content lower than 18 %. anyway , this decanter solids obtained from the previous cooker at a low speed has lower lipid content and non - emulsified lipids than the process wherein a contherm cooker is used . in some embodiments of the present invention , using a cooker calibrated for a low rotation speed , the decanter liquid obtained in such cooker is not emulsified and has higher lipid content compared to the decanter liquid using a conventional contherm cooker . table no 2 shows the lipid and moisture content of decanter solids and decanter liquid , wherein a contherm cooker has been previously used . this equipment is not preferred within the embodiments of this invention , as a large proportion of lipids remain in the decanter solids , and the lipids contained in the decanter liquid are emulsified . krill oil recovery using this equipment was very low and the resulting krill meal has a high fat content , specifically over 20 % when obtained in the krill fatty period . as a preferred embodiment in the process of the present invention , the obtained decanter liquid is passed through a separator centrifuge and then through a purifier separator centrifuge , for obtaining stick water and a krill oil enriched with neutral lipids with astaxanthin and substantially free or without ( or no detectable ) phospholipids . the obtained stick water has a low fat content , with a maximum of about 0 . 3 - 0 . 5 %, in a nonemulsified form suitable for further processing ( concentrate production ) and sludge . in some embodiments , there is provided a process for obtaining the neutral lipid - enriched oil , which has an exclusive and separated line including : separator centrifuge , purifier separator centrifuge , pumps , piping , heat exchangers , tanks and packaging station . in a preferred embodiment of the process of the present invention , the decanter solids phase are fed to a twin - screw press using a screw pump or a screw conveyor or other feeding system wherein agitation does not occur . the decanter solids phase are pressed using twin screw press with high pressing force or using another pressing system to release the oil with phospholipids linked to the denatured protein according to the production line for the product of the present invention . as a preferred embodiment the pressing step is carried out by continuous pressing at a full feeding condition using a 2 - 10 rpm speed , and more preferably 3 - 6 rpm and a decanter solids temperature feeding of 90 - 96 ° c . and more preferably 93 - 95 ° c . the pressing system is not particularly restricted . as described above , the decanter solids phase keeps all of the phospholipids inside of the coagulated protein , then a strong pressing of the decanter solids release an important percentage of the phospholipids to the press liquid . the moisture of this press cake is about 45 - 55 %, preferably 48 - 53 %. table 3 shows the lipid and moisture content from the press cake of the present invention at different feeding levels of the twin press in the krill fatty period . table no4 shows this press liquid composition in the krill fatty period . according to the process or system disclosed in the present invention , this press liquid has a high fat content in the range of about 3 - 25 %, preferably 5 - 20 % and more preferably 8 - 17 % ( wet base ), depending on the seasonal lipid content of krill and if it is not in an emulsified form . in the traditional krill meal processing using only a twin - screw press ( without prior use of a decanter ) the fat content in this press liquid is lower than 0 . 5 - 3 % ( wet base ) depending on the lipid content of krill and if it is not in an emulsified form . in some embodiments of the present invention , there is also provided a dried complex with oil containing phospholipids with dha and epa , proteins and astaxanthin obtained by drying the press liquid “ as - is ” without centrifuge separation . such dried complex corresponds to a human - grade krill - related product for being used in many human health applications . in some embodiments , a synergic action of the two - phase decanter and further pressing with twin - screw press or another strong pressing system is used to release the phospholipids with dha and epa in the oil , mixed with astaxanthin and neutral lipids . the press liquid , at a temperature of about 25 - 121 ° c ., preferably 50 - 110 ° c ., more preferably 80 - 100 ° c . and even more preferably 90 - 96 ° c ., is pumped to the separator centrifuge , using a screw pump or other feeding system , avoiding agitation , wherein the krill oil with phospholipids with dha and epa mixed with astaxanthin and neutral lipids is separated . the processing speed in the centrifuge separator operates at 4 , 000 - 8 , 000 rpm , more preferably at 4 , 600 - 6 , 800 rpm , with an automatic periodic discharge of solids . in one embodiment of the present invention , the oil separator centrifuge is not particularly restricted , i . e . any centrifuge equipment satisfying the indicated conditions can be used . this krill oil is once more centrifuged through a purifier separator to clarify it , operating at a processing speed of 5 , 000 - 10 , 000 rpm , more preferably at 6 , 000 - 8 , 200 rpm , with an automatic periodic discharge of solids for later being packaged . in the embodiments of the present invention , the purifier separator centrifuge is not particularly restricted , i . e . any centrifuge equipment satisfying the indicated conditions can be used . as an additional preferred embodiment , the krill oil with phospholipids with dha and epa mixed with astaxanthin and neutral lipids , product of the present invention , is obtained using an exclusive and separated oil process line including : a separator centrifuge , a purifier separator , pumps , piping , heat exchangers , tanks and a packaging station , completely different and separated from the other oil line with neutral lipid from the decanter liquid phase . examples 3 and 4 show the characteristics of krill oils obtained in the present invention : i ) the neutral lipid enriched krill oil of the present invention is also useful for human health application having a content of : neutral lipids from 50 to 100 % w / w , preferably from 60 to 100 % w / w , and more preferably from 70 to 100 % w / w , dha and epa content are from 2 to 45 % w / w , preferably from 2 to 40 % w / w , and more preferably from 5 to 35 % w / w , phospholipids content is lower than 10 % w / w , preferably lower than 5 % w / w , and more preferably lower than 2 % w / w , and astaxanthin content is from 200 to 1 , 500 mg / kg , more specifically from 300 to 1 , 200 mg / kg , and even more specifically from 400 to 1 , 000 mg / kg . ii ) the phospholipids enriched krill oil of the present invention can be useful for human health applications , having a content of : total phospholipids content from 30 to 70 % w / w , preferably from 35 to 60 % w / w , and more preferably from 35 to 55 % w / w , dha and epa content is from 10 to 70 % w / w , preferably from 15 to 60 % w / w , and more preferably from 20 to 55 % w / w , neutral lipids content is from 30 to 70 % w / w , preferably from 40 % to 65 % w / w , and more preferably from 45 to 65 % w / w , and astaxanthin content is from 200 to 1 , 500 mg / kg , preferably from 300 to 1 , 200 mg / kg , and more preferably from 400 to 1 , 000 mg / kg . according to the above declared compositions for both oil products , obtained through the process of the present invention , these oils are suitable for health human applications . from the above , considering the composition characteristics of this krill oil and the process for obtaining the same , it can be concluded that the process of the present invention provides a krill oil product containing dha and epa in the phospholipids fraction with astaxanthin and neutral lipids . the present invention provides for a different process , which is new and improved , regarding all those krill oils obtained through processes involving solvent extraction and / or using supercritical fluid extraction or through thermal fractionation and centrifugation ; with the resulting krill meal , in any antarctic krill season , having a maximum fat content of 15 %, a minimum protein content of 60 % for a maximum moisture content of 10 %. in some embodiments , krill oils obtained with the procedure disclosed in the present invention can be stabilized by the use of antioxidants and / or preservatives and / or with a nitrogen - barred layer . moreover , such krill oils can be stored within plastic or metal containers , necessarily suitable for food - grade , pharmaceutical - grade and / or cosmetic / grade applications , in special stainless steel containers , at room temperature or refrigerated , suitably protected from light . in some embodiments , the present invention provides uses of krill oils for preparing krill oil compositions for being used as a dietary supplement and / or nutraceutical product . this invention also discloses pharmaceutical compositions comprising an effective amount of krill oil and at least one pharmaceutically acceptable transporter , excipient , stabilizer , diluents and / or adjuvant . in some of the embodiments , said krill oil compositions are suitable as photoprotectors . said photoprotectors can be formulated as tanning creams and / or tanning oils . in some of the embodiments , said krill oil can be used to enhance cosmetic products . said cosmetic products are , but no limited to , moisture creams , powder make ups , powder eye shadows , cream eye shadows compact powders and lipsticks . in some of the embodiments , said krill oil compositions can be effectively used for decreasing cholesterol plasma levels , inhibiting platelet adhesion , inhibiting artery plaque formation , preventing hypertension , controlling arthritis symptoms , preventing skin cancer , enhancing transdermal transport , reducing the symptoms of premenstrual symptoms or controlling blood glucose levels in a patient . furthermore , in some embodiments , nutraceuticals , pharmaceuticals and cosmetics comprising the phospholipids - enriched krill oil are also embraced by the present invention . table 3 lipid and moisture content of the press cake of the present invention at different feeding levels of the twin press moisture dry lipids lipids (%) solids (%) wb (%) db (%) press cake 1 58 . 1 41 . 9 8 . 6 20 . 5 press cake 2 58 . 6 41 . 4 8 . 4 20 . 3 press cake 3 56 . 9 43 . 1 8 . 0 18 . 5 press cake 4 56 . 7 43 . 3 8 . 0 18 . 5 press cake 5 54 . 6 45 . 4 7 . 4 16 . 3 press cake 6 54 . 5 45 . 5 7 . 2 15 . 8 press cake 7 54 . 3 45 . 7 5 . 5 12 . 0 press cake 8 53 . 9 46 . 1 5 . 6 12 . 1 wb : wet base db : dry base press cake samples 1 to 6 were taken when the press was not fully fed with decanter solids press cake samples 7 & amp ; 8 were taken when the press was fully fed with decanter solids the present invention will be described in more detail using examples . it should be understood that the present invention is not limited by the following examples . process to obtain krill oils and low fat krill meal of the present invention the description represents an example of the process of the present invention . in fig1 there is depicted a flow diagram of this process . the process clearly does not involve the use of organic solvents and / or supercritical co 2 fluid . antarctic krill was captured during the period of march to may , preferably during the month of may , within krill &# 39 ; s fatty period in the orkney islands fishing ground , using a pumping catch system , the krill arriving alive on board a factory vessel and being immediately processed . table no5 shows the fresh raw whole krill composition used . whole krill was collected into bunkers to drain seawater and transported on belt conveyors to tanks from wherein it was pumped to the cooker using a screw pump . the continuous cooker with screw conveyor used live steam to increase the krill temperature from about 0 ° c . to 93 - 95 ° c . the cooker screw conveyor speed was set at 7 - 8 rpm . the cooked krill was then pumped to the two - phase decanter using a screw pump . the continuous working cooker with screw conveyor used live steam to increase the krill temperature from about 0 ° c . to 93 - 95 ° c . the cooker screw conveyor speed was set at 7 - 8 rpm . the cooked krill was pumped to a two - phase decanter . the two - phase decanter operated at 3 , 100 rpm and a 2 . 0 knm torque was used , resulting in a decanter liquid phase and a decanter solid phase . table no1 shows the decanter liquid and decanter solid composition . the decanter liquid phase was collected into tanks at a temperature of 93 - 96 ° c ., from wherein it was pumped with a screw pump to the separator centrifuge at a speed set at 4 , 600 rpm and immediately thereafter passed to a purifier separator at a speed set at 6 , 100 rpm , for obtaining a krill oil with neutral lipids without phospholipids . example 3 shows this neutral lipids oil composition and characteristics . the decanter solid phase was pressed in a twin - screw press resulting in a press liquid phase and press cake phase . table no 6 shows the composition obtained from these two phases . the press cake was dried until it reached a moisture content lower than 10 % using a rotaplate drier . example 5 shows the krill meal composition obtained from this test . the press liquid at a temperature of 93 - 96 ° c . was pumped with a screw pump to a specific separator centrifuge at a speed set at 4 , 600 rpm and immediately thereafter to a specific purifier separator at a speed set 6 , 100 rpm , to separate the krill oil with phospholipids . example 4 shows the composition characteristics of this krill oil with dha and epa linked to the phospholipids fraction obtained from the present experiment . flow diagram and mass balance of the process to obtain krill oils and low fat krill meal of the present invention this example shows an estimate mass balance of a production line for the product of the present invention when raw krill is within the season when fat content is high ( estimated at 5 %) although not necessarily the highest fat content found in raw south antarctic krill and without the addition or recovery of stick water . the following tables are an estimated mass balance of the process of the present invention without stick water recovery , utilizing raw krill with average - high fat content ( around 5 % w / w ). the following tables shows an estimate mass balance of a production line for the product of the present invention when raw krill is within the season when fat content is high ( estimated at 5 %) although not necessarily the highest fat content found in raw south antarctic krill and with the addition or recovery of stick water . lipid class composition of lipid samples and fatty acid compositions of individual lipids were determined by high performance thin - layer chromatography ( hptlc ) and quantitation using a scanning densitometry according to henderson and tocher ( henderson , r . j . and tocher , d . r . ( 1992 ) thin - layer chromatography . in lipid analysis : a practical approach ( hamilton , r . j ., and hamilton , s ., eds .) pp . 65 - 111 , oxford university press , oxford ). it is described a food rich in fat material for complementing essential fatty acids . such food was formulated in cookie form elaborated using krill oil , krill meal or krill dried complex . in a bowl 400 g quaker was mixed with 100 g of flour , 500 g of sugar , 1 egg , 150 ml of krill oil of this invention and 10 ml of vanilla extract . once completely homogenized , the cookies were molded weighing each 25 g , and were baked at 160 ° c . for 15 min as longer cooking times destroys the astaxanthin . the amount of cookies used in the diets will depend on the amount of essential fatty acids such as 18 : 2 and 18 : 3 required , and the necessary calories . the krill oil prepared as described in the examples 3 and 4 can be used for the preparation of tanning creams and tanning oils for solar protection . in this example are described two tanning creams , one with solar protection factor 5 ( spf5 ) and one with solar protection factor 20 ( spf20 ). since krill oil has several biological activities , such as being a pigmentant , antioxidant capacity , epa and essential fatty acids content , it is possible to design cosmetic products . table 55 compound composition per 100 g of makeup talcum powder 52 . 56 g krill oil 10 . 00 g mica : titanuim dioxide ( 2 : 1 ) 26 . 00 g magnesium estearate 3 . 50 g isopropyl miristate 1 . 60 g oleic alcohol 2 . 60 g octylpalmitate 3 . 40 g methylparabene 0 . 17 g propylparabene 0 . 17 g in this example a base formula for the elaboration of a powder eyeshadow that contains 10 % ( w / w ) krill oil of this invention is described . in this example a base formula for the elaboration of a cream eyeshadow that contains 5 . 7 % ( w / w ) krill oil of this invention is described . in this example a base formula for the elaboration of a compact powder that contains 10 % ( w / w ) krill oil of the present invention is described . krill and / or marine oil has been shown to decrease cholesterol in vivo . it also inhibits platelet adhesion and plaque formation and reduces vascular endothelial inflammation in a patient . it can offer hypertension prophylaxis . it prevents oxidation of low - density lipoprotein . it may have an inhibitory effect on the secretion of vldl due to increased intracellular degradation of apo b - 100 . it also offers a post - myocardial infarction prophylaxis because of its ability to decrease ciii apolipoprotein b , to decrease ciii non - apolipoprotein b lipoproteins and to increase antithrombin iii levels . krill and / or marine oil is suitable for prophylactic usage against cardiovascular disease in human where cardiovascular disease relates to coronary artery disease , hyperlipidemia , hypertension , ischemic disease ( relating to angina , myocardial infarction , cerebral ischemia , shock without clinical or laboratory evidence of ischemia , arrhythmia ). a pharmaceutical composition of krill oil of this invention comprises capsules containing 1 ml of krill oil described in examples 3 and 4 . a pharmaceutical composition of krill dried complex of this invention comprises capsules containing 1 to 5 g of krill dried complex .

the invention discloses a new solvent - free process for obtaining phospholipids and neutral lipids enriched krill oils containing dha and epa poly - unsaturated fatty acids and astaxanthin . the process includes cooking fresh krill at high temperature — without agitation and or grinding ; decanting the cooked krill for obtaining a partial de - fatted and de - watered solid and a liquid ; squeezing the obtained solid to obtain a press liquid and a solid fraction ; centrifuging the press liquid to obtain the phospholipids enriched krill oil ; centrifuging of the decanter liquid obtained to obtain the neutral lipid enriched krill oil and stickwater .

