Datasets:

farleyknight

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big_patent_10_percent

like 1

reference will now be made in detail to some possible embodiments of the invention , examples of which are illustrated in the accompanying drawings . wherever possible , the same reference numbers are used in the drawings and the description to refer to the same or like parts . fig1 , 2 , 3 a , 3 b , 4 , 5 a and 5 b depict an exemplary embodiment of a case 1 that comprises a first portion 3 ( e . g ., a cup ) and a second portion 20 . a side wall 4 of the first portion 3 defines a housing 7 and includes a free edge 5 delimiting an opening 6 for the housing 7 . the first portion 3 forms substantially circular external and / or internal cross - sections . the first portion 3 may be obtained by molding a material including 80 % san and 20 % abs . in the vicinity of its side wall 4 , the first portion 3 comprises a bore 8 intended to receive a pin 22 of the second portion 20 by , e . g ., snap - fastening . the bore 8 and the pin 22 are configured to permit pivoting of the second portion 20 with respect to the first portion 3 . the bore 8 and the pin 22 have a pivoting axis x that is parallel to the direction that the opening 6 of the first portion 3 faces , so as to enable pivotal movement of the second portion 20 with respect to the first portion 3 about the axis x . in this embodiment , the opening 6 faces in an upward direction ( with respect to the case orientation shown in fig5 a ). the direction that the opening “ faces ” generally refers to a direction that is opposite to a line of sight for an observer to view an entire outline of the edges ( s ) defining the opening . for example , when an observer views the opening 6 in a downward direction ( opposite to the direction that the opening 6 faces ) from a vantage point above the opening 6 , the observer is capable of seeing an entire outline of the edge defining the opening 6 . the opening 6 extends substantially entirely in a plane and the pivoting axis x is substantially perpendicular to that plane . although the embodiment shown in the drawings has a substantially planar opening 6 , it should be understood that alternative embodiments could be configured with an opening that is not substantially planar . in addition , the opening could be configured to face in more than one direction . as shown in fig1 and 3a , the side wall 4 includes a plate member 9 ( e . g ., an extra thickness on the external surface of the side wall 4 ) which may extend angularly over a few degrees . the plate member 9 is located on a portion substantially opposite of the bore 8 . the plate member 9 defines a guiding surface 10 facing in a direction opposite to a bottom 2 of the first portion 3 . the guiding surface 10 includes a first surface portion and a second surface portion , each of which has a different surface profile from one another . for example , as shown in fig3 a , the first surface portion has a surface profile substantially perpendicular to the pivoting axis x , and the second surface portion has a surface profile gradually increasing in the direction of the opening 6 of the first portion 3 . above the guiding surface 10 , the side wall 4 forms a locking groove 11 ( e . g ., a snap - fastening groove ). the locking groove 11 may extend in a direction parallel to the pivoting axis x . in a preferred embodiment , the locking groove may extend over a height of approximately 2 mm . proximate to the locking groove 11 ( e . g ., centered with respect to the groove 11 ), the side wall includes a guidance protrusion 12 ( e . g ., a flange ) extending in a direction substantially perpendicular to both the bottom 2 and the pivoting axis x . in the illustrated embodiment , the guidance protrusion 12 may have a length of approximately 3 mm . on the surface of the plate member 9 , an indicator 14 ( e . g ., an arrow parallel to the bottom 3 ) for indicating a prescribed pivoting direction of the first portion 3 for opening of the case is provided . the housing 7 is designed to receive an applicator 13 ( e . g ., a brush including a tuft of bristles arranged at an end of a handle ) for applying the product contained in the case . the housing 7 may also include a mirror 15 bonded to the internal bottom surface of the housing 7 . the second portion 20 comprises a bottom 21 configured to substantially cover the entire opening 6 of the first portion 3 in a closed position . the bottom 21 includes the pin 22 located in the vicinity of its periphery and configured to engage inside the bore 8 of the first portion 3 by , e . g ., snap - fastening mechanism . on the side substantially opposite of the pin 22 , the bottom 21 comprises a projection 23 extending towards the first portion 3 . the projection 23 includes an edge defining a second guiding surface 24 that has a surface profile complementary to the surface profile of the first guiding surface 10 , as shown in detail in fig3 b , so that the second guiding surface 24 may have an intimate contact with the first guiding surface 10 in the closed position . in this manner , the projection 23 is configured to engage with the plate member 9 of the first portion , so as to allow the pivotal movement of the second portion 20 only in one pivotal direction with respect to the first portion 3 for unlocking the first portion 3 and the second portion when the first portion 3 and the second portion 20 are in the closed position . on its internal surface , the projection 23 comprises a guidance groove 25 configured to receive the guidance