the present invention may be embodied by an implantable cardiac rhythm management device for delivering anti - tachyarrhythmia therapy through one or more electrical stimulation channels which is configured for temporary disablement of the anti - tachyarrhythmia therapy when the need arises . below is a description of an exemplary hardware platform followed by a detailed description of different techniques for implementing the temporary disablement feature . cardiac rhythm management devices such as icds and pacemakers are typically implanted subcutaneously on a patient &# 39 ; s chest and have leads threaded intravenously into the heart to connect the device to electrodes used for sensing cardiac activity , delivering pacing pulses , and / or delivering defibrillation shocks . fig1 depicts an implantable cardioverter / defibrillator device for treating atrial and ventricular tachyarrhythmias that also incorporates functionality for pacing the atria and / or the ventricles in a bradycardia pacing mode . the device includes a subcutaneously implantable housing or can 60 for enclosing the electronic circuitry of the device and a pair of leads l 1 and l 2 having electrodes incorporated therein . the lead l 1 has a tip electrode 33 a and ring electrode 33 b which are shown in the figure as disposed in the superior vena cava ( svc ) for pacing or sensing of the atria . the lead l 2 has a tip electrode 43 a , a distal coil electrode 43 b , and a proximal coil electrode 43 c . coil electrodes can be used to deliver pacing pulses but are designed especially for delivering cardioversion / defibrillation shocks . in the placement of the lead l 2 shown in the figure , tip electrode 43 a and distal coil electrode 43 b are disposed in the right ventricle ( rv ), and proximal coil electrode 43 c is disposed in the superior vena cava or right atrium . sensing or pacing of the ventricles may be performed using tip electrode 43 a and / or coil electrode 43 b . a ventricular cardioversion / defibrillation shock may be delivered between coil 43 b and the can 60 , or between coil 43 b and the can 60 electrically in common with the coil 43 c , and an atrial cardioversion shock may be delivered between the coil 43 c and the can 60 . fig2 is a system diagram the implantable device shown in fig1 . the controller of the device is made up of a microprocessor 10 communicating with a memory 12 , where the memory 12 may comprise a rom ( read - only memory ) for program storage and a ram ( random - access memory ) for data storage . a microprocessor - type controller 10 controls the overall operation of the device in accordance with programmed instructions stored in memory . the controller could be implemented by other types of logic circuitry ( e . g ., discrete components or programmable logic arrays ) using a state machine type of design , but a microprocessor - based system is preferable . as used herein , the terms “ circuitry ” and “ controller ” should be taken to refer to either discrete logic circuitry or to the programming of a microprocessor . a telemetry interface 80 is provided by which the controller may wirelessly communicate with an external programmer 300 . the external programmer 300 is a computerized device that can interrogate the implantable device and receive stored data as well as adjust the device &# 39 ; s operating parameters . the device is equipped with multiple sensing amplifiers and pulse generators which can be configured as channels for pacing and / or sensing selected heart chambers . a mos switch matrix 70 controlled by the microprocessor is used to configure a sensing or pacing channel by switching selected electrodes to the input of a sense amplifier or to the output of a pulse generator . the switch matrix 70 allows the device to employ either bipolar sensing / pacing using two closely spaced electrodes of a lead or unipolar sensing / pacing using one of the electrodes of a lead and the can 60 as a reference electrode . the switch matrix 70 can also connect atrial shock generator 75 to deliver an atrial cardioversion shock between coil electrode 43 c and the can 60 , and can connect ventricular shock generator 85 to deliver a ventricular cardioversion / defibrillation shock between coil electrode 43 b and the can 60 ( or the can 60 connected in common with the coil electrode 43 c ). in the device shown in fig2 , an atrial channel for sensing or pacing an atrial site is configured with tip electrode 33 a , ring electrode 33 b , sense amplifier 31 , pulse generator 32 , and an atrial channel interface 30 which communicates bidirectionally with a port of microprocessor 10 . a first ventricular channel for sensing or pacing a ventricular site is configured with tip electrode 43 a , coil electrode 43 b , sense amplifier 41 , pulse generator 42 , and ventricular channel interface 40 . a second ventricular sensing channel using ventricular channel interface 50 may be configured by connecting one of the differential inputs of sense amplifier 51 to the coil electrode 43 b and connecting the other input to the can 60 and coil electrode 43 c . the channel interfaces may include comparators for comparing received electrogram signals to reference values , analog - to - digital converters for digitizing sensing signal inputs from the sensing amplifiers , registers that can be written to for adjusting the gain and sensing threshold values of the sensing amplifiers , and registers for controlling the output of pacing pulses and / or adjusting the pacing pulse energy by changing the pulse amplitude or pulse width . the controller uses the sensing channels in order to detect intrinsic cardiac activity in a heart chamber , referred to as a chamber sense ( e . g ., an atrial sense or a ventricular sense ). in order to detect intrinsic cardiac activity , the signals emanating from the sense amplifier are compared with a reference potential . as described above , a sensing channel includes sense amplifier circuits for amplifying and filtering the electrogram signals picked up by an electrode disposed at a cardiac site . only when an electrogram signal from the sense amplifier exceeds a reference potential , referred to as a sensing threshold , is it treated as a chamber sense . the sensing threshold may be implemented with analog circuitry , where the sense amplifier output is applied to one input of a comparator circuit whose other input is connected to a reference potential , or with digital circuitry operating on digitized samples of the sense amplifier output which are compared with a digitized reference value . in either case , the sensing threshold for each channel is adjustable by the controller . detected chamber senses may be used for controlling the delivery of paces in accordance with a programmed pacing mode ( e . g ., bradycardia pacing or ventricular anti - tachycardia pacing ) and / or for diagnostic purposes . by counting the number of chamber senses over a defined time period or measuring the time intervals between senses , the controller is able to measure heart rate and detect arrhythmias using rate - based criteria . the atrial and ventricular sensing channels described above are used to separately measure the atrial and ventricular rates in this embodiment . when the measured atrial and / or ventricular rates exceed specified threshold values , the device detects a tachyarrhythmia and is programmed to respond with appropriate anti - tachyarrhythmia therapy . for example , if a ventricular rate is measured which is in the vf zone , the device delivers a ventricular defibrillation shock . if a ventricular rate is measured which is in the vt zone , the device decides whether vt or an atrial tachyarrhythmia is present using rate and / or electrogram morphology criteria . if the ventricular rate is greater than the atrial rate , vt is detected , and the device may be programmed to initiate ventricular anti - tachycardia pacing . if the atrial rate is greater than or equal to the ventricular rate and a specified minimum number of normally conducted beats are detected , an atrial tachyarrhythmia is detected , the device is programmed to deliver an atrial cardioversion shock . the device would also detect an atrial tachyarrhythmia and deliver an atrial cardioversion shock if the atrial rate is above a specified threshold value and the ventricular rate is in the normal range , as could occur in a patient without an intact av conduction pathway . to lessen the risk of inducing a ventricular arrhythmia , the device may deliver the atrial cardioversion shock synchronously with a sensed ventricular depolarization ( i . e ., an r wave ) and may delay delivering the shock until the intrinsic ventricular rhythm is below a specified maximum rate . as described above , certain medical and surgical procedures involve the use of instrumentation capable of producing electromagnetic interference which can trigger the delivery of anti - tachyarrhythmia therapy by an implantable device . such a device would typically include , as illustrated in fig2 , a sensing channel for sensing an electrogram signal representing cardiac electrical activity and circuitry for generating a chamber sense when the electrogram signal exceeds a specified threshold , one or more stimulation channels for delivering electrical stimulation to a subject &# 39 ; s heart , a controller programmed to detect a tachyarrhythmia from the rate at which chamber senses are generated and to cause delivery of ant - tachyarrhythmia therapy through one or more of the stimulation channels upon detection of a tachyarrhythmia , and a telemetry interface by which the controller may communicate with an external device . the one or more stimulation channels may include a pacing channel for delivering pacing therapy ( e . g ., anti - tachycardia pacing or bradycardia pacing ) and / or a shock channel for delivering cardioversion / defibrillation shocks , where the controller is programmed to cause delivery of anti - tachyarrhythmia therapy in the form of anti - tachycardia pacing and / or a cardioversion / defibrillation shock upon detection of a tachyarrhythmia . if the device is capable of delivering anti - tachycardia pacing and cardioversion / defibrillation shocks , the controller is programmed to deliver anti - tachycardia pacing upon detection of a tachyarrhythmia in a tachycardia zone and deliver a cardioversion / defibrillation shock upon detection of a tachyarrhythmia in a fibrillation zone . in accordance with the invention , the device is configured by appropriate programming of the controller to disable the delivery of anti - tachyarrhythmia therapy for a specified time interval upon receipt of a temporary suspend command from the external device via the telemetry interface and to re - enable the delivery of anti - tachyarrhythmia therapy upon expiration of the specified time interval . the specified time interval for which the delivery of anti - tachyarrhythmia therapy is disabled may be a fixed interval or a variable interval communicated to the implantable device by the external device via the telemetry link . disablement of anti - tachyarrhythmia therapy may be accomplished in different ways . in one embodiment , the device continues to sense cardiac activity but is prevented from delivering anti - tachyarrhythmia therapy if a tachyarrhythmia is detected while the disablement feature is active . in another embodiment , disablement of anti - tachyarrhythmia therapy is effected by disabling the device &# 39 ; s sensing channels . a sensing channel may be disabled directly or indirectly such as by raising its sensing threshold to render it refractory . raising the sensing threshold of a sensing channel to its maximum value ( e . g ., infinity ) means that no cardiac activity , and hence no tachyarrhythmias , will be detected , and the device will therefore be disabled from delivering anti - tachyarrhythmia therapy . disabling anti - tachyarrhythmia therapy by disabling the sensing functions of a device may also be advantageous in the case where the device is also delivering bradycardia pacing therapy to the patient . bradycardia pacing modes refer to pacing algorithms used to pace the atria and / or ventricles in a manner that enforces a certain minimum heart rate . because of the risk of inducing an arrhythmia with asynchronous pacing , most pacemakers for treating bradycardia are programmed to operate synchronously in a so - called demand mode where sensed cardiac events occurring within a defined interval either trigger or inhibit a pacing pulse . inhibited demand pacing modes utilize escape intervals to control pacing in accordance with sensed intrinsic activity . in an inhibited demand mode , a pacing pulse is delivered to a heart chamber during a cardiac cycle only after expiration of a defined escape interval during which no intrinsic beat by the chamber is detected . in an environment where electromagnetic interference is present , a device operating in an inhibited demand pacing mode may interpret the electromagnetic interference as intrinsic beats which then inhibit the delivery of paces . some patients are not able to tolerate the complete cessation of pacing therapy , however . disabling the sensing channels of the device deals with this problem by preventing the device from detecting cardiac activity . the device then delivers paces at the programmed lower rate limit , thus essentially reverting to an asynchronous pacing mode during the time the sensing channels are disabled . fig3 illustrates an exemplary algorithm for implementing this feature as it would be executed by the controller . at step a 1 , the device waits for a temporary suspend command from an external programmer via the telemetry interface . upon receipt of such a command and a specified suspend interval from the external programmer , the device disables anti - tachyarrhythmia therapy and initializes a timer ( e . g ., a timer implemented in code executed by the controller ) to the specified suspend interval at step a 2 . at step a 3 , the device waits for expiration of the suspend interval or receipt of a resume command from the external programmer . upon occurrence of either of these events , the device re - enables anti - tachyarrhythmia therapy at step a 4 and returns to step a 1 . in other embodiments , the implantable device further includes a magnetic switch actuated by application of a magnetic field ( illustrated as switch 250 in fig2 ) so that delivery of anti - tachyarrhythmia therapy is re - enabled before expiration of the specified suspend interval by actuation of the magnetic switch and / or an activity sensor for measuring an activity level ( illustrated as accelerometer 200 in fig2 ) so that delivery of anti - tachyarrhythmia therapy is re - enabled before expiration of the specified suspend interval upon measurement of an activity level above a specified threshold value . it may be desirable in certain circumstances , of course , to indefinitely disable anti - tachyarrhythmia therapy in an implantable device . therefore , the controller may be programmed to disable the delivery of anti - tachyarrhythmia therapy indefinitely upon receipt of an indefinite suspend command from the external programmer via the telemetry interface and to re - enable the delivery of anti - tachyarrhythmia therapy upon receipt of a resume command . in order to eliminate the need for an external programmer in order to re - enable anti - tachyarrhythmia therapy , the implantable device may further include a magnetic switch actuated by application of a magnetic field so that the resume command is communicated to the implantable device by actuation of the magnetic switch and / or an activity sensor for measuring an activity level so that the resume command is generated upon measurement of an activity level above a specified threshold value . as described above , disablement of anti - tachyarrhythmia therapy may be effected in one embodiment by disabling the sensing functions of the device . it should be appreciated that a temporary sensing channel disablement feature may be incorporated into a bradycardia pacemaker without the capability of delivering anti - tachyarrhythmia therapy . disabling the sensing channels of such a device causes it to revert to an asynchronous pacing mode which may be desirable in situations where electromagnetic interference is expected to be present . disabling and re - enabling the sensing channels of the device may be accomplished in different embodiments by any of the techniques for disabling and re - enabling anti - tachyarrhythmia therapy described above . although the invention has been described in conjunction with the foregoing specific embodiment , many alternatives , variations , and modifications will be apparent to those of ordinary skill in the art . such alternatives , variations , and modifications are intended to fall within the scope of the following appended claims .

an implantable cardiac rhythm management device for delivering anti - tachyarrhythmia therapy is provided with a temporary disablement feature so that the delivery of anti - tachyarrhythmia therapy may be conveniently disabled and re - enabled . the feature is particularly useful to patients who are undergoing imaging procedures or surgical procedures where electro - cauterizing instruments may cause inadvertent triggering of cardioversion / defibrillation shocks and / or anti - tachycardia pacing .

the following description and examples illustrate a preferred embodiment of the present invention in detail . those of skill in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope . accordingly , the description of a preferred embodiment should not be deemed to limit the scope of the present invention . a rodent repellent composition based on a grease - like gel composition for use on exterior and interior surfaces of a structure , such as homes , restaurants , and office buildings is provided . the repellent composition is particularly preferred for use on rodents ( e . g ., mice , rats , moles , voles , squirrels , and chipmunks ); however , the repellent is also suitable for use on other mammals , e . g ., raccoons and opossums . the repellent composition is suitable for use on any organism which possesses taste receptor cells sensitive to capsaicin or similar substances . insects can also be repelled by the repellent compositions of preferred embodiments ; however , birds do not have the receptor to which capsaicin binds , so it does not function as an irritant for them . unlike conventional rodent repellents that rely on odiferous components such as menthol , the repellents of preferred embodiments rely on a different mechanism of action and thus can be odor - free . the repellents of preferred embodiments work by the rodent making contact with the composition , which contains capsaicin , white pepper , or other components that produce a strong burning sensation in the mouth upon ingestion , but which are odorless or relatively odor - free . use of menthol and other odiferous components conventionally employed in repellents is avoided , as such components can reduce the effectiveness of a gel repellent composition because it discourages rodents from making physical contact with the composition . the repellent ingredient of the compositions of preferred embodiments is preferably capsaicin ( 8 - methyl - n - vanillyl - 6 - nonenamide ). it is the active component of chili peppers , which are plants belonging to the genus capsicum . it is an irritant for mammals , including humans , and produces a sensation of burning in any tissue with which it comes into contact . birds do not have the receptor to which capsaicin binds , so it does not function as an irritant for them . capsaicin and several related compounds are called capsaicinoids and are produced as a secondary metabolite by chili peppers . pure capsaicin is a hydrophobic , colorless , odorless , crystalline to waxy compound . capsaicin is the main capsaicinoid in chili peppers , followed by dihydrocapsaicin . these two compounds are also about twice as potent to the taste and nerves as the minor capsaicinoids nordihydrocapsaicin , homodihydrocapsaicin , and homocapsaicin . besides the six natural capsaicinoids , one synthetic member of the capsaicinoid family exists , the vanillylamide of n - nonanoic acid . table 1 provides a listing of several capsaicinoids . other components exhibiting similar properties can also be used as the repellent ingredient of the compositions of preferred embodiments . one such preferred component is piperine , the active piquant chemical in white and black pepper . allyl isothiocyanate , the active piquant chemical in mustard , radishes , horseradish , and wasabi can also be employed , as can allicin , the active piquant flavor chemical in uncooked garlic and onions . a particularly preferred repellent additive is capsaicin , due to its lack of odor in purified form . piperine also exhibits minimal odor in purified form . in applications where odor is not a concern , allyl isothiocyanate and allicin can advantageously be employed . while one repellent additive can advantageously be employed , combinations of two or more additives , e . g ., capsaicin and piperine , are also suitable for use . the repellent additive ( s ) typically comprise from about 0 . 005 wt . % or less to 0 . 5 wt . % or more of the repellent formulation , preferably from about 0 . 025 wt . % to about 0 . 1 wt . % of the repellent formulation . repellent additives are preferably employed in purified form ; however , in certain embodiments it can be acceptable to provide at least a portion of the repellent additive in a form of powdered vegetable product ( e . g ., chili powder ). the repellent additive can be mixed into to the grease base in powder or other solid form , or in a solubilized form . to improve the solubility of the repellent additive or other additives in the grease formulation , in certain embodiments it can be preferred to add an activator agent or other solubility improver to the grease base ( the term “ solubility improving additive ” as employed herein is used to collectively refer to both activator agents and solubility improvers ). esters , such as polyol esters can optionally be employed as solubility improving additives . alternatively , if the repellent additive is provided in a purified form , the additive can be dissolved or dispersed in a suitable solvent , which is then mixed into the grease base . suitable solvents for capsaicin include , e . g ., hexane , chloroform , ethylacetate , ethyl ether , acetonitrile , acetone , and ethanol . ethanol , petroleum ether , and dichloromethane are solvents for piperine . allyl isothiocyanate and allicin are soluble in most organic solvents and are slightly soluble in water . while any suitable solvent for the repellent additive can be employed , if desired , ethanol , e . g ., denatured ethanol , is generally preferred as the most environmentally acceptable activator agent . when ethanol is provided in denatured form , it can contain ethanol in combination with other additives . for example , the denatured ethanol may contain about 1 - 99 % ethanol and about 1 - 99 % additives , about 95 % ethanol and about 5 % additives , about 90 % ethanol and about 10 % additives , about 75 % ethanol and about 25 % additives , about 50 % ethanol and about 50 % additives . additives employed in denatured alcohol include , for example , methanol , isopropyl alcohol , acetone , methyl ethyl ketone , methyl isobutyl ketone , and denatonium . in a preferred embodiment , the denatured ethanol contains 95 % ethanol and 5 % additives . the solubility improving additive ( s ) typically comprise from about 0 . 25 wt . % or less to 5 wt . % or more of the repellent formulation , preferably from about 0 . 5 wt . % to about 3 wt . % of the repellent formulation , and more preferably from about 1 wt % to about 2 wt % of the repellent formulation . the capsaicin or other rodent repelling ingredient is provided in a grease - like base . preferred grease - like bases include one or more base oil or fluid components as a carrier . the oil or base fluid may include any number of materials , which are typically divided into two groups : petroleum derived oils ; and synthetic fluids , which are generally chemical reaction products . petroleum derived oils include paraffinic oils , naphthenic oils , and aromatic oils . synthetic fluids including polyalphaolefins , glycols , alkylated naphthalenes , alkylated benzenes , and esters have been used in compounding oil - based products . it is generally preferred to employ base oils that are both low cost and exhibit low toxicity . accordingly , light or heavy grade white oil ( a transparent , colorless mineral oil composed mainly of c15 - c40 alkanes and cyclic paraffins ), preferably of a purity suitable for use in food or cosmetics , is preferably employed as a base oil . alternatively , or in addition to mineral oil , vegetable oils can be utilized . vegetable oils are lipids ( esters ) derived from plants . suitable vegetable oils include , but are not limited to , coconut oil , corn oil , cottonseed oil , olive oil , palm oil , peanut oil , rapeseed oil , safflower oil , soybean oil , sunflower oil , almond oil , casher oil , hazelnut oil , macadamia oil , mongongo nut oil , pecan oil , pine nut oil , pistachio oil , walnut oil , bottle gourd oil , buffalo gourd oil , pumpkin seed oil , watermelon seed oil , acai oil , blackcurrant seed oil , borage seed oil , evening primrose oil , amaranth oil , apricot oil , apple seed oil , argan oil , artichoke oil , avocado oil , babassu oil , ben oil , borneo tallow nut oil , cape chestnut oil , carob pod oil , cassia oil , cocoa butter oil , cocklebur oil , cohune oil , coriander seed oil , dika oil , false flax oil , flax seed oil , grape seed oil , hemp oil , kapok seed oil , kenaf seed oil , lallemantia oil , manila oil , meadowfoam seed oil , mustard oil , nutmeg butter , okra seed oil , papaya seed oil , perilla seed oil , pequi oil , pine nut oil , poppyseed oil , prune kernel oil , quinoa oil , ramtil oil , rice bran oil , royle oil , sacha inchi oil , tea seed oil , thistle oil , tigernut oil , tomato seed oil , wheat germ oil , algae oil , copaiba , honge oil , jatropha oil , jojoba oil , milk bush , and petroleum nut oil . polyalphaolefins can be employed as base oil . such polyalphaolefins include high viscosity polyalphaolefins as described in u . s . pat . no . 4 , 827 , 064 . for example , high viscosity polyalphaolefins possess a higher viscosity index than conventional polyalphaolefins of similar molecular weight . high viscosity polyalphaolefins generally exhibit higher film strengths than conventional viscosity polyalphaolefins are generally of higher viscosity than conventional polyalphaolefins of similar molecular weight , but exhibit lower pour points than the corresponding conventional polyalphaolefins . the lower pour point of high viscosity polyalphaolefins makes them suitable for use at lower temperatures than conventional polyalphaolefins . high viscosity polyalphaolefins also exhibit superior oxidative stability than conventional polyalphaolefins . high viscosity polyalphaolefins are characterized by a uniform molecular structure with low branch ratios . the branch ratio is the ratio of methyl (— ch 3 ) to methylene (— ch 2 —) moieties in the molecular structure ). high viscosity polyalphaolefins typically possess a branch ratio of less than about 0 . 19 , while conventional polyalphaolefins branch possess a branch ratio greater than 0 . 2 . the polymerization reaction by which high viscosity polyalphaolefins are formed is generally highly specific , resulting in a low number of isomers formed . the resulting high viscosity polyalphaolefin product oligomers have an atactic molecular structure of mostly head - to - tail attachments , with some head - to - head connections . high viscosity polyalphaolefins generally possess an average molecular weight of from about 300 to about 45 , 000 , a carbon number of from about 30 to 1000 , and a viscosity at 100 ° c . of about 3 to about 5000 cst . the viscosity is typically in the range of about 150 to about 3000 cst at 100 ° c . the branch ratio is typically less than 0 . 19 . a high viscosity polyalphaolefin is marketed under the trade name supersyn ™ by exxon mobil corporation of houston , tex . polyalphaolefin base oils suitable for use in formulations of preferred embodiments include exxon mobil corporation &# 39 ; s spectrasyn ™ line of polyalphaolefin fluid . examples of spectrasyn ™ polyalphaolefin fluid include spectrasyn ™ 100 , spectrasyn ™ 40 , spectrasyn ™ 10 , spectrasyn ™ 8 , spectrasyn ™ 6 , spectrasyn ™ 5 , spectrasyn ™ 4 , spectrasyn ™ 2c , and spectrasyn ™ 2 . the viscosities of the spectrasyn ™ polyalphaolefin fluid vary . for example , spectrasyn ™ 100 and spectrasyn ™ 40 have relatively high viscosities . spectrasyn ™ 100 has a viscosity of 1240 cst at 104 ° f ., and spectrasyn ™ 40 has a viscosity of 396 cst at 104 ° f . spectrasyn ™ 10 , spectrasyn ™ 8 , spectrasyn ™ 6 , spectrasyn ™ 5 , spectrasyn ™ 4 , spectrasyn ™ 2c , and spectrasyn ™ 2 have relatively low viscosities . for example , spectrasyn ™ 10 has a viscosity of 66 cst at 104 ° f ., spectrasyn ™ 2 has a viscosity of 5 cst at 104 ° f ., spectrasyn ™ 2c has a viscosity of 6 . 4 cst at 104 ° f ., spectrasyn ™ 4 has a viscosity of 19 cst at 104 ° f ., spectrasyn ™ 5 has a viscosity of 25 cst at 104 ° f ., spectrasyn ™ 6 has a viscosity of 31 cst at 104 ° f ., and spectrasyn ™ 8 has a viscosity of 48 cst at 104 ° f . the viscosity of the polyalphaolefin can be selected in order to achieve a formulation with desired characteristics . generally , it is preferred to employ a high viscosity polyalphaolefin so as to provide greater structural integrity , weather resistance and stickiness to the repellant formulation . alkylated naphthalene is generally employed as additional base fluid to impart increased thermal and oxidative stability to a grease composition . see , e . g ., u . s . pat . no . 5 , 177 , 284 and u . s . pat . no . 5 , 457 , 254 . mono or poly substituted alkylated naphthalenes can be employed . similar to the alkylated naphthalenes are the polymers of alkyl benzenes , such as dodecylbenzenes , tetradecylbenzenes , dinonylbenzenes , di -( 2 - ethyl - hexyl )- benzenes , and the like . alkylated aromatics are formed by the reaction of olefins or alkyl halides with aromatic compounds , such as benzene . suitable alkylated naphthalenes can be obtained from exxon mobil corporation . alkylated naphthalene fluids suitable for use in formulations of preferred embodiments include exxon mobil corporation &# 39 ; s synesstic ™ line of alkylated naphthalene . examples of synesstic ™ alkylated naphthalene fluids include synesstic ™ 5 and synesstic ™ 12 . synesstic ™ 12 alkylated naphthalene has a viscosity of 109 cst at 104 ° f ., and synesstic ™ 5 alkylated naphthalene has a viscosity of 29 cst at 104 ° f . one preferred class of synthetic fluid bases is that of synthetic polyolefins , particularly hydrogenated polyalphaolefins , although other synthetic polyolefins may be utilized as well . examples of the synthetic hydrocarbon oils which may be utilized as additional synthetic fluid base oils for the formulations of preferred embodiments are preferably saturated . such oils may be prepared by polymerizing unsaturated monomers ( e . g ., ethylene ) and hydrogenating the resulting polymer prior to use to remove any residual unsaturation from the oil . examples of the saturated hydrocarbon and halo - substituted hydrocarbon oils include polyethylenes , polypropylenes , polybutylenes , propylene - isobutylene copolymers , chlorinated polybutylenes , poly ( 1 - hexenes ), poly ( 1 - octenes ), poly ( 1 - decenes ); polyphenyls such as biphenyls , terphenyls , alkylated polyphenyls , and the like ; alkylated diphenyl ethers and alkylated diphenyl sulfides and derivatives , including deuterated and hydrogenated derivatives . the hydrogenated polyolefins derived from alphaolefins such as ethylene , propylene , 1 - butene , and the like are especially preferred for use as additional synthetic base oils . in certain embodiments , however , it may be preferred to use a polyolefin derived from a branched chain monomer , for example , isobutylene . dibasic acid esters can be employed as base oils . polyol esters include molecules containing two or more alcohol moieties , such as trimethylolpropane , neopentylglycol , and pentaerythritol esters . synthetic polyol esters are the reaction product of a fatty acid derived from either animal or plant sources and a synthetic polyol . polyol esters have excellent thermal stability and generally resist hydrolysis and oxidation better than other base stocks . naturally occurring triglycerides and vegetable oils , as discussed above , are in the same chemical family as polyol esters . trimethylolpropane esters may include mono , di , and tri esters . neopentyl glycol esters may include mono and di esters . pentaerythritol esters include mono , di , tri , and tetra esters . dipentaerythritol esters may include up to six ester moieties . preferred esters are typically of those of long chain monobasic fatty acids . esters of c20 or higher acids can be employed , e . g ., gondoic acid , eicosadienoic acid , eicosatrienoic acid , eicosatetraenoic acid , eicosapentanoic acid , arachidic acid , arachidonic acid , behenic acid , erucic acid , docosapentanoic acid , docosahexanoic acid , or ligniceric acid , or esters of c18 or lower acids , e . g ., butyric acid , caproic acid , caprylic acid , capric acid , lauric acid , myristoleic acid , myristic acid , pentadecanoic acid , palmitic acid , palmitoleic acid , hexadecadienoic acid , hexadecatienoic acid , hexadecatetraenoic acid , margaric acid , margroleic acid , stearic acid , linoleic acid , octadecatetraenoic acid , vaccenic acid , or linolenic acid . in certain embodiments , it may be preferred to esterify pentaerythritol with a mixture of different acids . particularly preferred synthetic ester oils are the esters of trimethylol propane , trimethylol butane , trimethylol ethane , pentaerythritol and / or dipentaerythritol with one or more monocarboxylic acids containing from about 5 to 10 carbon atoms . polyol polyesters may be obtained by reacting various polyhydroxy compounds with carboxylic acids . when the carboxylic acids are dicarboxylic acids , monohydroxy compounds can be substituted for the polyols . for example , synthetic esters include the esters of dicarboxylic acids such as phthalic acid , succinic acid , alkyl succinic acid , alkenyl succinic acid , maleic acid , azelaic acid , suberic acid , sebacic acid , fumaric acid , adipic acid , linoleic acid dimer , malonic acid , alkyl malonic acid , alkenyl malonic acid , and the like . these dicarboxylic acids may be reacted with alcohols such as , for example , butanol , hexanol , dodecyl alcohol , 2 - ethylhexyl alcohol , and the like . specific examples of such esters include dibutyl adipate , di ( 2 - ethylhexyl ) sebacate , di - n - hexyl fumarate , dioctyl sebacate , diisooctyl azelate , diisodecyl azelate , dioctyl phthalate , didecyl phthalate , and the like . silicon - based oils including siloxanes , such as polyalkylsiloxane , polyarylsiloxane , polyalkoxysiloxane , and polyaryloxysiloxane oils and silicone oils may also be suitable for use as additional base oils . specific examples of some suitable polysiloxanes include methyl phenyl silicone , methyl tolyl silicone , methyl ethylphenyl silicone , ethyl phenyl silicone , propyl phenyl silicone , butyl phenyl silicone , and hexyl propylphenyl silicone . preferred silicon - based oils also include silicones such as alkyl phenyl silicones . preferred alkyl groups for alkyl phenyl silicones include aliphatic groups , e . g ., methyl , propyl , pentyl , hexyl , decyl , and the like ; alicyclic groups , e . g ., cyclohexyl , cyclopentyl , and the like ; aryl groups , e . g ., phenyl , naphthyl , and the like ; aralkyl groups ; and alkaryl groups , e . g ., tolyl , xylyl , and the like ; and halogenated , oxygen - containing , and nitrogen - containing organyl groups such as halogenated aryl groups , alkyl and aryl ether groups , aliphatic ester groups , organic acid groups , cyanoalkyl groups , and the like . the alkyl groups preferably contain from 1 to about 30 carbon atoms . alkyl phenyl silicones are particularly preferred . alkyl phenyl silicones are particularly preferred , especially those having a viscosity of from about 20 , 25 , 50 , 75 , 100 , 125 , or 150 cst to about 200 , 250 , 500 , 750 , 1000 , 1250 , 1500 , 1750 , or 2000 cst at 25 ° c . particularly preferred base oils for use in formulations of preferred embodiments include dow corning ® brand silicone fluids . silicone fluids from dow corning are high - performance , liquid lubricating materials that demonstrate excellent performance over a wide temperature range . dow corning ® 200 fluid , a dimethyl silicone fluid , is available in a range of viscosities ( 10 cst or lower to 1 , 000 cst or higher ). dow corning ® 510 fluid , a phenyl methyl silicone fluid , is available in 50 cst or lower to 30 , 000 cst or higher viscosities . it functions over a wide range of ambient temperatures ( from − 51 ° c . to 204 ° c .). dow corning ® 550 fluid is a 125 cs phenyl methyl silicone fluid . it resists oxidation and has a wide service temperature range ( from − 40 ° c . to 232 ° c .). dow corning ® 710 fluid is a 500 cs phenyl methyl silicone fluid with excellent heat stability and resistance to evaporation and oxidation , and functions over a wide temperature range ( from − 18 ° c . to 260 ° c .). dow corning ® fs - 1265 fluid is a fluorosilicon fluid with a viscosity of from 300 cst or less to 10 , 000 cst or more . it resists oxidation , harsh chemicals , fuels , and high temperatures , and functions over a temperature range of from − 40 ° c . to 204 ° c .). particularly preferred white , off - white , and translucent white base oils for use in formulations of preferred embodiments include dow corning ® brand silicone fluids . dow corning ® brand silicone fluids are available in light to heavy consistencies . for example , dow corning ® 7 release compound is a white - translucent light consistency dimethyl silicone compound with a service temperature range of − 40 ° c . to 204 ° c . and a specific gravity at 25 ° c . of 1 . 0 . dow corning ® 4 electrical insulating compound is a white - translucent medium consistency dimethyl silicone compound with a service temperature range of − 57 ° c . to 204 ° c . and a specific gravity at 25 ° c . of 1 . 0 . dow corning ® 111 valve lubricant and sealant is a white - translucent heavy consistency dimethyl silicone compound with a service temperature range of − 40 ° c . to 204 ° c . and a specific gravity at 25 ° c . of 1 . 0 . the fda has permitted dow corning ® 4 and 7 electrical insulating compounds and dow corning ® 111 valve lubricant and sealant for food contact and they are listed under nsf standard 51 for food processing , and nsf 51 for potable water applications . another white , off - white , or translucent white base oil for use in formulations of preferred embodiments is dow corning ® 112 high performance lube / sealant . dow corning ® 112 sealant is a white - translucent stiff grease - like silicone compound containing an inert amorphous silica filler in combination with selected polydimethyl silicone fluids . dow corning ® 112 has a specific gravity at 25 ° c . of 1 . 1 . serviceability from − 40 ° c . to 232 ° c ., excellent water and oil resistance , good resistance to most chemicals , and low volatility . instead of or in addition to a base oil , a grease can be employed in formulations of preferred embodiment . such greases typically comprise a base oil and a thickener . particularly preferred greases are designated as suitable for food contact or processing , or potable water applications . dow corning &# 39 ; s ® molycote ® bg 20 high performance synthetic grease is an example of a grease that can be used instead of or in addition to a base oil in formulations of preferred embodiments . molycote ® bg 20 high performance synthetic grease is a beige synthetic polyolester grease with lithium complex thickener . molycote ® bg 20 &# 39 ; s properties include a wide temperature range if − 45 ° c . to 182 ° c . polyethers suitable for use as base oils may include polyphenyl ether fluids , preferably those containing from 3 to 7 benzene rings and from 2 to 6 oxygen atoms , wherein the oxygen atoms link the benzene rings , which may be hydrocarbyl - substituted . the hydrocarbyl substituents are preferably free of unsaturated hydrocarbon groups . the preferred aliphatic substituents include saturated hydrocarbon groups containing from 1 to 6 carbon atoms , such as ethyl , propyl , butyl , and t - butyl groups . preferred aromatic substituents include aryl groups such as phenyl , tolyl , t - butyl phenyl , and alphacumyl . polyphenyl ethers consisting exclusively of chains of from 3 to 7 benzene rings with at least two oxygen atom joining the benzene rings exhibit superior thermal stability , for example , the polyphenyl ethers such as 1 -( p - methylphenoxy )- 4 - phenoxy benzene and 2 , 4 - diphenoxy - 1 - methyl benzene ; 4 - ring polyphenyl ethers such as bis [ p -( p - methylphenoxy ) phenyl ] ether and bis [ p -( p - t - butylphenoxy ) phenyl ] ether , and the like . polyalkylene glycols ( also referred to as polyalkylene oxides ) are polymers of alkylene oxides . polyalkylene oxides and derivatives thereof wherein the terminal hydroxyl groups have been modified by esterification , etherification , and the like , also constitute a class of synthetic lubricating oils that can be utilized as a component of the base oil . these oils include those prepared through polymerization of ethylene oxide and propylene oxide , the alkyl and aryl ethers of these polyoxyalkylene polymers such as methyl polyisopropylene glycol ether having an average molecular weight of about 1000 , diphenyl ether of polyethylene glycol having a molecular weight of about 500 to 1000 , and diethyl ether of polypropylene glycol having a molecular weight of about 1000 to about 1500 . polyalkylene glycols suitable for use in formulations of preferred embodiments include plurasafe ® brand silicone fluids from basf . the base fluid may contain as its sole component a single base oil or a mixture of two or more base oils ( e . g ., of different chemical compositions or same category but different characteristics , e . g ., different viscosities , viscosity indexes , molecular weights , produced by different manufacturing processes , and the like ). in certain embodiments , however , it may be preferred to combine one or more high viscosity polyalphaolefins with one or more other mineral or synthetic base fluids . the base oil ( s ) and / or base fluid ( s ) typically comprise from about 70 wt . % or less to about 95 wt . % or more of the repellent formulation , preferably from about 75 wt . % to about 90 wt . % of the repellent formulation . the base oil is thickened into a grease base by addition of a thickener . thickener systems that can be advantageously employed include fumed silica , hydrophobic fumed silica , modified clay , dye and pigment thickeners , thickeners such as carbon black , graphite , polytetrafluoroethylene ( ptfe ), polyurea , and the like . the thickener can be added to the base oil using methods conventionally employed for preparing greases . generally , a base oil is provided , or a blend of base oils is prepared , and then the thickener is added to the base oil with mixing . silica gel is advantageously employed as it can increase the adhesiveness of the composition , thereby increasing the time of contact between the composition and the target rodent . silica gel is a granular , vitreous , highly porous form of silica . silica gel is commonly employed as a food grade desiccant . fumed silica , also known as pyrogenic silica , is a non - crystalline , fine - grain , low density and high surface area silica . fumed silica has a very strong thickening effect . primary particle size is 5 - 50 nm . the particles are non - porous and have a surface of 50 - 600 m 2 / g . density 2 . 