protrusion 12 of the first portion 3 in the closed position . for this purpose , the guidance groove 25 has an open mouth portion on one of the side edges 28 of the projection 23 . optionally , the mouth portion has a gradually widening width facing the guidance protrusion 12 so as to facilitate engagement between the guidance protrusion 12 and the guidance groove 25 . the remaining portion of the guidance groove 25 , other than the mouth portion , is defined by two edges aligned substantially parallel to each other . between the guidance groove 25 and the second guiding surface 24 , the projection 23 comprises a locking protrusion 26 ( e . g ., a flange 26 ) on its internal surface . the locking protrusion 26 has a curved outer surface profile in a plane substantially parallel to the pivot axis x and is configured to be fastened in the groove 11 ( e . g ., snap - fastened ), so as to enable reversible locking of the pivotal movement . for example , the locking protrusion 26 may be in the form of a grain of rice . on the external surface of the projection 23 , an indicator 27 ( e . g ., an arrow ) may be provided for indicating a prescribed pivoting direction of the second portion 20 for opening of the case from the closed position . the second portion 20 includes an annular skirt 29 extending from the upper surface of the bottom 21 . the annular skirt 29 is separated by a distance from the peripheral edge of bottom 21 . the annular skirt 29 , in combination with the bottom 21 , defines a second housing 30 . the second housing 30 is designed to receive a product ( e . g ., a blush , a eye shadow , a rouge , etc .) to be applied . the product may be supplied in a container 31 ( e . g ., a cup ) configured to contain the product . the container 31 may be bonded to or snap - fastened with the second housing 30 . the external surface of the annular skirt 29 comprises a screw thread 32 configured to cooperate with a corresponding screw thread 42 provided on the internal surface of a closure member 40 ( e . g ., a lid ). the closure member is configured to substantially close the second housing 30 and , optionally , made of transparent or translucent material . at least a portion of the case may be formed of a material comprising at least one of polypropylene , polystyrene acrylonitrile ( san ), and acrylobutadiene styrene ( abs ). in an exemplary embodiment , the second portion 20 is made by molding polypropylene material , and the closure member 40 is made by molding polystyrene acrylonitrile ( san ). fig1 , 4 , and 5 a show how the case 1 is assembled . the assembly of the case 1 involves two major steps : first , the pin 22 is snap - fastened inside the bore 8 , and , second , the closure member 40 is screwed onto the second portion 20 . optionally , an applicator 13 may be introduced into the housing 7 . in operation , to close the case 1 the second portion 20 may be rotated with respect to the first portion 3 about the pivot axis x so as to engage the guidance protrusion 12 of the first portion 3 with the guidance groove 25 of the second portion 20 . from this moment , the pivotal movement of the second portion 20 with respect to the first portion 3 is guided only in a direction perpendicular to the pivot axis x , so that the bottom 21 of the second portion 20 cannot deviate appreciably from the plane of opening 6 of the first portion 3 . the pivotal movement guided in that manner may be continued until the locking protrusion 26 of the second portion 20 engages ( e . g ., snap fastens ) with the locking groove 11 of the first portion 3 to close the case . in this closed position , due to the structural configuration of the guidance protrusion 12 associated with the guidance groove 25 , it becomes virtually impossible , unless a user applies an excessive force and damages the opening / closing mechanism of the case to an irreversible condition , to open the case by a movement other than the reverse , pivotal movement in the direction opposite of that used to close . the configuration of the opening / closing mechanism in the closed position of the case is shown in detail in fig5 b . in an exemplary embodiment , the pin 22 and the bore 8 are disposed on a side of the case 1 substantially opposite ( e . g ., diametrically opposite ) to the guidance groove 25 and the guidance protrusion 12 . for opening the case , substantially identical steps that are used to close the case may be taken , except that a relative pivotal movement of the second portion 20 with respect to the first portion 3 is conducted in the opposite direction to that of closing . ( the pivotal movement in the same direction is substantially prevented by the presence of the complementary first and second guiding surfaces 10 and 24 .) to apply the product contained in the case , a user can open the first housing 6 of the first portion to take out an applicator 13 . then , the user can remove the closure member 40 , take up the product with the applicator 13 , and apply it in a conventional manner . alternatively , the user can also choose to remove the closure member 40 before or without opening the first housing 6 , directly having access to the second housing 30 containing the product . it will be apparent to those skilled in the art that various modifications and variations can be made to the structure and methodology of the present invention . thus , it should be understood that the invention is not limited to the examples discussed in the specification . rather , the present invention is intended to cover modifications and variations .