2 g / cm 3 . fumed silica is made from flame pyrolysis of silicon tetrachloride or from quartz sand vaporized in a 3000 ° c . electric arc . fumed silica serves as a universal thickening agent , a thickener in milkshakes , and an anticaking agent in powdered foods . like silica gel , it serves as a desiccant . hydrophobic silica is a silica that has hydrophobic groups chemically bonded to the surface . hydrophobic silica can be made both from fumed and precipitated silica . the hydrophobic groups are normally alkyl or polydimethylsiloxane chains . the toxicological properties of silicas make them desirable thickening agents for the grease bases of preferred embodiments . fumed silicas suitable for use in formulations of preferred embodiments include aerosil 972 ™ manufactured by degussa corporation of orange , calif . or cabosil ts720 ™ manufactured by cabot corporation of boston , mass . aerosil 972 ™ is a hydrophobic fumed silica after treated with dimethyldichlorosilane . aerosil 972 ™ has a specific surface area of about 110 ± 20 m 2 / g , an approximate tamped density of about 50 g / l , and an average primary particle size of about 16 nm . it is preferable that when using aerosil 972 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. cabosil ts720 ™ is an insoluble white powder having a density of 2 . 2 g / cm 3 at 20 ° c . it is preferable that when using cabosil ts720 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. soap thickeners prepared by combining one or more fatty acids with one or more metal metal - containing components , e . g ., alkali or alkaline earth metal hydroxides , oxide and / or isopropoxides can also be advantageously employed as low cost , low toxicity additives . when a soap thickener is employed , the soap itself can be added to the base oil , or the reactants yielding the soap can be added separately to the base oil and allowed to react . in certain embodiments it can be desirable to alter the mixing process and / or parameters , or the sequence of addition of components , as is appreciated by one skilled in the art . for example , the reactants yielding the soap may be added separately to different base oil components , or different portions of the base oil blend , then the partially additized blend components may be mixed . when reactants yielding soap are employed , the reactants are typically added to the base oil blend , and the mixture is heated to saponify the grease . after the saponification reaction reaches a sufficient degree of completion , the grease is allowed to cool and the remaining additives are incorporated into the grease . preferred metal containing components include alkaline earth metal hydroxides , such as calcium hydroxide , which exhibits good water resistance . preferred fatty acids generally include those obtained from vegetable sources which contain from 10 to 22 carbon atoms . a single fatty acid or two or more fatty acids can be employed . fatty acids containing 18 carbon atoms are particularly preferred , especially stearic acid or 12 - hydroxy stearic acid ; however , other fatty acids can advantageously be employed , including but not limited to gondoic acid , eicosadienoic acid , eicosatrienoic acid , eicosatetraenoic acid , eicosapentanoic acid , arachidic acid , arachidonic acid , behenic acid , erucic acid , docosapentanoic acid , docosahexanoic acid , ligniceric acid , butyric acid , caproic acid , caprylic acid , capric acid , lauric acid , myristoleic acid , myristic acid , pentadecanoic acid , palmitic acid , palmitoleic acid , hexadecadienoic acid , hexadecatienoic acid , hexadecatetraenoic acid , margaric acid , margroleic acid , stearic acid , linoleic acid , octadecatetraenoic acid , vaccenic acid , and linolenic acid . one or more or more additional fatty acids may be employed to provide a more complex structure to the grease with increased cross - linking . although , higher molecular weight acids can provide additional lubricity to the grease , they are generally inferior as additional complexing acids . accordingly , one or more lower molecular weight fatty acids are used , preferably fatty acids containing from 2 to 10 carbon atoms , so as to provide greater cross - linking . especially preferred is acetic acid . to form the grease , the preferred alkaline earth ( e . g ., calcium ) oxide or hydroxide is added to the base oil blend . then , the fatty acids are added . the saponification reaction occurs upon heating the metal and fatty acids to a suitable temperature , typically about 175 ° c . the elevated temperature is then maintained , e . g ., for about 20 minutes or until the reaction proceeds to a satisfactory degree of completion . the mixture is preferably stirred , either continuously or intermittently , during heating . after the resulting soap - containing mixture is cooled , the remaining additives are added . the preferred metal complex soap thickener is a calcium complex in which the fatty acid complex is formed by the reaction of calcium hydroxide with several organic acids including acetic acid and 12 - hydroxystearic acid . the thickener ( s ) typically comprise from about 3 wt . % or less to 20 wt . % or more of the repellent formulation , preferably from about 4 wt . % to about 15 wt . % of the repellent formulation . the base greases of preferred embodiments may contain various polymers which function as tackifying agents . the addition of polymers may add to the viscosity and also to the adhesive qualities of the composition so that the composition can be applied to both horizontal and vertical surfaces . the ability to apply the composition to vertical surfaces enhances its utility because this increases the potential number of surfaces on which the composition may be used . useful tackifying agents include polymers like polybutene , polybutylene ( e . g ., polyisobutylene ), olefin copolymers , methacrylates , polyalphaolefins , and ethylene / propylene copolymers . food grade tackifiers are particularly preferred . tackifiers are generally provided in a suitable carrier , e . g ., paraffinic oil , naphthenic oil , while oil , or polyalphaolefin , and can include polyisobutylene in white mineral oil and have a viscosity of , e . g ., 2500 cst @ 100 ° c . or more ( e . g ., 3000 or 4000 cst @ 100 ° c .). the tackifier ( s ) typically comprise from about 2 . 0 wt . % or less to 20 wt . or more of the repellent formulation , preferably from about 3 wt . % to about 15 wt . % of the repellent formulation . other additives as are known in the lubricating arts may also be employed in the base greases of preferred embodiments . these include metal deactivators such as benzotriazole , substituted benzotriazole and 2 , 5 - di - mercapto - 1 , 3 , 4 - thiodiazole , which protect ferrous and nonferrous metal surfaces from corrosion . the base grease can also include conventional fillers , thickeners , thixotropic agents , antioxidants , corrosion prevention materials , and the like , depending upon the surface to which the repellent formulation is to be applied . solid lubricant components can be added at any suitable step in the grease manufacturing process , for example , when the thickener is added if the thickener is not a metal soap type which is formed by a chemical reaction in the oil . solid additives are preferably added to the grease with sufficient mixing , working , homogenizing , or the like , to ensure a complete , uniform , and thorough dispersion of solid particles . preferably , solid lubricants are added to the grease after the thickener is formed or added . various compounds known for use as oxidation inhibitors can be utilized in grease formulations of various embodiments . these include phenolic antioxidants , amine antioxidants , sulfurized phenolic compounds , and organic phosphites , among others . is it especially preferred that the antioxidant includes predominately or entirely either a hindered phenol antioxidant such as 2 , 6 - di - tert - butylphenol , 4 - methyl - 2 , 6 - di - tert - butylphenol , 2 , 4 - dimethyl - 6 - tert - butylphenol , 4 , 4 ′- methylenebis ( 2 , 6 - di - tert - butylphenol ), and mixed methylene bridged polyalkyl phenols , or an aromatic amine antioxidant such as the cycloalkyl - di - lower alkyl amines ( n , n ′- di - lower - alkyl phenylenediamines , such as n , n ′- di - sec - butyl - p - phenylenediamine , and its analogs ), and phenylenediamines , or a combination of one or more such phenolic antioxidants with one or more such amine antioxidants . a variety of corrosion inhibitors are also available for use in the grease formulations of various embodiments , including dimer and trimer acids , such as are produced from tall oil fatty acids , oleic acid , linoleic acid , and the like . other useful types of corrosion inhibitors are the alkenyl succinic acid and alkenyl succinic anhydride corrosion inhibitors such as , for example , tetrapropenylsuccinic acid , tetrapropenylsuccinic anhydride , tetradecenylsuccinic acid , tetradecenylsuccinic anhydride , hexadecenylsuccinic acid , hexadecenylsuccinic anhydride , and the like . also useful are the half esters of alkenyl succinic acids having 8 to 24 carbon atoms in the alkenyl group with alcohols such as the polyglycols . also useful are the aminosuccinic acids or derivatives . preferably a dialkyl ester of an aminosuccinic acid is used containing an alkyl group containing 15 - 20 carbon atoms or an acyl group which is derived from a saturated or unsaturated carboxylic acid containing 2 - 10 carbon atoms . most preferred is a dialkylester of an aminosuccinic acid . the various additives that can be included in the base greases of preferred embodiments are used in conventional amounts as are known in the grease industry . the amounts used in any particular case are preferably sufficient to provide the desired functional property to the grease composition , and such amounts are well known to those skilled in the art . the repellent formulations of preferred embodiments typically include a carrier agent , an activator agent , a repellent , a thickener , and a tackifying agent , as described above . in some embodiments , the activator agent , the carrier agent , and / or the tackifying agent may be omitted from the composition . preferably , the repellent formulation utilizes a white oil . white oils include any of various highly refined , colorless mineral or hydrocarbon oils of low volatility and a wide range of viscosities . they are typically used for lubrication of food and textile machinery and as medicinal and mineral oils . white oils include technical white oils such as usp or technical grade white oil , and can be used as a carrier agent / base oil in formulations of preferred embodiments . in such embodiments , the white oil is typically present at from about 78 . 0 to 88 . 0 wt . % in the formulation , and more desirably at about 83 . 9 wt . %. in other embodiments , white oil is desirably present at about 82 . 9 wt . % in the formulation . the repellent formulation preferably utilizes fumed silica , such as aerosil 972 ™ manufactured by degussa corporation of orange , calif . or cabosil ts720 ™ manufactured by cabot corporation of boston , mass . when using aerosil 972 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. when using cabosil ts720 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. the repellent composition preferably includes one or more tackifying polymers , preferably an olefin copolymer , polybutene , polyalphaolefin , or polymethacrylate of suitable viscosity . the tackifying agent is preferably present in the formulation in total at from 5 . 0 to 10 . 0 wt . %, and more desirably at about 5 . 0 wt . %. the repellent composition preferably includes an activator agent such as denatured ethanol . when using denatured ethanol , it is preferably present in the formulation in total at from 1 . 0 to 2 . 0 wt . %, and more desirably at about 1 . 0 part by weight . the repellent additive in the repellent composition is preferably natural capsaicin . when using natural capsaicin , it is preferably present in the formulation in total at from 0 . 025 to 1 . 00 wt . %, and more desirably at about 0 . 075 wt . %. preferably , the repellent compositions of preferred embodiments contain no menthol , peppermint oil , citronella , or other components that repel rodents by emitting an odor that rodents find offensive . the repellent composition may preferably include one or more tackifying polymers , preferably an olefin copolymer , polybutene , polyalphaolefin , or polymethacrylate of suitable viscosity . in some embodiments , the repellent formulation utilizes two different tackifiers , preferably polyalphaolefin and an olefin copolymer . in such a preferred embodiment , the tackifiers are preferably present in the formulation in total at from about 0 . 05 wt . % to about 10 . 0 wt . %. more preferably polyalphaolefin is present in the formulation at about 5 . 0 wt . % and an olefin copolymer is present in the formulation at about 1 . 0 wt . %. in preferred embodiments where polyalphaolefin is present in the formulation at about 5 . 0 wt . % and an olefin copolymer is present in the formulation at about 1 . 0 wt . %, the white oil is preferably present at about 82 . 9 wt . %. although the repellent compositions of preferred embodiments can be made by various methods as will be appreciated by one of skill in the art , the following is an exemplary method for use in preparing a repellent composition of a preferred embodiment comprising technical grade white oil , denatured ethanol , fumed silica , tackifying polymer , and capsaicin . in a first step , the full amount of technical grade white oil is added to a mixer . in a next step , denatured ethanol and fumed silica are sequentially or concurrently added to the white oil while mixing . next , the mixture is heated up to about 120 ° f . ( 49 ° c .). the mixture is maintained at this temperature while mixing until the fumed silica is completely or nearly completely dispersed and the mixture clear . thereafter , the polymer tackifier is added while mixing and maintaining the mixture at about 120 ° f . ( 49 ° c .). mixing at about 120 ° f . ( 49 ° c .) is continued until the polymer is completely or nearly completely dissolved and the mixed product is clear . then , the capsaicin is completely mixed in , and the product is cooled down to about 120 ° f . ( 27 ° c .). the repellent composition thus prepared is stable at ambient temperatures in environments supporting rodents . the examples below list different exemplary formulations for the rodent deterrent composition of preferred embodiments . in the examples below , the column “ component ” lists exemplary ingredients for the composition , the column “ mass %” lists desirable parts by weight of the ingredients in the composition and the column “ range mass %” lists exemplary parts by weight of the ingredients . the asterisk “*” indicates that the base oil component is added to bring the total mass % up to 100 %, after the other ingredients are accounted for . the repellent compositions of preferred compositions can be applied to surfaces using similar techniques to application of caulk . a line , bead , or strip of the repellent composition is applied to a surface in an area where rodents are to be repelled . when a rodent contacts the repellent composition , e . g ., by stepping on it , the repellent composition is transferred to the rodent &# 39 ; s paw . when the rodent attempts to remove the repellent composition , e . g ., by eating it off , the repellent additive in the repellent composition produces an unpleasant taste , thereby discouraging the rodent from contacting the repellent composition again ( e . g ., attempting to cross a strip of the repellent composition ). the repellent compositions of preferred embodiments can offer numerous advantages over conventional repellent compositions . the repellent compositions of preferred embodiments can be odor free or low odor , enabling them to be employed in areas such as restaurants , stores , and homes where odors would otherwise be offensive or unacceptable . the repellent compositions of preferred embodiments are non - toxic and environmentally friendly , making them acceptable for use near soil or water sources ( rivers , streams , canals , water features , ground water , etc . ), or areas inhabited by children , pets ( e . g ., dogs , cats ) or non - pest native species ( e . g ., native birds , mammals , reptiles , amphibians , fish ). the repellent compositions of preferred embodiments are tacky , enabling them to remain in place when applied to non - horizontal surfaces ( e . g ., slanting , vertical , or inverted ), and to persist on rodents &# 39 ; paws when contacted , which increases the repellent effect when the rodents groom themselves to remove the repellent composition . the repellent compositions of preferred embodiments are also water resistant , such that they can remain in place and retain their repellency when exposed to the elements ( rain , snow ). the repellent compositions of preferred embodiments are stable and maintain good viscosity / tackiness when exposed to hot or cold ambient conditions . all references cited herein are incorporated herein by reference in their entirety . to the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification , the specification is intended to supersede and / or take precedence over any such contradictory material . unless otherwise defined , all terms ( including technical and scientific terms ) are to be given their ordinary and customary meaning to a person of ordinary skill in the art , and are not to be limited to a special or customized meaning unless expressly so defined herein . terms and phrases used in this application , and variations thereof , especially in the appended claims , unless otherwise expressly stated , should be construed as open ended as opposed to limiting . as examples of the foregoing , the term ‘ including ’ should be read to mean ‘ including , without limitation ,’ ‘ including but not limited to ,’ or the like ; the term ‘ comprising ’ as used herein is synonymous with ‘ including ,’ ‘ containing ,’ or ‘ characterized by ,’ and is inclusive or open - ended and does not exclude additional , unrecited elements or method steps ; the term ‘ having ’ should be interpreted as ‘ having at least ;’ the term ‘ includes ’ should be interpreted as ‘ includes but is not limited to ;’ the term ‘ example ’ is used to provide exemplary instances of the item in discussion , not an exhaustive or limiting list thereof ; adjectives such as ‘ known ’, ‘ normal ’, ‘ standard ’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time , but instead should be read to encompass known , normal , or standard technologies that may be available or known now or at any time in the future ; and use of terms like ‘ preferably ,’ ‘ preferred ,’ ‘ desired ,’ or ‘ desirable ,’ and words of similar meaning should not be understood as implying that certain features are critical , essential , or even important to the structure or function of the invention , but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention . likewise , a group of items linked with the conjunction ‘ and ’ should not be read as requiring that each and every one of those items be present in the grouping , but rather should be read as ‘ and / or ’ unless expressly stated otherwise . similarly , a group of items linked with the conjunction ‘ or ’ should not be read as requiring mutual exclusivity among that group , but rather should be read as ‘ and / or ’ unless expressly stated otherwise . with respect to the use of substantially any plural and / or singular terms herein , those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application . the various singular / plural permutations may be expressly set forth herein for sake of clarity . it will be further understood by those within the art that if a specific number of an introduced claim recitation is intended , such an intent will be explicitly recited in the claim , and in the absence of such recitation no such intent is present . for example , as an aid to understanding , the following appended claims may contain usage of the introductory phrases “ at least one ” and “ one or more ” to introduce claim recitations . however , the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “ a ” or “ an ” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation , even when the same claim includes the introductory phrases “ one or more ” or “ at least one ” and indefinite articles such as “ a ” or “ an ” ( e . g ., “ a ” and / or “ an ” should typically be interpreted to mean “ at least one ” or “ one or more ”); the same holds true for the use of definite articles used to introduce claim recitations . in addition , even if a specific number of an introduced claim recitation is explicitly recited , those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number ( e . g ., the bare recitation of “ two recitations ,” without other modifiers , typically means at least two recitations , or two or more recitations ). furthermore , in those instances where a convention analogous to “ at least one of a , b , and c , etc .” is used , in general such a construction is intended in the sense one having skill in the art would understand the convention ( e . g ., “ a system having at least one of a , b , and c ” would include but not be limited to systems that have a alone , b alone , c alone , a and b together , a and c together , b and c together , and / or a , b , and c together , etc .). in those instances where a convention analogous to “ at least one of a , b , or c , etc .” is used , in general such a construction is intended in the sense one having skill in the art would understand the convention ( e . g ., “ a system having at least one of a , b , or c ” would include but not be limited to systems that have a alone , b alone , c alone , a and b together , a and c together , b and c together , and / or a , b , and c together , etc .). it will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms , whether in the description , claims , or drawings , should be understood to contemplate the possibilities of including one of the terms , either of the terms , or both terms . for example , the phrase “ a or b ” will be understood to include the possibilities of “ a ” or “ b ” or “ a and b .” all numbers expressing quantities of ingredients , reaction conditions , and so forth used in the specification are to be understood as being modified in all instances by the term ‘ about .’ accordingly , unless indicated to the contrary , the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained . at the very least , and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application , each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches . furthermore , although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding , it is apparent to those skilled in the art that certain changes and modifications may be practiced . therefore , the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein , but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention .

grease - like compositions are provided for repelling rodents . the compositions utilize nontoxic mineral , synthetic , or vegetable oil based gels containing silica , clay , urea , polytetrafluoroethylene , or metallic soap thickeners and capsaicin .

memtrax test consists of specifications for tests and games ( the test ) designed to measure cognition . the specific aspect of cognition assessed by the test is retentive memory , the mental function that most specifically deteriorates with increasing age and that declines in the time before and during a diagnosis of dementia . the test also assesses related aspects of cognition . the test is a brief slide show , administered by a computer ( in any format , computer - program , or platform ) which displays a series of visual image stimuli ( pictures or words ) and records the performance of tested subjects on each image . a major aspect of cognition is memory . memory involves the retention of perceived information , whether it is for an immediate circumstance ( attentive memory ), preserved for an indefinite period of time after the immediate circumstance has changed ( retentive memory ), or maintained for long periods of time , days , weeks , months , after the information was perceived ( persistent memory ). the earliest sign of alzheimer &# 39 ; s disease is generally considered an impairment of retentive memory , and this type of memory is also known to deteriorate substantially with the normal aging process . 1 ) retentive memory — information retention after distraction ( minutes to hours , short - term memory , declarative memory ). 3 ) perceptual attention — attention to information details , which may include discriminating differences between pictures or words . 4 ) recognition reaction time — time to perceive an item of information and react according to the instructions of the test . 5 ) attentive memory — information retention before distraction ( for the duration of attention without distraction , e . g ., before an intervening stimulus , immediate memory , working memory ). 6 ) persistent memory — information that is maintained for long periods of time ( days to years , long - term memory , semantic memory ) the test displays a series of images and a portion of the images are repeated . the novel aspect of the test is that duplicated images are interspersed with images being shown for the first time . as the series advances , the individual being tested must make a binary decision when each image appears , whether the image is a target ( e . g ., a repeated image that is recognized ) or a non - target ( e . g ., a new image to be observed and retained ). memory performance is reflected in the percent of previously shown pictures that are recognized . validity and attention are indicated by the percent of pictures shown for the first time which are perceived as being new images . recognition reaction time can be measured . images are selected to test specific aspects of perception and memory and may be pictures or words . the attributes of the images ( e . g ., nameable , memorable ) can be varied to assess a broad range of cognitive abilities . the difficulty of the test may be adjusted to test retentive memory across a broad range of ability and with narrow precision . variations of the test can more specifically assess general attention , perceptual attention , attentive memory , and persistent memory . the memtrax memory test has particular utility to detect memory dysfunction in subjects otherwise appearing normal that have very early alzheimer &# 39 ; s disease or other related types of dementia . method to assess retentive memory — memtrax memory test the memtrax memory test is a method to assess retentive memory . the correct response of a subject which is examined is an indication that a particular image on a slide is a repeat of an image from a prior slide . the indication is most simply a press of a button , usually either the space bar on the computer keyboard or a touch of a touch sensitive screen as on a mobile phone . the indication may also be pressing one of two buttons , one to indicate recognition of the picture , one to indicate non - recognition of the picture . other types of overt behavior may also be used as indicators of response , including any movement or vocalization . performance is tallied as correct recognitions ( percent correct indicates retentive memory function ) and correct rejections ( percent non - responses or non - recognition indicators to initial presentations indicates level of perceptual attention to the stimuli and the validity of the memory assessment value ). signal detection theory provides measures d ′ which is an estimate of discrimination between non - target and target items , beta which an estimate of the tendency to be more likely to respond to a target than a non - target , and c which is a measure of the tendency to respond as opposed to not respond ( more independent of the d ′ measure than beta ). receiver operator characteristic analysis uses sensitivity and specificity measures to determine how much information is provided by a test given a range of cut - offs for making a particular decision . item response theory provides information about the performance of individual test items with respect to difficulty , discriminability and goodness - of - fit , with an established method to use this information to estimate a subject &# 39 ; s level of function ( as used by the scholastic aptitude test and iq tests ). neural network model analyzes each item for its weighted relationship to the outcome measure in the context of all of the other items . reaction time can also be measured . measurement of the reaction time to a response to a repeated picture indicates how quickly the subject is able to process , perceive , and recognize the information as a repeated item . if measurement is made of reaction time to new pictures , the reaction time indicates the time which the individual processes and perceives information and makes an attentive decision that the information has not been perceived previously during the test . another way that the test can be administered is by showing slides to an audience . audience members can respond to repeated slides by indicating that a numbered slide is a repeat of a previously shown image . the audience member can make this indication either by marking a numbered sheet ( attached paper ) or by pushing a button on a “ polling transmitter ”. the test may contain any number of images , but works well with as few as 40 slides and 15 unique pictures . a second administration with a different set of stimuli in a different order can be used to confirm or further specify the levels of the various aspects of memory function . alternatively , a longer test can be administered in which hundreds of slides are shown , with repeated slides interspersed . between the initial presentation of an image and the repetition of the image , the test must contain a minimum of one intervening images , usually 5 to 20 images , and possibly over 200 images . images may be repeated additional times , providing some items easier to recognize for more impaired and older individuals , so that performance in impaired ranges can be precisely assessed . 1 . a variable n - back design memory test for a series of stimulus presentations . for testing of retentive memory , n must be at least 2 , possibly over 20 , and is variable , with an average of at least 5 . 2 . this n - back design memory test can use photographs of objects and other images . 3 . the specific photographs and electronic images dedicated to this test . 4 . the specific images and photographs include , but are not limited to , representations of nameable and unnameable objects in the environment , scenes of any kind , line - drawings , abstract representations , text , and combinations of these . the specific images and photographs extend to faces ( male and / or female ), words ( nouns , verbs , etc ., abstract , concrete , simple , complex ) and line drawings which vary from concrete , nameable to abstract and un - nameable . 5 . the duration of a single test is from 30 seconds to 30 minutes . optimal implementation is 3 minutes for elderly individuals . the test has a multitude of similar versions , so that the test can easily be repeated several times without the individual seeing repeated stimuli . 6 . in the n - back design , images are shown for an initial presentation and then are subsequently shown later in the series to see if the subject recalls having seen the image before in the series . the subject may respond with a simple button ( bar ) press , for either recognition or non - recognition , and other buttons may be used to discriminate these response options . 8 . scoring of this test is percent correct = true positive /( true positives + false negatives ) and percent new identification = true negatives /( true negative + false positive ). reaction time is a performance measure . other scoring methods include use of item response theory , receiver - operator characteristic theory , and neural - network analysis , which can enhance the precision and stability of the test results , both for assessing memory in younger individuals through a continuum of such measures to the purpose of detecting early alzheimer &# 39 ; s disease . another analytic method includes signal detection theory . 9 . many memory tests have been developed and have been widely used . however , this test is unique in its design for automatic administration and scoring as a brief test , using interspersed new and repeated images and a specified order of display . 10 . the test can assess a broad range of memory function . different versions of the test may use longer display times ( 3 to 10 seconds ) and specially selected , predominantly easily discriminated images , for the purpose of detecting mild memory problems in elderly individuals that are in the early stages of developing alzheimer &# 39 ; s disease . alternatively , images which are more difficult shown for shorter display times ( i . e ., under 3 seconds ) may be used to measure high levels of memory function , particularly in younger individuals . 11 . the different versions of the memtrax memory test may be directly compared due to the pre - tested comparability of various sub - categories of item bundles , so that an unlimited number of test versions can be available , while any version is able to reliably estimate an individual &# 39 ; s memory on the specified continuum of retentive memory function . the memory function of an individual may be evaluated precisely over time and evaluated for small but significant changes . 12 . the test is surprisingly well - received by subjects , who nearly unanimously agree that the test is fun to take ( potentially more than cross - word puzzles or sadokus ). accordingly , subjects are willing to take the test repeatedly over a period of time , which increases the likelihood that a subject will take the test enough times for a significant change to be detected if it occurs . 13 . the images used in the memtrax memory test are unique in their grouping and selection for testing a broad range of memory function precisely . 14 . the order with which the images are displayed is unique for measuring retentive memory and establishing validity of the measurement . the memtrax memory test involves looking at a number of images and indicating which are duplicated . in the memtrax memory test , correct responses are defined before the slide show begins . the instructions are : “( number ) images will be shown . carefully look at each image . when you see an image for the first time , look at it carefully and try to remember it . if you see an image that you have seen before , respond to indicate that you recognize the image .” the administration of the test by computer to an individual requires the following : 1 ) a slide or text - file which specifies the directions for performing the test which will be shown to the test taker ( the subject taking the test ). 2 ) a file with the identifiers of the specific images to be shown . 3 ) a file which contains the order in which images should be shown . 5 ) the database that will store and the system to analyze the test data . memory function generally deteriorates with age , and memory impairments are a commonly unrecognized symptom of dementia . the objective was to characterize an audience - based memory test suitable for simultaneous screening of a large number of individuals . referring to fig1 the test can also be administered as a slide show ( e . g ., microsoft powerpoint ), with the pictures and picture orders pre - established , each image shown for 5 seconds automatically , for which subject performances in an audience can be assessed either by a pencil and paper ( e . g ., audience members indicating the number of a slide which they think is a repeat ) and by audience voting electronic technology , where audience members indicate if they think a picture is repeated , and the data for each individual &# 39 ; s performance is stored in the administering computer &# 39 ; s memory ( e . g ., turning point technologies ). the test was developed to assess recognition memory in audiences using a slide - show with 50 images , of which 25 are repeated . audience members responded by recording if an image was a repetition . in test administrations to over 1050 participants , 868 individuals aged 40 - 97 years provided complete data . recognition memory performance as measured by discriminability ( d ′) showed a progressive , exponential decline with age and a progressive increase in variability . individuals with low levels of education had lower scores than those with more education . gender showed no effect . this audience - based memory test was sensitive to effects of both age and education . such memory tests represent a practical approach to screen for early dementia and further development of this type of test is warranted . one critical issue is to define suitable cut - points for memory screen failure , since the same value is not appropriate for both young and old individuals . the cut - point should also reflect cost - worthiness of screening relative to age . memory impairment is often the most disabling feature of many pathological processes including neurodegenerative diseases , such as alzheimer &# 39 ; s disease ( ad ), stroke , etc . ( mesulam , 2000 ; newman et al ., 2001 ). epidemiological studies indicate that 5 % to 15 % of adults aged 70 and older exhibit signs of dementia , and memory impairment is a core feature of dementia ( hy & amp ; keller , 2000 ). despite widespread understanding of the significance of memory disorders , they often go unrecognized ( ashford et al ., 2007 ; callahan , hendrie , & amp ; tierney , 1995 ; finkel , 2003 ; ross et al ., 1997 ; sternberg , wolfson , & amp ; baumgarten , 2000 ; valcour , masaki , curb , & amp ; blanchette , 2000 ). several factors interfere with the detection of memory impairment associated with dementia , including a failure to screen , avoidance of this difficult problem by affected individuals and their health care providers , and under use of available testing methods . with changes in the delivery of health care , physicians must work under strict time constraints , leading many physicians to not routinely screen their patients for dementia ( lawrence et al ., 2003 ). one solution to the failure to detect memory impairments is to implement large - scale community memory screening . numerous approaches have been advocated to screen for memory problems in the community ( ashford & amp ; borson , 2008 ), and studies demonstrate that such programs can detect such individuals ( crews , harrison , keiser , & amp ; kunze , 2009 ; lawrence , davidoff , katt - lloyd , auerbach , & amp ; hennen , 2001 ; lawrence et al ., 2003 ). however , community screening programs are logistically difficult . currently available memory tests must be administered by a trained psychometrician in a one - to - one interaction in a confidential , quiet environment . such tests are expensive to administer and uncomfortable for the individuals taking the tests , leading to poor motivation for repeat testing . audience - based methods for testing large numbers of individuals simultaneously have not been widely developed as cognitive screening tools . however , such tests could be used to screen groups of people for memory problems in order to identify high - risk individuals for further evaluation . because memory impairment associated with dementia is commonly undiagnosed , a simple audience - based memory test designed to detect patients with early dementia would be valuable . a significant issue is how to assess the utility of an audience - based memory - screening test to detect early dementia . any population of older adults will contain individuals with diverse memory impairments . however , ad is the most common form of dementia , accounting for approximately two thirds of all dementia cases ( alzheimer &# 39 ; s association , 2010 ). the initial symptom of ad is typically a prominent amnesia in which the core symptom is difficulty in encoding new information ( ashford , kolm , colliver , bekian , & amp ; hsu , 1989 ; salmon & amp ; bondi , 1999 ). even when patients with early ad can perceive and immediately reproduce new information ( e . g ., repeating a series of words ), many neuropsychological studies have shown that the encoded information is easily lost under conditions of delay or interim distraction ( ashford & amp ; schmitt , 2001 ; elias et al ., 2000 ). this specific type of memory impairment in ad has led to the suggestion that ad pathology is specifically affecting basic mechanisms subserving neuroplasticity ( ashford & amp ; jarvik , 1985 ; teter & amp ; ashford , 2002 ). the process of memory encoding can be tested in several different ways . however , recognition memory tests are especially suitable for this purpose as they provide the target stimuli within the test framework . poor performance on a test of recognition memory provides strong evidence for an underlying encoding impairment , raising the possibility of an emerging alzheimer process ( lowndes & amp ; savage , 2007 ). in contrast to individuals with early ad , healthy adults can quickly and accurately encode massive amounts of new information . for example , landmark studies in the 1960s , 1970s , and 1980s demonstrated that healthy individuals perform well above chance on tests of recognition memory after viewing thousands of images for a few seconds each ( shepard , 1967 ; standing , 1973 ) and after viewing highly complex images ( wright , santiago , sands , kendrick , & amp ; cook , 1985 ). taken together with the encoding deficits found in early ad , these studies suggest that recognition memory tests should provide an effective screen for early ad . it is important to note that even though recognition memory has a huge capacity in healthy adults , it is nonetheless vulnerable to age - associated cognitive decline and increased age is associated with lower levels of performance ( grady et al ., 1995 ; schacter , cooper , & amp ; valdiserri , 1992 ). the aim of the current study was to measure ad - related memory performance in an audience population . for this purpose a variable n - back task ( vnbt ) was designed to detect memory problems in audience members . the vnbt was designed to be interesting in order to maintain audience attention . the current study sought to characterize this repeat detection task and evaluate age - related changes in recognition memory in order to determine normal performance ranges . the vnbt performance was expected to decrease with age . the vnbt was administered to over 1050 subjects between july , 2007 and june , 2008 at 26 sites ( community events , senior citizen centers , retirement living communities , etc . in san francisco bay area ). the audiences ranged from 9 to 142 individuals ( m = 39 ; sd 34 ; range 9 - 142 ). there were 940 subjects who appropriately performed the memory test , and of these participants , 868 individuals provided three specific demographic items of information : age , education , gender ( age : m = 75 . 9 years old ; sd 11 . 4 ; range 40 . 0 - 97 . 6 ; education : m = 16 . 1 years ; sd 2 . 52 ; range 6 - 21 ; gender : 68 . 7 % female ). in this group 86 . 6 % of the participants were reported being “ white ”. referring to fig2 participants were divided into six sub - groups according to age . education level declined by 1 . 3 years from 16 . 9 to 15 . 6 from the youngest to the oldest age group , though the variation did not reach statistical significance ( f 5 , 867 )= 1 . 93 , p & gt ; 0 . 05 ). all age groups contained more females than males . the groups varied significantly in the number of males to females ( n = 868 )= 12 . 9 , p = 0 . 