a case for packaging a product may include a first portion defining a housing and an opening permitting access to the housing . the opening may face in a first direction . the case may include a second portion pivotally coupled to the first portion via a pivot member so as to permit pivoting of the second portion with respect to the first portion about a pivot axis substantially parallel to said first direction . the second portion may be pivotally movable with respect to the first portion between a closed position covering the opening and an open position .

in referring to the drawings , and in particular fig1 , therein is shown the bra 1 of this invention , which incorporates the standard cups 2 and 3 , in addition to the shoulder straps 4 and 5 , and a strap that locates around the back , as at 6 , and having its usual fastener 7 located therein . structured within this bra , as will be subsequently described , and preferably within an openable pouch , as noted at 8 and 9 , are the individual suction cups 10 , which may locate within the pouches 8 or 9 during usages . there may be 2 such suction cups 10 employed . see fig2 . fig3 discloses a milk reservoir 11 , which also fits within one of the pouches 8 or 9 , and for use for the collection of milk from the mother , when time requires as such . it can be seen that the reservoir has a connector 12 to which the various tubing operatively associated with this invention may connect , and then likewise , such tubing may connect with the integrated connector 13 , operatively associated with each suction cup 10 . fig2 discloses the micropump 14 of this invention . such a micropump may be obtained from knf global company , located at 2 black forest road , trenton , n . j . 08691 , under model no . wms020 , identified as the high - efficiency micropump . such a micropump incorporates a small pump , preferably may be battery operated , and such a battery may be rechargeable , to provide for the operation of the micropump , when turned on . the pump may incorporate an off / on switch , and a shut off valve as at 15 , and it may have a tube connector 16 that provides for the interconnection of tubing , for pumping purposes , with the connector 17 functionally provided upon the suction cup 10 , as can be noted . hence , when the pump is operative , it provides for the expression of milk from the mothers breast , an it &# 39 ; s passing through tubing from the outlet 13 , to the inlet 12 , of the milk reservoir 11 , for collection purposes . as noted , the reservoir may be designed for removable insertion within the pouches 8 or 9 , when used , or the reservoir may be located externally , and connected by tubing , for operative purposes , for the collection of the expressed milk . obviously , any battery provided within the micropump 14 will desirably be rechargeable . fig2 discloses the bra 1 of this invention , and shows the location of the micropump 14 intermediate the bra cups 2 and 3 , with the individual suction cups 10 , one operatively associated with each of the bra cups , and which connect by tubing 18 between the pump and the suction cups , and through further tubing 19 to the shown reservoirs 11 . fig3 shows how the suction cups 10 are of thin line construction may be made of a latex or polymer , or easily cleansable , and which have the various tubing ports 18 and 19 integrated therewith . the cup has an arcuate shape to provide for its conformity when locating upon the breast of the mother . fig4 shows the provision of the pouches 8 or 9 that are formed within the bra , and which may accommodate the locating of one of the suction cups 10 therein , and which discloses the tubing connector , as at 20 for connecting with tubing that leads to the pump , and in addition , shows the connector 21 for connecting with the tubing 19 for securement with one of the reservoirs 11 for fluid connecting purposes . fig2 shows the approximate length and size of the type of tubing 18 and 19 that may be used for interconnecting between the micropump , and the suction cup , when the structured bra is assembled for usage . fig3 shows the configuration of a reservoir 11 , with its connector 12 , and as can be seen , the reservoir has an arcuate shape , so that it can be easily accommodated within a pouch 8 formed within the bra , when it is desired to function as a reservoir for collection of any expressed milk . or , as stated , the reservoir may be located externally , for the convenience of the mother , depending upon the circumstances under which mother &# 39 ; s milk is being collected for further usage . fig2 discloses the micropump 14 of this invention . it can be obtained as previously described from its supplier . it has the identified off / on switch 15 all embodied upon the encasement 21 , it may have a d / c or a / c chargeable connecting port 22 , and has the various tubing connectors 16 provided thereon . the micropump is of miniature size , so that it conveniently can fit either within the bra , or externally thereof , between the shown cups 2 and 3 , during its application and usage . see also fig1 . what is important is that the concept of this invention integrates directly within a brassiere , one that can function almost under normal condition , and look no different than the standard bra worn by any women . see fig8 . but , all the integrated components , as previously described , can be embodied therein , within

a breast pump brassiere , designed to provide hands free experience for the mother when collecting mother &# 39 ; s milk , and which integrates various operative components in the category of a micro pump , at least one suction cup , and a milk reservoir , preferably within each cup , to provide for hands free collection of expressed milk , as desired and required by the mother for use in the feeding of her infant .