02 ). the audience - based memory test was developed for testing recognition of easily remembered images . a “ variable - n - back task ” ( vnbt or repeat detection after multiple intervening stimuli ) format was used with numerous complex visual stimuli . generally the images were of discrete objects , though similar objects and difficult to name objects were used to avoid strict reliance on verbal cues , provide a challenge , and maintain the interest of the subjects ( the assortment of images was developed over several years ). this approach reduced the ceiling and floor effects ( only 8 % of the subjects had a perfect score ). although audience testing is used widely in educational assessment , such testing procedures are unusual in cognitive neuroscience or clinical research . accordingly , a primary aim of the study was to demonstrate that a recognition memory test can be administered to a large number of individuals simultaneously . twenty - five color images ( digital camera ) of manmade items were selected from a range of pictures . from these 25 items , a 50 - item recognition memory test was constructed in the following way . the 25 items were first arranged in a random sequence , with repeated images interspersed . fourteen of the items were one - time repeats and were inserted among the initial presentations of the test items . eleven of these items were shown for a third time , making recognition easier for subjects with impaired memories , providing more learning regarding a particular stimulus set , and allowing a comparison of first repeat recognition with second repeat recognition . the order was arranged such that there was an average inter - repetition - interval to the first repeat of 7 . 93 items ( range = 2 to 25 intervening items ). the eleven items that were second repeats were inserted into the test with an average inter - repetition interval of 21 . 1 , ( range = 10 to 36 items between the second and third presentations ). the eleven un - repeated test items served only as foils . the 50 items were numbered in sequence ( 1 - 50 ) with a large numeral in the top left hand corner and transferred to a powerpoint presentation . a second series of ten items was constructed using similar color images and was used as a practice test before the full test was given ( 5 images , 3 repeated once , 2 repeated a second time ). the need for such a practice test had become obvious during pilot work , which indicated that about 10 % of audience members could not follow the verbal instructions on the first try . participants were provided with a single sheet of paper . demographic information was collected on one side of the page ( age , education and race ) and the other side was used as an answer sheet for the recognition memory testing . the answer sheet had columns of numbers corresponding to the 10 slides of the practice - test and the 50 slides of the full test . a single circle was adjacent to each number on which a subject could indicate their response by filling in the circle , and the sheet was organized so that it could be scanned for data entry . testing at all sites adhered to a standard format , which began with a 20 - minute introductory talk , with slides about alzheimer &# 39 ; s disease and the signs of dementia . as part of the talk , all participants were offered the vnbt memory test , and the audience was told that participating in the memory test was optional , but that individual test scores would be provided anonymously at the end of the presentation . a statement outlining the subjects &# 39 ; rights was provided to all audience members on a written page and reviewed on a slide ( protocol approved by stanford university institutional review board ; no identifying information was collected , and therefore written consent was not required ). the same 10 - item practice test and 50 - item memory test were used at all sites ( 2 individuals publicly acknowledged taking the test before , but were not identified ). the vnbt was presented by projecting test items onto a screen using a laptop computer and projector . no effort was made to assess visual acuity of audience members or to assure adequate visibility from all parts of the room . however , the slides were generally easily seen from all vantage points of every room in which the test was administered . participants were told that they would see a series of 50 pictures one at a time for 5 s per image ( no inter - image interval ). they were instructed to look at each picture carefully and any time they thought an image was repeated they should note the image number shown in the top left hand corner and immediately mark the circle corresponding to that number on their answer sheet . no response was required if they thought an image was not repeated ( i . e ., novel ). the 10 - item practice test was given first . the presenter then addressed any questions relating to the test procedure , and then the full 50 - slide test was given ( 250 seconds ). after the test , the participants handed their papers to the rater to be scored . a rater scored each participant &# 39 ; s answer sheet , after which the scores were returned anonymously to each participant . if scores indicated a high probability of memory problems , a notation was made on the anonymous score sheet encouraging the subject to visit their clinician for further evaluation ( note that it has been reported that about 50 % of individuals receiving positive screens will accept such a referral — boustani et al ., 2005 ). results from the vnbt were analyzed using the correct and incorrect response information . the correct recognition rate ( hit rate ) and the false positive rate were used to determine a signal detection parameter , discriminability score ( d ′) ( green & amp ; swets , 1966 ). the correct recognition scores included responses to only the first repetition of the items ( n = 14 ), while the false positive applied to all 25 items . a standard correction was necessary when calculating d ′ values if the hit rate or the false positive rate were 100 % or 0 %. following macmillan and creelman ( macmillan & amp ; creelman , 1991 ), we converted 0 % to 1 /( 2n ) % and 100 % to 1 - 1 /( 2n ) % where n = the number of items . vnbt scores were analyzed in two ways . first , the relationship between individual test scores ( d ′) and age was examined using regression analysis . next , three - way univariate analysis of variance ( anova ) was used to examine the effect of age , education , and gender on errors and d ′ scores . to determine the effects of age on test performance , participants were divided into six age - groups ( see table 1 ). to determine the effects of education on test performance , participants were divided into five groups corresponding with major divisions of attainment in the u . s . educational system [ i . e ., & lt ; 12 years ( high school ), 13 - 15 years ( some college ), 16 years ( college completion ), 17 - 19 years ( masters degree ), and 20 - 21 years ( advanced degree )]. significant effects were investigated using the tukey studentized range / hsd post - hoc test procedure to identify homogenous subgroups . referring to fig3 increased age was associated with a significant increase in both miss rate and false alarm rate . the corresponding hit rates and correct rejection rates decreased with age as error rates accelerated in the oldest individuals with a non - linear relationship to age . data were analyzed using nonlinear exponential and logarithmic data transforms . error rates were found to be best explained using an exponential model ( i . e ., r2 of the regression was higher fitting an exponential transform than fitting a straight line ). regression analysis showed that miss rates increased significantly with age , exponential trend , f ( 1 , 866 )= 64 . 2 , p & lt ; 0 . 001 ; r2 = 0 . 069 , beta =− 0 . 02 , constant = 0 . 017 , and likewise , false alarm rates increased significantly with age , exponential trend , f ( 1 , 866 )= 129 . 3 , p & lt ; 0 . 001 ; r2 = 0 . 130 , beta =− 0 . 026 , constant = 0 . 01 . referring t fig4 there is a relationship between the individuals &# 39 ; d ′ values and their ages . regression analysis revealed that test d ′ scores decreased significantly with age , linear trend , f ( 1 , 867 )= 138 . 5 , p & lt ; 0 . 001 ; r2 = 0 . 138 , beta =− 0 . 026 , constant = 4 . 81 . data were also analyzed using an inversion of d ′ scores ( subtracted from the maximum value , 4 ), then regressed with an exponential model . this procedure explained the variance in the test scores better than a linear regression ( r2 linear trend = 0 . 138 , r2 exponential trend = 0 . 144 ), and regression analysis of the d ′ inversion scores revealed that they decreased significantly with age with greater explanation of the variance than the linear model described above , exponential trend ; f ( 1 , 867 )= 145 . 7 , p & lt ; 0 . 001 ; r2 = 0 . 144 , beta = 0 . 026 , constant =− 0 . 81 . the 3 - way anova revealed significant main effects of age ( f ( 5 , 811 )= 12 . 97 , p & lt ; 0 . 001 ) and education ( f ( 4 , 811 )= 5 . 46 , p & lt ; 0 . 001 ) on vnbt scores . no significant effects were found for gender ( f = 0 . 62 , p & gt ; 0 . 05 ). no significant interactions were found between age , education , and gender ( all fs & lt ; 1 . 2 , all ps & gt ; 0 . 05 ). for post - hoc test analysis , homogenous subsets were examined : six age groups by decade from 40 to 99 and the 5 education groups described above . additional separate analyses for age were performed using participants having more than 12 years of education since there was no significant education effect noted above 12 years . referring to fig5 in conjunction with fig6 anova results indicated that the vnbt was sensitive to age and was more difficult for older adults than younger adults . again , age - associated effects were investigated further by examining the error rates : the missed items and the false positive rates that contributed to the overall d ′ scores . increased age was associated with significant increases in both the miss rate ( f ( 5 , 867 )= 14 . 10 , p & lt ; 0 . 001 ) and the false alarm rate ( f ( 5 , 867 )= 13 . 96 , p & lt ; 0 . 001 ). test discriminability gradually but significantly declined numerically with increasing age . of note , the standard deviation of d ′ performance increased progressively with increasing age . although the six age groups did not differ significantly in number of years of education ( see participant section ), it was noted that the oldest group also had numerically the lowest average level of education . in order to verify that the effect of age on the vnbt performance was not confounded by educational level , participants in the group with the lowest level of education ( i . e ., & lt ; 12 yrs of education , n = 82 ) were excluded in a secondary analysis . results were essentially the same as when all participants were included . these data strongly indicate that test discriminability declined significantly with increasing age , f ( 5 , 785 )= 26 . 20 , p & lt ; 0 . 001 . again , increased age was associated with significant increases in both the miss rate , f ( 5 , 785 )= 11 . 48 , p & lt ; 0 . 001 , and the false alarm rate , f ( 5 , 785 )= 13 . 30 , p & lt ; 0 . 001 . the post - hoc subsets consistently showed exponential declines of performance with age . to confirm this effect , data were further analyzed with post - hoc tukey tests , which automatically correct for multiple comparisons . this analysis supported a significant decline in discriminability with increasing age . significant differences in test scores were found between the following groups of participants : 40 - 59 yrs , 50 - 69 yrs , and 70 - 89 yrs . the group older than 90 - 99 yrs of age was significantly worse than all other groups . further , the miss rate was not statistically different within the groups with age range 40 - 79 yrs or 50 - 89 yrs , but showed a significant increase in the age group 90 - 99 yrs relative to the younger groups . false alarm rates showed a similar pattern and were homogenous within each of the following age ranges : 40 - 69 yrs , 60 - 89 yrs , and 90 - 99 yrs . when the individuals ( n = 82 ) with education less than or equal to 12 years were removed , the post - hoc tests showed that test performance expressed as d ′ was similar across the age ranges 40 - 59 yrs , 50 - 69 yrs , 60 - 79 yrs , 70 - 89 yrs , and 90 - 99 yrs . the miss rates showed a similar pattern as for the previous analysis and were not statistically different within the age range 40 - 89 yrs , but the age range 90 - 99 yrs showed a significant decrease relative to the younger ages . false positive rates showed a similar pattern to the previous analyses and were homogenous within each of the following age ranges : 40 - 59 yrs , 50 - 69 yrs , 60 - 89 yrs , and 90 - 99 yrs . referring to fig7 there is an effect of education on test performance . test performance was lower for those with education levels of 12 years or less relative to those with more education . however , performance reached a plateau after 12 years of education above which no significant improvement in performance was seen . post - hoc tests showed that the test scores of the group with 12 yrs of education were significantly below all other groups ( i . e ., 13 - 21 yrs of education ). a one - way anova confirmed that the mean age did not vary significantly across the five education groups , f ( 4 , 867 )= 2 . 15 , p & gt ; 0 . 05 . however , the lowest educational group (& lt ; 12 yrs ) was also numerically the oldest ( 79 . 5 yrs old vs . group mean of 76 . 4 yrs old for those with over 12 yrs of education ), suggesting that levels of education vary systematically with age , and the poorer performance of the lower education group may actually be due to an age effect . in order to demonstrate that the effects of education on test score were associated with low levels of education ( i . e ., & lt ; 12 yrs of education ), the analysis was repeated using only individuals having more than 12 years of education . this anova showed that when individuals with low education were excluded , no significant effects of education on test performance were found , f ( 3 , 785 )= 1 . 65 , p & gt ; 0 . 05 . due to the repeat - detection format of the vnbt , participants were required to hold items in memory for a variable delay . referring to fig8 the inter - repetition - interval ranged from 2 to 25 images . this delay could disrupt recognition performance in two ways . first , as the number of intervening items increased , the time delay between the first and subsequent presentations of the same item could reduce recognition . second , as other test items were presented during the time delay , interference could build up across the delay . to explore these effects , a linear regression analysis was performed between the number of intervening items and percent correct . no significant relationship was found between the number of intervening items and recognition performance , f ( 1 , 8 )= 0 . 10 , p & gt ; 0 . 05 , r2 = 0 . 02 , beta = 0 . 12 , constant = 88 . 6 . the inter - repetition - interval had little overall effect on recognition and performance was maintained at a high level across repeated items ( average = 89 %). referring to fig9 another issue related to the repeat - detection format is that when test items are repeated multiple times , each subsequent presentation serves as a retrieval cue to reactivate and strengthen the memory representation of the information stored during earlier study ( thios & amp ; d &# 39 ; agostino , 1976 ). in the current test , eleven items were shown three times , and recognition performance did increase across repeated presentations . a paired t - test compared the mean percent correct between the first and second repetitions and showed that this difference ( 91 . 6 % vs . 95 . 5 % correct ) was statistically significant , t ( 867 )=− 10 . 30 , p & lt ; 0 . 005 . the results from this study of community audiences show that memory can be measured in a large group setting . the decreased memory with age found in this study is consistent with the general pattern of age - related memory loss ( crook , larrabee , & amp ; youngjohn , 1993 ; salthouse , 2009 ; schacter et al ., 1992 ; schaie , 2009 ). the present study focused on memory for complex information retained after a delay . in this test , memory storage was assessed using a recognition format . the experience presented here with this vnbt indicates that it is feasible to test audiences of older individuals for recognition of this type of information . this vnbt provides a strong assessment of the type of memory , frequently referred to as declarative memory ( squire , stark , & amp ; clark , 2004 ), which is impaired in alzheimer &# 39 ; s disease . impairments in declarative memory are often found to be among the first symptoms during the progression from normal aging to ad ( ashford , 2008 ; mickes et al ., 2007 ). the observation that declarative memory is selectively impaired early in ad is consistent with the finding that the neurodegeneration associated with ad begins in the medial temporal lobes ( braak & amp ; braak , 1996 ; delacourte , 1999 ), an area of the brain known to be important for encoding declarative memory ( squire & amp ; zola , 1996 ). further , several studies have suggested that the specific aspect of memory most commonly impaired in preclinical ad is a difficulty in encoding new information ( ashford et al ., 1989 and 1995 , and ashford , 2008 ; salmon & amp ; bondi , 1999 ). accordingly , this vnbt is well suited for measuring memory most relevant for the detection of the early memory difficulties found in ad patients . memory encoding can be tested in many different ways . recognition memory is particularly suitable for the assessment of encoding as the target stimuli are given as part of the test materials ( lowndes & amp ; savage , 2007 ). thus , recognition memory is less dependent on retrieval processes than are other commonly used testing formats such as free - and cued - recall . impairment in recognition memory is evidence for impairment in encoding which raises the possibility of an emerging alzheimer &# 39 ; s process ( wisdom , callahan , & amp ; hawkins , 2011 ). referring again to fig5 and fig6 from the testing in the population examined by this study , the vnbt appears to measure learning across a broad range of memory abilities . the analysis of the standard error of the mean ( sem ) and the multiple statistical analyses of education showed the sensitivity of the vnbt to age - related changes in memory . the vnbt test also showed a substantial increase in the standard deviation of each sample group ( sd ) with increasing age , and therefore , the vnbt provides limits for estimating the statistical variation that would be expected at various ages . after establishing the expected variation in memory function for a specific age , abnormal memory function levels can be defined for individuals of a specific age . in showing the capacity to assess memory deficits , the vnbt shows potential for detecting memory problems that are indicative of early signs dementia related to ad or other disorders and could be used to screen populations for dementia . there are specific issues that must be addressed when considering a test for screening . performance which are poorer than 2 sds below the mean for any population may be defined as abnormal . younger individuals ( e . g ., 40 - 50 years ) with performance levels which are poorer than 2 sds below the mean for this age group should definitely be considered to be of clinical concern . the problem is that low scores in older individuals may lie within 2 sds of the mean for their own older age group , and thus would not be “ abnormal ”. accordingly , a further consideration is below what absolute memory performance level might individuals of any age be at risk for having functional impairment ? these are two different approaches to determining cut - off levels that might be considered when using a test for screening purposes . however , when developing a screen for memory problems , it is necessary to consider cost - effectiveness ( including consideration of the pathological entity targeted for screening ). the decision about whether to screen an individual and the critical level for clinical concern depend on an analysis of many factors . the factors to consider for such an analysis include : incidence of disease ; the benefit of a true - positive screen ; the cost of a false - positive screen ; the incidence of the target problems in the population ; and the cost of the test ( ashford , 2008 ). a large factor in the decline of memory performance with age is likely to be the exponential increase of dementia incidence ( jorm & amp ; jolley , 1998 ). the value of using a particular level of test performance as a positive screen for an individual is approximated by a cost - worthiness analysis ( ashford , 2008 ). this approach is more difficult than a simple cut - off value for screening as described above , but is better for addressing clinical needs . the vnbt may be useful for detecting memory problems related to a variety of disorders . it is unclear whether the alterations in memory associated with early ad are different from those associated with age - related changes in memory . further , ad itself may be a complex