referring now to fig1 , there is shown an optical hot tip device 2 , composed of a fiber with a core 4 and cladding 6 ( e . g ., a single - mode silica smf 28 fiber ). the light propagates through the core 4 , affixed to an optical fiber of similar dimensions that has a scattering core 8 . the fiber can be any fiber and not only the one in the example . the scattering core is produced , e . g ., by the “ fiber fuse ” method . the scattered light 10 goes through the silica cladding 6 into an absorber outside . the absorber may be any optically absorbing fluid or solid . the absorber may be a black epoxy or black paint . alternatively , the absorber may be a metal such as tantalum , molybdenum , or a combination thereof the scattered light wavelength preferably matches the absorbing medium lines in order to be absorbed efficiently . in fig2 , there is shown an optical hot tip device 2 composed of a fiber with a core 4 and cladding 6 ( e . g ., a single - mode silica smf 28 fiber ). the light propagates through the core 4 affixed to an optical fiber of similar dimensions that has a scattering core 8 produced by the “ fiber fuse ” method . the scattered light 10 goes through the silica cladding 6 into an absorber 12 , which covers the entire external area of cladding . the absorber 12 has a surface area that is about 100 times that of the surface area of the scattering core 8 . the larger area of the absorber 12 allows better heat conduction outwardly . the absorber 12 should be a relatively short distance from the fiber in order to more easily conduct or convect the heat . preferably , the absorber 12 should , at a maximum , be 100 microns away from the scattering core 8 . preferably , the absorber should be between about 50 microns and 70 microns away from the scattering core 8 . the absorber 12 may be an optical black paint or epoxy paint , thus allowing for a wide range of wavelengths to be absorbed . in other embodiments , the absorber 12 includes a metal made of tantalum , molybdenum , or a combination thereof . in other embodiments , other metals may be used . fig3 illustrates a device similar to that shown in fig2 . however , here the hot tip 2 is exposed to a fluid flow 14 around the tip , longitudinal or transverse , providing heat to the fluid by conduction and convection . fig4 shows a schematic cross - section of the laser - plasma method of hot tip production . here , high - energy laser light ( e . g ., providing 30 - 35 dbm cw power at 1550 nm wavelength ) from the core 4 of the fiber / waveguide impinges on a partially transparent conductive layer 16 . the layer 16 is very thin ( only a few atomic layers , e . g ., a few nanometers ), and is made of an electrically conductive material , preferably a conductive metal such as rhodium , aluminum , gold , silver , chromium or nickel , or a combination or alloy of such metals . such thin layers of conducting material are known to enhance the electric field strength in their vicinity due to local irregularities of their surface , where the surface irregularities induce field concentration , resulting in lower power needed to create an electrical breakdown , and damage . such thin nanometric layers may be modeled as a plurality of aggregates of nano - particles ( see , e . g ., m . quinten , “ local fields close to the surface of nanoparticles and aggregates of nanoparticles ,” appl . phys . b 73 , 245 - 255 ( 2001 ) and the book “ absorption and scattering of light by small particles ” by c . f . bohren and d . r . huffmann , wiley - interscience ( 1998 ), chapter 12 [ showing strong field enhancement factors ( up to 105 ) for few - nanometer particles as well as wide extinction spectra for various materials and shapes ]. when the thin layer of conductive material is impinged with optical power exceeding a predetermined threshold , strong electric fields , which can lead to local electrical breakdown , are generated at certain sites in proximity to the metal surface . this leads to a visible - light - emitting arc discharge , where plasma is created . the generated plasma greatly increases the absorption of the propagating light , and the energetic discharge creates catastrophic damage at or near the metal surfaces . this damage includes cratered regions in the end surfaces of the waveguide sections on opposite sides of the conductive metal layer . thus , the waveguide end permanently becomes highly scattering . following the conductive layer 16 is another dielectric layer 18 , and more conductive layers 16 may follow it . the combination of a highly scattering material and embedded absorbers ( either the conductive particles created by the discharge from layer 16 or artificially introduced absorbers like nano - particles of carbon ) create an absorbing volume 21 that is heated to elevated temperatures . after this process is finished , the light impinging from core 4 into the absorbing volume 21 is scattered in directions 22 and is absorbed by the conductive and absorbing particles , thus heating the volume 21 to elevated temperatures over 1000 ° c . the hottest spot is in the symmetry point 20 . fig5 illustrates the result of the process and method of fig4 , showing a highly scattering and absorbing volume 24 ( that includes the conductors 16 and the dielectric layer 18 ) having dimensions of about 1 - 2 micrometers in length and a diameter of , e . g ., 125 micrometers . the hottest spot is in the symmetry point 20 . fig6 illustrates some applications of the hot tip of fig1 , 2 , 3 , 4 , 5 and 7 when immersed in fluid or solid 26 . the matter 26 can be , e . g ., an air and fuel mixture , as in an internal combustion engine , where the hot tip 24 serves as an ignition device , optically energized and operated . the matter 26 can be , e . g ., an explosive or pyrotechnic material , as in a rocket engine or an exploding device , where the hot tip 24 serves as an ignition fuse , optically energized and operated . the matter 26 can be , e . g ., a living tissue to be cut in an operation , where the hot tip 24 serves as a cutting knife , optically energized and operated . fig7 illustrates another way to create the hot tip of fig5 , with a controllable area of the impinging light . here a fiber having a constant index of refraction across 28 is coupled ( e . g ., by fusion splicing ) to the light - conducting fiber 6 . the light output , not being confined by an index step , diverges in a cone 30 , reaching its maximum diameter at spot 32 . in this way the light impingement diameter is controlled by the index and length of the core - less fiber 28 , enabling the selection of any diameter from the core diameter ( e . g ., 10 micrometers ) to the clad diameter ( e . g ., 125 micrometers or more ). it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing embodiments , and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof . the present embodiments are therefore to be considered in all respects as illustrative and not restrictive , the scope of the invention being indicated by the appended claims rather than by the foregoing description , and all changes , which come within the meaning and range of equivalency of the claims , are therefore intended to be embraced therein .

an optical hot tip and method for manufacturing the same . the hot tip is for conducting high optical power beams at the tip of a fiber or waveguide . the light from the fiber or waveguide is absorbed in and end tip in order to generate heat . the heat can then be used in a variety of applications .

based on the scattering and anisotropy characteristics of tissue , tissue sampling depth is defined by the photon - path - distribution function for photons migrating from a source to a detector on the surface of the skin . using the assumption that tissue is homogenously scattering medium , the spatial photon distribution function has a banana - like shape . if one considers weak absorption within the tissue , then the banana - like shape of the photon propagation in tissue is approximated by the equation which describes a curve of the most probable direction of photon migration . from fig1 it is evident that the maximum sampled tissue depth , z max , occurs approximately at the mid - point between a light source ( e . g ., led 1 , led 2 , led 3 ) and a light detector ( e . g ., photodetector pd ). light - emitting diodes led 1 , led 2 , and led 3 shown in fig1 may or may not be of the same wavelength . different surface positions of light - emitting elements such as led 1 , led 2 , and led 3 with respect to a photodetector element affect sampling from different tissue depths . the distance between a light source and a light detector may be referred to as the inter - optode distance . therefore , setting the surface position x at the middle of an inter - optode distance , r sd , yields the value of the approximate maximum sampled tissue depth z max , with respect to r sd : where z is tissue depth , r sd is inter - optode distance , and x is surface position . the present disclosure encompasses a portable , battery - operated , non - invasive , multi - modal , depth - resolved , tissue status monitor . a description of functional testing of an embodiment of such a monitor may be found in the exemplification section below . such monitors may include a multi - channel low - power depth - resolved near infrared spectroscopy module , ultrasound module , pressure sensors , temperature sensor , and stretch sensors . these physiological sensors , individually or in various different combinations , are used to obtain depth - resolved information about the tissue health status . some of the information that may be acquired from the patient to determine tissue health status include , but are not limited to : oxygenated and deoxygenated hemoglobin concentrations , total hemoglobin , carboxyhemoglobin , tissue saturation , photoplethysmography , onsets of hypo - and hypervolemia states , muscle intracompartmental pressure , body temperature , blood flow velocity , and change in size of tissue under observation . some systems and methods of the present disclosure may be used to acquire and analyze signals representative of a physiological quantity , and to inform the clinician about the health status of tissues under observation . in some embodiments , a device is designed for use on the surface of the skin and placed under a cast or splint at the time of surgery to monitor tissue viability . in some embodiments , a patch , such as a lightweight and / or adhesive patch , is placed over an area that has suffered trauma and the patch provides real - time physiologic monitoring data of the affected area and can be used as an acute compartment syndrome detector or tissue flap monitor . some of the other examples where systems and methods of the present disclosure may be used include , but are not limited to : monitoring of tissue after vascular surgery ; monitoring of lower or upper limb tissue viability during prolonged surgeries ; or monitoring of skin flaps after mastectomy . certain monitors of the present disclosure allow the clinician to obtain depth - resolved information . this is useful , for example , in cases where tissue is very thin or consists of multiple layers . this monitor can be set to allow differentiation of signals from different layers . technology described herein is also capable of including a variety of other sensor modalities to complement this information . in some embodiments , a monitor consists of three main components : ( 1 ) a sensor strip to be placed on patient skin , the strip containing physiological and other sensors ; ( 2 ) a data acquisition module , which contains signal processing circuitry as well as storage and communication modules ; and ( 3 ) analysis software , which can be used to analyze signals collected from the sensor strip , to view and analyze patient data , and to configure the data acquisition module for different recording sessions . the sensor strip can include a flexible substrate ( e . g . polyimide film or similar material ) with biocompatible adhesive on bottom side ( toward patient skin ) and electrical components , sensors , and electrical traces on the opposite side . in some embodiments the sensor strip will contain multiple pressure sensors , light sources ( e . g ., light - emitting diodes , leds ), stretch sensors , and one or more photodetectors ( e . g ., photo diode , photo transistor ). fig2 schematically shows a sensor strip with a single photodetector ( pd ). in various embodiments , single or plural numbers of pds may be used in different geometric configurations to obtain depth - resolved nirs information from underlying tissues . any photodetector capable of detecting the emitted light as it emerges from the tissue can be used . the number of photodetectors and light sources can depend on the clinical application . examples of different geometric configurations are shown in fig2 - 4 . depth - resolved information may be obtained either using a single photodetector element and multiple light - emitting elements , or with multiple photodetector elements . embodiments having only a single photodetector typically make use of one or more