interaction of at least two pathological processes ( amyloidopathy and tauopathy ), which have different time - courses ( morris et al ., 2010 ) and roles in different aspects of memory impairment that are otherwise considered “ normal aging ”. further , for proper screening of older individuals for cognitive impairment , more issues than just memory performance need to be considered . performance levels on a test like the vnbt could be monitored over time to detect indicative of a progressive cognitive disorder . an important issue for this vnbt is that the test is “ fun ” so that individuals may be willing to take the test repeatedly . changes over time should be assessed with respect to age - cohorts since normal performance levels and changes over time do vary according to age ( schaie , 2009 ). of note , the pattern of memory deterioration with age was best fit by an exponential model , suggesting that the underlying aging physiology follows the gompertz law , which states that the rate of system failures increases exponentially with age , in this case , the failure of mechanisms subserving the performance of this memory task ( ashford et al ., 2005 ). the vnbt is not affected by education level beyond high - school , probably because the memory processes targeted by this test require relatively simple object - information storage and processing , similar to what laboratory animals can be trained to do ( ashford , coburn , & amp ; fuster , 1998 ; mishkin & amp ; appenzeller , 1987 ; wright et al ., 1985 ). accordingly , education appears to have at most a minimal effect to confound assessment . subjects with a high - school education or less performed significantly less well , and there needs to be further study of individuals with low education on this test . another issue is how effective is the vnbt for assessing information encoding ? it is well established that there are significant declines in delayed - recall performance as individuals get older ( petersen , smith , kokmen , ivnik , & amp ; tangalos , 1992 ). much accumulated data indicate that these differences pertain to the fact that it takes older individuals longer to learn new information ( encoding ), but once learned , it is retained well over numerous delay intervals e . g ., ( craik , 1971 ; wickelgren , 1975 ). for example , if one compares the decline on recall scores from immediate to delayed recall , there are no statistically significant age - related differences ( petersen et al ., 1992 ). thus , if one allows healthy older subjects to learn material well ( i . e ., to the point where few errors are made ), they do not forget what they have learned more rapidly than the young . however , if healthy older subjects are not given the ability to learn material to the same level of proficiency as younger individuals , after a delay , less information on average will be retained by the older person ( albert , 1996 ). based on these prior findings , there is a question about whether older individuals may have performed better if the stimuli were presented for a longer period of time ( i . e ., more than 5 seconds per image ). widespread individualized testing of older subjects to screen for memory difficulties has not been practiced in the past . however , it is important to screen older people for memory problems that may indicate dementia ( ashford et al ., 2007 ). while screening tests are widely used throughout medicine , they are not yet recommended for dementia or alzheimer &# 39 ; s disease ( boustani et al ., 2005 ), and this lack of recommendation is based in large part on the lack of an easily administered and validated screening tool . the vnbt test presented here could be developed to serve this important need . clinically , any screening test must be seen as a preliminary assessment and definitely not a diagnostic test . however , the use of a test to screen for memory problems is appropriate ( ashford & amp ; borson , 2008 ). further , the vnbt approach offers a process that can be adapted for many settings and cultural milieus . in summary , a brief , easy to administer test for audience or large - population administration was found to have significant sensitivity to the changes in memory accompanying normal aging and could form the basis of a screening system to detect memory problems indicative of clinically significant memory disorders . since the vnbt measures the type of memory most affected in early ad , this test could serve as a practical approach to screen for early dementia associated with ad . further development and study of this type of testing and population assessment is warranted . this specification also provides for the presentation of visual stimuli ( pictures or words ) using a computer : a specific test is defined by its instructions which appear on a specific image file ( the “ instruction sheet ”). the stimuli are specifically referenced by a file ( the “ images index file ”, which is stored in a specific directory , e . g ., isets ) which indicates the address locations of the stimuli . the order of the stimuli is specified by a second file ( the “ order file ”, which is stored in a specific directory , e . g ., osets ). the stimuli are presented in the order specified by the “ order file ”. the duration of stimulus presentation is set for a specific test administration . ( option ) the stimulus presentation duration for an individual subject can be set for a specific individual and can be set to vary during the administration of the test according to the performance of the subject . responses may consist of a single indication from the subject taking the test and may include the press of a key ( e . g ., the “ space bar ”), any other similar response or measurable movement , or an utterance ( detected by a microphone ). ( option ) secondary responses may be instructed ( e . g ., for indicating that the subject decides that the displayed image is new ), using a different indicator ( e . g ., left - arrow for old versus right - arrow for new ), and reaction time to the second indicator may be measured as well . the computer detects the responses ( or lack of responses to a specific stimulus within a certain period of time ) and records the reaction time with millisecond precision for each stimulus presentation . the reaction time ( response data ) from each individual stimulus presentation is recorded for subsequent analysis . if a reaction is indicated within the observation window , the precise reaction time is recorded . a response is a reaction time within the observation window and is correct or not according to the instructions specified for the test . analysis of the data for presentation of summary results can occur immediately following the response ( or lack of response ) to the last stimulus or may be done at any later time . the platform administering the test ( computer program , slide - show ) may also be used to show tests for : simple reaction time ( the image set is a single content image and blank image , or a series of images , with the order set indicating that correct response is responding to the content image — or blank image , depending on the cognitive function being assessed ). choice reaction time ( the picture set contains two or more content images , and the order set indicates that a response is required only for a specific image or defined set of images . alternatively , if two types of response can be made , alternate responses may be instructed as correct for each of the images or defined sets of images . the “ super - simple ” reaction - time test ( a test developed by dr . ashford in 1986 that has the response instruction included in the stimulus itself , e . g ., an arrow indicating which way to respond .) n - back attentive memory ( 1 - back , 2 - back , or 3 - back : in this well - established testing paradigm , the correct response is to the repetition of an image shown 1 , 2 or 3 images before the most recent image . this paradigm is a test of attentive memory ”. continuous performance task ( in this well - established paradigm , a series of images is shown with a rare target image occurring which requires a response . this paradigm is a test of general attention ). these ancillary tests may be used for determining impairment of a variety of cognitive functions . in many patients with mild cognitive impairment or mild dementia , only retentive memory is impaired and other tests of cognition are preserved . a computerized test may include a tapping speed test , which can also help to determine if the subject &# 39 ; s movement functions are in the normal range . this information can be used in adjusting the interpretation of the reaction - times measured in the test , to distinguish the component of the speed related to movement function from the component related to cognitive function . images may be complex pictures that can be easily named or not named . images may also be words that are easily visualized as nameable objects or not easily visualized ( abstract , emotional , complex ). the working model for the memtrax memory test uses picture images in which there are 25 new pictures and 25 repeated pictures . for each set of pictures , there are 25 total pictures divided into 5 bundles of 5 pictures . all pictures are from real , color photographs , no black & amp ; white , no line drawings , no sketches . for these bundles , there are 5 categories that have been developed : there are sub - categories under each category , then groups of 5 pictures under each sub - category . among each group of 5 pictures , there are 2 items that are slightly similar , while the rest are easily perceived to be different . there are no people , no animals , and no writing / lettering , with a general avoidance of inanimate animals and statues . there are no emotion - generating pictures , such as food , expensive jewelry , weapons , sexual material , burning , gruesomeness and gore . there are no pictures that would immediately be recognized by more than 10 % of the population ( golden gate bridge , taj mahal , pyramids , etc .) ( note that these items could be used in alternative tests , but not a test focusing on objective , non - emotional memory . photographs of paintings or complex pictures are generally avoided , though they could be under the abstract bundle . unique cultural items are generally to be avoided , but can be selected for specific populations , following the same rules ( e . g ., chinese dishware and furniture has been used for a presentation to be given in china ). these exclusions only apply to a version of the test for preliminary screening of older individuals for memory dysfunction . the excluded categories may be used for evaluating memory in younger individuals or specific areas of deficits in individuals of any age . order definition is the number of single , double , or higher repetitions , can be specified to modify test difficulty . the pictures vary in color , and background color should have some variation . however , the pictures are clearly distinguishable independent of color . the pictures should be clear . they may be 20 - 80 k jpeg images — medium resolution , 320 × 240 , with good quality and no noticeable pixilation . a high resolution version of the images of 640 × 480 or higher is permissible if the computer capacity is feasible for rapid down - load of the images and perceptually instantaneous presentation of each image . there can be several bundles that are similar , but not so similar that they can be confused from day to day across 20 image sets . pictures should be named by convention , a - e ; category , sub - group , number , example of name : a - waterfall - 01 . jpg there are five categories of bundled items and examples of groups of five are as follows : a ) nature : landscape , rocks , minerals , water , flowers , difficult to name are interesting rocks and minerals , landscapes including vistas and forests , waterscapes including lakes , ocean , rivers and waterfalls , flowers and flower arrangements . among buildings are houses , barns , fences , wall , windows and outdoor items , outdoor ornaments . among kitchen and household items are utensils , cups , bowls , furniture and sewing items . among kitchen wares are glass bottle , pots / pans , mugs , bags , champagne / wine glasses , crystal wares , sewing items , buttons , jewelry ( not stunning ), hair items , furniture : desks , chairs , tables : side , end , coffee , dining , chandeliers , lamps , door knobs , machinery : vehicles ( trucks , boats ), tools , equipment , automobile / parts : tire treads , trucks , tractors , ships , boats , tools , electronic equipment : speakers , bells , and keys the following is an example of an order of the 50 images include 25 new pictures ( new ) and 25 old pictures ( old ) that has been implemented in several computer platforms and an audience presentation platform . rules are adapted from gellerman , l . w . chance orders of alternating stimuli in visual discrimination experiments . journal genetic psychology , volume 42 , pages 206 - 208 ( 1933 ). no more than four images of a specific type , new or old , occur together . no more than four alterations in a row ( new , old , new , old ). first 2 items are new . last 2 items are old . in first 10 items there are 7 new items and 3 old items . in last 10 items there are 3 new items and 7 old items . in the middle three groups of 10 , there are 5 new items and 5 old items in each group . twenty images are repeated once , 5 images are second repeats , and 5 images are not repeated ( 2 in last 10 , and 1 in each of the middle 10 ). examples of orders of the items from the 5 bundles ( all from a single sub - group within each bundle ) within the 50 image presentations . one of each of the 5 bundles must appear as a new in the first 10 images . one of each of the 5 bundles must appear as an old in the last 10 images . for each of the 5 bundles , there must be one item for which the old item occurs at least 20 items after the new image . each bundle has one item which is repeated after just one intervening stimulus . there are no adjacent images from the same bundle . each bundle has one item shown 3 times ( new , old , old ), with the second old stimulus occurring after at least 10 intervening items . each bundle has one item which is not repeated . 1 ) show loading - progress indicator if more than 5 seconds for loading is possible . a . length of permissible reaction time , shortest , longest ( example for complex images : 150 to 2900 msecs ) 7 ) show instruction that esc key may be pressed to end test at any time . i . if esc key pressed — stop ; query about restart with different test . ii . if non - space - bar key pressed , wait for full allowed time to exit . 1 . if too short , wait for full allowed time to exit wait routine i . if display time less than allowed time , go to “ d ”, display time . ii . if display time greater than or equal to allowed time , exit wait routine 12 ) check performance of subject ( note option to change image display time ) 14 ) calculate performance of subject based on order set and response times offer choice to end program or continue with new process . computer programs in which the test has been implemented : prototypes of the test have been written in : the test has been given in several versions as a powerpoint presentation , to over 2000 individuals . screening for memory problems , particularly those associated with dementia and alzheimer &# 39 ; s disease , has presented a significant logistical problem . the currently available memory tests are time - consuming and generally must be administered by a psycho - metrician in a one - to - one interaction with a participant in a confidential and quiet environment . such tests must trade duration and participant burden with poor accuracy and a low ceiling effect making assessment of normal individuals problematic . there is a need for a simple , accurate memory test that can be administered in a group setting that is feasible for testing older individuals . the memtrax memory game was adapted to a slide show format and an approach reminiscent of college aptitude testing for a large group . over the course of two years , this format was used over forty times at various community events , senior citizen centers , and retirement living communities , with over 1500 participants tested . between jul . 1 , 2007 and jun . 30 , 2008 , the test was administered at 26 sites using a single sheet , demographic information on one side and on the other , an answer sheet on which participants could indicate recognition of repeated pictures , in a format that could be scanned for data entry and analysis . the answer sheet had pre - assigned identification numbers and columns with numbers and single adjacent circles . participants were shown a series of numbered slides , 5 seconds for each . participants were asked to fill in the circle next to the number on a repeated slide . after a brief introduction and a short practice test of 10 slides , the participants completed a 50 - slide test , that had 25 unique pictures , 15 repeated once , and 10 of those repeated a second time . after the test , the participants handed their papers to the rater to be scored . while the rater scored each participant &# 39 ; s answer sheet , a presenter answered audience questions , after which the scores were returned anonymously to each participant . ( protocol approved by stanford university institutional review board .) data were obtained on 1063 participants at the 26 sites ( average 41 participants per site , range 8 to 142 ), mean age ( for 697 participants ) was 74 . 5 + 14 . 5 years , range 20 to 95 , with 41 participants over 90 years of age and 52 participants less than 50 years of age . for individual participants , test results were scored as the overall percent correct , the number of false - positive errors , and the number of false - negative errors . of 708 scored tests , 540 participants ( 76 %) scored 90 % correct or better , with 48 participants ( 7 %) having perfect scores and only 8 % scoring below 80 % correct . there were 67 participants ( 10 %) who had more than 5 false - positive errors ( incorrectly indicating an image was a repeat ), while the same number of participants , 67 , had more than 5 false - negative errors ( failure to recognize a repeated picture ). performance on individual images was also analyzed . of the new images , 2 were missed 64 % and 58 % of the time ( false - positives ), with 7 being missed between 5 % and 27 % of the time ( all in previously shown categories ), and the remaining 16 of the new images were missed less than 5 %. of the repeated images , 2 were missed 33 % and 20 % of the time ( complex images ) and all the rest were missed 16 % or less . only 3 repeated images were missed less than 5 %. thus , the repeated image errors showed less variability than the variability of the errors on new pictures . these results suggest that particular items triggered false recognitions , but recognition failures occurred more uniformly across pictures . the effects of age were also analyzed . percent true negatives decreased from 95 % at age 50 to 85 % at 95 years of age . percent true positives decreased from 100 % at age 50 to 80 % at age 90 years . there were statistically significant associations of performance with age . while the accuracy , reliability , and validity of this testing format has not been conclusively determined , generally , participants getting more than five false - negative responses are of concern for the presence of alzheimer &# 39 ; s type dementia and those getting more than five false - positive responses are suspected of having problems with attention or disinhibition suggestive of fronto - temporal dementia . the memtrax slide - test is not reliable for those participants with visual impairment or problems limiting their ability to fill in a circle with a writing implement . however , the experience with this format is that it is well accepted by audiences and has the potential to provide highly accurate and cost - effective screening for memory problems . in an era of increasing pressure to detect and manage prevalent disorders as early in their course as possible , screening has become an accepted norm for many conditions . if medical professionals and the public accept screening for hypertension , diabetes , breast cancer , and colon cancer , why is there no widespread demand to screen for dementia ? detection of dementia — the most disabling common condition of later life ( aguerro - torres h et al ., 2001 )— is currently left to chance ( ashford et al ., 2006 ; 2007 ). numerous approaches have been advocated to screen for memory problems , dementia , and alzheimer &# 39 ; s disease ( ashford , 2008 ). however , most of the approaches involve direct testing of potential cases or questioning of reliable sources ( case - finding ). many of the tests have poor sensitivity and specificity for dementia , are cumbersome to administer , and are generally unpleasant for the patients . there is a clear need for a screening system that is attractive to prospective users , both patients and clinicians , which can provide reliable information , including baseline evaluation and frequent repetitions . by focusing on memory function , a screening test can address the issue most important for recognizing the earliest indications of alzheimer &# 39 ; s disease , new - learning memory difficulties . visual information provides an essentially unlimited challenge to the brain &# 39 ; s memory storage mechanisms . performance information can be used to determine when further testing is appropriate . the purpose of this presentation is to report on the experience with a computerized memory test system that was adapted to a power - point slide presentation to be administered to a group of subjects . results are presented from administrations between jul . 11 , 2007 - aug . 14 , 2008 . the principle psycho - pathological factor in alzheimer &# 39 ; s disease is the attack of the formation of new memory traces that can be retrieved after distraction ( neuroplasticity , ashford & amp ; jarvik , 1985 ; teter & amp ; ashford , 2002 ). for example , recall of learned words after an interval is the earliest problem seen in alzheimer patients ( ashford et al ., 1989 ; ashford & amp ; schmitt , 2001 ). this process is commonly tested using several different memory challenges . however , providing complex stimuli that are easy for a normal person to remember would provide the most effective test for the alzheimer process . memtrax was developed based on the concept of providing a large volume of easily remembered information to a subject , then testing the recollection . the format used is referred to a “ long - n - back ” paradigm , with multiple complex visual stimuli , based on work by shepard , 1961 . generally the images are of discrete objects , though similar objects and difficult to name objects were used to avoid strict reliance on verbal cues and to provide a challenge and maintain the interest of the subjects . the initial paradigm used a computerized administration format and then a web - based format . however , due to the difficulty in getting older individuals to participate in web - based games , particularly those individuals with mild cognitive problems , the memtrax game was reformatted to a powerpoint slide show , running automatically with 5 seconds presentations for each stimulus . 25 discrete objects are shown , with 20 of them repeated , 5 repeated a second time , making a total of 50 objects , requiring 250 seconds to display . the audience is given a formatted answer sheet and instructed to fill in the circles next to the numbers on the images which are repetitions . the memtrax test has been under progressive development since 2000 . the current version was given between jul . 11 , 2007 - aug . 14 , 2008 on 26 occasions to senior citizen groups and health - fair participants , with a total of 1018 subjects filling out the questionnaire and submitting it for scoring ( at most venues , a few subjects watched without taking the test or did not hand in their answer sheet , but no count was made of these individuals ). there were an average of 39 subjects completing the form at each site ( range 9 - 142 , stdev = 34 ). data were entered with a scanner into a spread sheet format ( remark software and excel spreadsheet , results triple checked by hand ). analyses were computed from the excel spreadsheet , which was also used to produce the graphs . data entered as of dec . 2 , 2008 - 1018 individuals from 26 sites collected and considered that the individual had been able to perform the test . 805 reported being “ white ”. 31 & lt ; 40y / o of the 1018 individuals that were considered to have taken the test in a fashion that could be scored ( about 20 were eliminated , 31 were below chance ( 12 / 25 or less ) on the true negative or true positive score ( true —: 3 males , 10 females true +: 8 males , 11 females ) ( not included in graphs . of these 1018 individuals , those scoring less than 80 % correct for true −, 19 males , 51 females ; for true +, 25 males , 54 females . of these 1018 individuals , those scoring better than 80 % for true −, 276 male ( 93 . 6 %), 602 female ( 92 . 3 %); for true +, 270 male ( 91 . 5 %), 598 female ( 91 . 7 %). only 82 subjects had perfect scores , 230 made 1 error , 700 made 5 or fewer errors ( about 70 %), and 132 made 6 - 10 errors . plots are shown for the 858 individuals with age , gender , ed data , red is first presentation , green is repeat , males in blue , females in pink . performance on new images ( true −) was more variable than performance on old images ( true +). there is minimal difference in performance of individual items between males and females , in spite of significant “ male - role ” and “ female - role ” items . there is a significant decline of function with age , with the age - effect best explained by an exponential increase of errors with age (“ failure theory ”). females had a greater association of false - positive errors with age than males , while the false - negative error association with age was similar by gender . education was not significant in performance . memtrax is a brief , convenient , fun test of the type of complex memory affected by alzheimer pathology . recognition failure ( false −) indicates failure of learning circuits — typical of alzheimer &# 39 ; s disease . false - recognition ( false +) responses are indicative that the subject is not paying attention and is failing to inhibit the recognition response , thus more suggestive of other types of psychopathology , including fronto - temporal dementia . memtrax can test many levels of memory impairment accurately , validly , and reliability . alzheimer &# 39 ; s disease is not a dichotomous diagnosis but a continuum of impairment best assessed probabilistically using item response theory ( modern test theory )—( ashford & amp ; schmitt , 2001 ). from the foregoing it can be seen that a method of testing memory for alzheimer &# 39 ; s disease has been described . it should be noted that the sketches are not drawn to scale and that distances of and between the figures are not to be considered significant . accordingly it is intended that the foregoing disclosure and showing made in the drawing shall be considered only as an illustration of the principle of the present invention .

a method for assessing memory in a subject include the steps of presenting to the subject a list of items to be retrieved from memory by the subject , having the subject recognize the presented items from memory , determining the subject &# 39 ; s response speed to each of the recognized repeated items and analyzing a plurality of the response speeds for the recognized repeated items . the items which presented to the subject are intermixed with repetitions of the items being tested for recognition . the subject is tested to determine if he recognizes each repeated item as being a repeated item . the response speed for each of the recognized repeated item is the time required between when the subject is shown a repeated item and when the subject responds that he recognizes the repeated item .

as shown in the exemplary drawings wherein like reference numerals indicate like or corresponding elements among the figures , embodiments of a system according to the present invention will now be described in detail . the following description sets forth examples of multi - surface towels . reference is made to the multi - surface towel in terms of a golf towel . while the multi - surface towel presents various advantages for use in the game of golf , one skilled in the art will recognize that the multi - surface towel has uses in a variety of sports and activities in general . referring now to fig1 a front side of a towel 100 is shown . the front side includes an absorbent material 102 . the absorbent material 102 may be terry cloth , for example . the towel 100 further includes an opening 104 . the opening 104 may further include a reinforcer 106 , such as a grommet . additionally , a clip 108 may be inserted through the opening 104 in order to fasten the towel 100 to a bag or other equipment . for example , the towel 100 may be a golf towel , which may be attached to a golf bag . as shown in fig1 a graphic 110 may be printed on the towel 100 for purposes of advertising , identifying the owner , etc . a variety of materials or fabrics may be used for the absorbent material 102 that forms the front side of the towel 100 . as previously discussed , terry cloth fabric may be utilized . typically , terry cloth is made with cotton . however , terry cloth itself is available in various forms and may be made with various materials . for instance , terry cloth may be made with microfiber , such as a polyester blend , a stretch type material , etc . further , terry cloth may be categorized as rich pile , velour , looped pile , sheared pile , etc . ideally , loosely twisted loops tend to be softer and more absorbent , while tightly twisted loops tend to make a rougher fabric . additionally , long pile tends to be more absorbent than short pile . although terry cloth has been described for use in the present invention , any suitable absorbent material 102 may be utilized to form the front side of the towel 100 in accordance with the present invention . additionally , any type of opening 104 may be formed and any type of reinforcer 106 may be employed that is suitable for use with the present invention . advantageously , the reinforcer 106 strengthens and / or augments the opening 104 so as to bolster the opening 104 , and allow entry of the clip 108 . the clip 108 may be any type of clip 108 that is suitable for use with the present invention . for example , a heavy duty clip 108 , such as a carabiner , may be utilized . as another example , a light clip , such as a ring typically used with key chains may be utilized . as a further example , any type of attachment mechanism suitable for use with the present invention may be utilized . for instance , a strap and buckle may be inserted through the opening , allowing the towel 100 to be buckled to an object in some manner . referring now to fig2 a back side of the towel 100 is shown . the back side of the towel 100 includes a polishing material 202 that extends only a portion of the way down the back side . the remainder of the back side includes an abrasive material 204 . as shown in fig2 the opening 104 on the back side of the towel 100 is contiguous with the opening 104 from the front side of the towel 100 . further , the reinforcer 106 extends through , or is otherwise attached , to the back side of the towel 100 consistent with the front side of the towel 100 . in the exemplary embodiment of fig2 the polishing material 202 is 13 . 5 inches along its length and 12 inches along its width , while the abrasive material 204 is 2 . 5 inches along its length and 12 inches along its width . this configuration dictates that the polishing material 202 extends down its elongated portion ⅚ to ⅞ of the way , with the abrasive material 204 extending down its elongated portion ⅙ to ⅛ of the entire length of the second side of the towel 100 . the towel 100 shown in fig2 is 16 inches by 12 inches . however , any suitable size towel 100 may be employed in accordance with the present invention . the length and width may be any variety of sizes . for example , a larger size may be particularly useful for cleaning the inside and outside of automobiles . furthermore , any suitable proportions of the polishing material 202 and abrasive material 204 may be employed . for example , the polishing material 202 may only extend down ¾ of the total length of the towel 100 , while the abrasive material extends down ¼ of the entire length of the towel 100 . as another example , the polishing material 202 and abrasive material 204 may each occupy equal space on the second side of the towel 100 , etc . the polishing material 202 may include any material suitable for polishing . for example , chamois ( i . e . a soft , pliant leather ) is a polishing material that may be utilized . although chamois originates from the skin of a chamois , it may be made from the skin of sheep , goat , kid , deer , and calf . as another example , cotton fabric may be made to resemble chamois , and may also be utilized as a polishing cloth . the abrasive material 204 may include any materials suitable for use with the present invention . a scrub pad , for example , may be utilized . scrub pads and abrasive materials , generally , may include nylon , linen , loufa , sisal , wool , abrasive walnut shell , etc . the abrasive material 204 may also be scratch free . the front side and the back side of the towel 100 may be attached to form the towel 100 in any suitable manner . for example , the front side and the back side of the towel 100 may be sewn together , snapped together , adhered together in some manner , etc . an advantage of the towel 100 is that it is washable . traditional golf towels , for example , often fray when washed . the towel 100 of the present invention maintains its form due to the front side of the towel 100 being bound to the second side of the towel 100 . in an alternative embodiment of the present invention , the abrasive material 204 may be located on the front side of the towel 100 , sharing a portion of the elongated section with the absorbent material 102 . in such an embodiment , the polishing material 202 constitutes the entire back side of the towel 100 . alternatively , any combination of the absorbent material 102 , polishing material 202 , and abrasive material 204 is possible in accordance with the present invention . in use , the towel 100 of the present invention offers many advantages . for example , rather than carrying several towels or cleaning items , only one towel 100 is needed . the absorbent material 102 is useful for drying hands , drying a golf club , etc . the abrasive material 204 is often needed for cleaning stubborn dirt off a club , removing residue from seams in a club head , etc . the polishing material 202 is useful for polishing club heads , club shafts , etc . the towel 100 of the present invention may be utilized in accordance with any sport or activity in general . for example , the towel 100 of the present invention may be utilized to clean and polish a pair of shoes , golf related or otherwise . further , furniture , jewelry , audio visual equipment , etc . may be cleaned utilizing the towel 100 of the present invention . as previously discussed , the towel 100 may be particularly useful for cleaning the interior and exterior of an automobile . a variety of uses are contemplated . [ 0036 ] fig1 and fig2 both indicate stitch lines along the periphery of the towel 100 and along the abrasive material 204 section . stitch lines may show both on the side of the towel 100 on which the particular material is sewn , as well as on the opposing side . it shall be noted that any manner of combining the materials discussed herein suitable for use with the present invention may be employed . in other words , although the fig1 - 7 indicate stitch lines , the materials may be joined via any other methods . for example , the materials may be joined via an adhesive . in one embodiment , an opening may be included along a side of the towel 100 . in other words , the materials may be joined together , except for a section that does not join the materials together . such a section provides an area for a user to insert a hand , for better manipulation of the towel 100 and item for which the towel 100 is being utilized . referring now to fig3 an alternative embodiment as discussed herein is shown . a front side of a towel 300 comprises an absorbent material 302 . the absorbent material 302 extends down a portion of the front side of the towel . an abrasive material 304 extends down the remaining portion of the front side of the towel . as discussed herein , the respective portions may be any portions suitable for use with the present invention . a back side of the towel 300 comprises a material suitable for polishing . it should be noted that reference to a front side and a back side of the towel 100 , 300 is made for purposes of illustration and accordingly , the materials discussed may be located on either the front side or the back side of the towel 100 , 300 . referring now to fig4 an alternative embodiment of a towel 400 is shown . a front side of the towel 400 comprises an absorbent material 402 extending down a portion of the front side , while a polishing material 404 extends down the remaining portion of the front side of the towel 400 . the back side of the towel 400 comprises an abrasive material 406 . referring now to fig5 an alternative embodiment of a towel 500 is shown . the front side of the towel 500 is either an absorbent material or a polishing material . an abrasive material 506 extends vertically down the left side of the towel 500 . thus , the abrasive material 506 extends along a portion from a top to a bottom of the front side of the towel 500 , the absorbent material 502 or the polishing material 504 extending along the remaining portion between the top and bottom of the front side of the towel 500 . alternatively , the abrasive material 506 may extend down the right side of the towel 500 . the back side of the towel 500 is comprised of whichever material ( i . e ., absorbent material 502 or polishing material 504 ) does not comprise the front side of the towel 500 . referring now to fig6 an alternative embodiment of a towel 600 is shown . a front side of the towel 600 comprises an absorbent material 602 . a back side of the towel 600 comprises a polishing material 604 . further comprising the second side of the towel 600 is a triangular section of abrasive material 606 at either the right or left edge of the towel 600 . alternatively , the front side of the towel 600 may comprise the polishing material 604 , having a back side comprised of the absorbent material 602 and a triangular section of abrasive material 606 . as another alternative , a triangular section of abrasive material 606 may comprise both edges of either the front or back side of the towel 600 . another embodiment includes a portion of each material occupying a portion of each side of the towel 600 . for example , a front side of the towel 600 may include a strip of absorbent material , polishing material , and abrasive material arranged either horizontally or vertically along the front side . a back side of the same towel 600 may include a similar configuration or one of the materials , two of the materials , etc . furthermore , a front side of the towel 600 may include an absorbent material with a strip of abrasive material occupying a portion of the space of the front side , while a back side of the towel 600 includes a polishing material with a strip of abrasive material occupying the remaining space on the back side . accordingly , both the front side and the back side of the towel may include abrasive material , in strip form , triangular form , a square section on either edge of the towel 600 , etc . referring now to fig7 an alternative embodiment of the towel 100 is shown . in this embodiment , the opening 104 and reinforcer 106 are replaced by a snap 702 for attaching the towel to an object via snapping it in place . the snap 702 may include either the male or female section only , the object including the reciprocating section . as an alternative , the towel 700 , itself , may include the reciprocating section of the snap 702 in another area on the towel 100 . for example , an opposing edge may include the reciprocating section of the snap 702 , allowing the towel 100 to be snapped around an object , to an object , etc . in yet another embodiment of the present invention , strings may extend from the towel 700 , allowing the towel 100 to be tied to an object . as another example of attachment means , a button may be included on the towel 700 for attaching the towel to an object . an opening for the button may be included on the object for fastening the towel 700 thereto . alternatively , the towel 700 , itself , may include the opening for the button , allowing the towel to be fastened to the object by buttoning the towel 700 together . as another option , the towel 700 may be fastened to a button on the object via the button hole on the towel 700 . any attachment means suitable for use with the present invention is possible . the above description is illustrative and not restrictive . many variations of the invention will become apparent to those of skill in the art upon review of this disclosure . the scope of the invention should , therefore , be determined not with reference to the above description , but instead should be determined with reference to the appended claims along with their full scope of equivalents .

a multi - surface towel is afforded . a first piece of material has an absorbent surface . a second piece of material is coupled to the first piece of material and has a surface suitable for polishing . a third piece of material is coupled to the first and second piece of material and has an abrasive surface . thus , the towel is multi - functional .