methods of discriminating between the signals associated with different light - emitting elements . the following are examples of how to effect such discrimination . while some of the following methods apply only to single photodetector embodiments or multiple photodetector embodiments , other methods apply to both . ( 1 ) only a single light - emitting element is turned ‘ on ’ ( i . e ., emits light ) at a single point in time . it may be desirable to convert an analog signal acquired by the photodetector element into a digital signal to facilitate a determination of which light - emitting element corresponds to the acquired signal . thus , the photodetector element may be used in conjunction with an analog - to - digital converter ( adc ). analog circuitry may be used to process the analog signal acquired by the photodetector element , and the adc may digitize the analog signal into digital data for further analysis to determine which light - emitting element was ‘ on ’ at which time . a sensor strip control unit may be responsible for both emitter and photodetector / adc control . ( 2 ) light from the emitters may be modulated and then demodulated by processing circuitry . in this case , each light - emitting element would have its own unique modulation sequence generated by a sensor strip control unit . ( 3 ) each photodetector element may detect only a specific wavelength that matches a specific emitter wavelength , or a single photodetector element may detect multiple wavelengths and distinguish each source light - emitting element based on the wavelength of the received signal . ( 4 ) any combination of the above techniques ( e . g ., turning on a subset of the light - emitting elements , each of the light - emitting elements having a unique modulation sequence relative to the other light - emitting elements activated at the same time ; activating subsets of light - emitting elements such that each of the simultaneously - activated light - emitting elements emits a different wavelength ; having the some light - emitting elements emit signals of the same wavelength , but using different modulation sequences for different emitters that are operating at the same wavelength ; etc .). light - emitting elements may be selected based on the clinical application of the monitor . for example , emitters having a particular output ( e . g ., emitted wavelength ), or several emitters collectively having a range of wavelengths , may be selected depending on the specific chromophore of interest that is to be investigated . the selection of light - emitting elements may guide the selection of an appropriate photodetector element or elements . a photodetector element may be selected that best matches the output of the emitters ( e . g ., a detector that detects a particular wavelength or range of wavelengths ), or that best matches only a subset of the emitters . a wide variety of light emitting elements is known in the art , and any appropriate light emitter may be used . in some embodiments , the sensor strip may include two or more photodetector elements . multiple emitters and one or more detectors may be used in different configurations depending on the clinical application of the monitor . as explained above , the farther a photodetector is from the light emitting element whose light is being detected , the deeper the maximum tissue depth being probed . by arranging photodetectors and light emitting elements around the sensor , a variety of depths can be probed at a variety of different locations beneath the surface , allowing the user to build three - dimensional information on the nature of the tissue beneath the sensor strip . many different configurations of light emitters and photodetectors may be useful in different contexts , for example , detectors and emitters could be arranged to probe only a narrow range of depths by over a large area if the tissue to be investigated a relatively shallow , flap - type incision or wound . or if the tissue is known to include a deep , generally vertical incision or wound , i . e ., a cut that is along a plane perpendicular to the exterior surface of the tissue , a sensor strip with emitters and detectors arranged so as to probe a larger variety of depths along a single plane might be preferable . in some embodiments , the sensor strip may include one or more ultrasound transducers . for certain clinical applications , a single ultrasound transducer may be sufficient . multiple ultrasound transducers , however , may provide better depth - resolved information compared to a single transducer . for example , each transducer may emit a different frequency in order to preferentially obtain information from different depths of tissue ( e . g ., higher frequency transducers have shorter penetration depth but better resolution and vice versa ). the information from the ultrasound transducer ( s ) may be used to complement information obtained from light - emitting elements , or may be processed as a stand - alone modality . the ultrasound information is not necessary for operation of the light - emitting elements . the ultrasound transducer module ( s ) are an optional part of the sensor strip depending on the clinical application of the device . additionally , the sensor strip may include a single or plural number of accelerometers , gyroscopes , and temperature sensors , for example as solid state devices such as mems . furthermore , the sensor strip may contain analog signal processing circuitry , signal filtering circuitry , sensor driving circuitry , analog - to - digital conversion circuitry , power supply circuitry , ultrasound acquisition unit , digital data processing circuitry , data communication unit , and connector for being operably connected to a data acquisition module . the sensors and electrical components may be placed in any number of geometric combinations on the sensor strip . moreover , the information from each sensor may be used individually or in combination with any or all other sensor data to monitor tissue viability , and / or tissue flap status , and detect acute compartment syndrome . an operable connection between the sensor strip and the data acquisition module can be a wired connection or can be wireless . as with many medical monitors , a wired connection might be convenient where the sensor strip is placed on an in - patient or other person confined to a bed . wireless connections between the various parts of the system may be preferable where the patient is mobile . however , even for mobile patients , a wired connection may be useful , since the entire system can be designed to be light - weight and easily transportable . different portions of the system may be designed to be carried on the patient &# 39 ; s person . in some embodiments , the sensor strip itself may have a wireless connection to the rest of the system , in which case the patient need only keep the sensor strip . in other embodiments , the sensor strip can be wired to the data acquisition module where signals are stored . data can then be transferred from the data acquisition module in any number of ways . the data acquisition module can include a wired or wireless connection to a computer on which analysis software can be executed . or the data acquisition module can store data on a removable memory medium , such as flash memory , which can then be physically removed to a computer that is not otherwise connected to the data acquisition module . alternatively , the data acquisition module can have a wired or wireless connection directly into a network , such as a lan , so as to transmit received and stored data in real - time to a computer . in any of the above embodiments , the data can be analyzed and compared to criteria designed to detect one or more pathologies in the patient &# 39 ; s tissue . as described in more detail below , the analysis of the data can trigger an alarm if a criterion is met or if a pathology is detected or inferred . a data acquisition module can include a printed circuit board ( flexible or solid ), a primary or secondary battery pack , and an enclosure . the printed circuit board can include power supply circuitry ( including a battery charger ), a data communication unit , a wireless module , sensor strip control circuitry , a user interface control unit , a data processing unit , memory media ( e . g ., an sd card or other data storage unit , possibly removable ), a connector for the sensor strip , a visual status indicator ( s ), a visual alarm indicator ( s ), an audio alarm indicator , a power ‘ on / off ’ control , and / or a connector for battery charger and / or wired communication . many of the above units , such as the sensor strip control circuitry , the user interface control unit the data processing unit , and the memory media , are capable of storing software . such stored software can be used , for example , for data processing and / or analysis , or operational control and can include algorithms specific to those or other tasks . fig5 and fig6 show examples of a data acquisition module . in some embodiments , a personal computer or similar mobile device is provided with analysis software that includes a computer code programmed with a series of instructions that allow a user to view , download , store , and analyze data from the data acquisition module . in addition , software can be used to create and upload one or more data acquisition configuration files specific to each patient into the data acquisition module . the configuration file may contain information such as , but not limited to , patient number , length of the recording session , alarm threshold levels , communication parameters and relevant elements of patient history . a particular aspect of the present disclosure is the use of a series of emitters and at least one photodetector sensor to obtain depth - resolved information in a substrate , such as living tissue . to ensure stable outputs , the emitters may be constant current leds and a detector is chosen to match the outputs of the leds . this unique combination of inputs and outputs is combined with geometric placement of the emitters on the sensor strip to achieve differentiation in signals from various tissue layers . we have already validated this in an initial human trial . various monitors and systems disclosed herein can be used in at least the following ways : 1 . a reusable or single - use sensor strip is attached to the patient skin and a data acquisition module is connected to the strip . 2 . a clinician or authorized person powers - up the data acquisition module and loads the appropriate data acquisition configuration file . 3 . the data acquisition module initializes and verifies proper state of the sensors embedded in the sensor strip , for example by calibration as explained below . 4 . after the successful start - up , the data acquisition module goes into acquisition mode for the duration of session ( e . g ., according to a predetermined acquisition routine or as determined by the clinician ). 5 . data acquired during the session may be stored onto a device - based memory medium for later retrieval and analysis . at the discretion of the clinician , real - time physiological data may be viewed on a designated platform via wireless or wired interface . 6 . during data acquisition , the data acquisition module may utilize an embedded processing unit to process the acquired physiological signals and determine if , for example , any of the pre - selected physiological abnormalities or conditions are present in tissues under observation . i . if no abnormalities are present , the unit does not alarm . ii . if the algorithm determines that there may be an abnormality present , it alarms by either visual , audio , or both means . an optional communication link may be established with a server at a healthcare center that would enable real - time viewing of patient acquired data by trained healthcare providers , or that may send an alarm signal or other appropriate notice to the patient &# 39 ; s physician or other healthcare provider . iii . for outpatients , if necessary , the monitoring center personnel may contact the patient and instruct them to call their clinician for follow - up or observation , or may contact the patient &# 39 ; s physician or other healthcare provider directly . 7 . at the end of the data acquisition , data acquisition module finalizes the recorded data file on the local memory medium and then powers - down . 8 . the clinician removes the sensor strip from the patient and either discards it ( if it is a single - use strip ) or disinfects it for the next patient ( if a reusable strip ). 9 . at some point , either before , after or during use on the patient , the sensor strip can be applied to a calibration pad . data can be recorded , and characteristics of the calibration pad analyzed and compared to a template based on the calibration pad &# 39 ; s predetermined characteristics . differences between the measured and known properties of the calibration pad can then be used to calibrate the data acquired from the patient tissue . in some embodiments a device or kit includes a sensor strip , data acquisition module and receiver station . the sensor strip can be either reusable or disposable . the device may be used under a cast or dressings to monitor tissue viability . for example , if a patient has a complex lower limb fracture and a clinician is concerned about acute compartment syndrome , the device would be placed over the anterior compartment prior to casting or bandaging . the bandage or cast would be applied as usual and the data acquisition module would be monitored to provide real - time data . depending on the condition of the patient , monitoring could be in real - time ( e . g ., continuous ) or at various time increments . for inpatients this could be displayed on a monitor . for outpatients who have a cast placed , but are otherwise able to go home , the technology would allow for remote monitoring , for example over the internet or a telephone line , allowing the clinician to obtain a range of physiologic data remotely . when the cast is removed the device can be recovered . in some embodiments a calibration pad can be used to verify that the system is working properly before , after and / or interleaved with data collection . a calibration pad can be generally sized and shaped to be complementary to the sensor pad . the calibration pad can include a test pattern in its interior or on its surface . the test pattern can be detectable in one or more wavelengths of light . for example , the calibration pad could have material with a first near infrared chromophore at a first depth and a second , different chromophore at a second different depth . the calibration pad could have a wide variety of materials with different infrared properties throughout its interior and on its surface , e . g ., arranged in a two or three dimensional pattern , gradient or other suitable configuration . the calibration pad can be used by positioning the sensor strip adjacent to the surface of the calibration pad , activating on or more light - emitting elements on the sensor strip , detecting light emitted by the activated light - emitting elements to generate one or more signals representative of the test pattern , and processing the signals to determine a characteristic of the test pattern . the characteristic could be , for example , a particular near infrared spectral response at a first depth within the calibration pad and a second , distinct near infrared spectral response at a second depth , for example on the surface of the calibration pad . the calibration pad can include a test pattern that is designed to allow for determination of the performance of the sensor pad . the sensor pad can be positioned on the calibration pad with light emitting element ( s ) and photodetector ( s ) facing the calibration pad , light emitting elements on the sensor pad activated , emitted light detected by a photodetector or photodetectors on the sensor strip , and the detected light translated in to signals that are transmitted to a data acquisition module or other processor where a representation of the signals is stored . the stored representations can then be compared to a template based on the predetermined properties of the calibration pad , thereby determining one or more response characteristics of the sensor strip , or other component of the above system . because the test pattern can have a predetermined form , analysis of the signals can be used to determine the location of a photodetector and / or light emitting elements of the sensor pad relative to the test pattern on the calibration pad , and thus to each other . the detected characteristics of the calibration pad can also be used to determine other properties of a photodetector and light emitting elements , such as brightness , sensitivity . a wide variety of characteristics of the system can be characterized and the system calibrated by comparing the known , predetermined properties of the test pattern to how the test pattern is actually detected . comparing the data collected on the calibration pad to a template of the calibration pad can include , for example , determining how to best fit a predetermined model response function to the data , and inferring from that best fit the properties of the sensor strip and its components and / or other elements of the system . once aspects of the sensor strip , such as sensitivity , brightness , and / or relative positions of the various emitters and / or sensors , have been determined in the calibration process , that information can be used by the system to interpret the signals stored by the data acquisition module . as explained above , knowing how far a particular light emitter is from a particular photodetector is important in understanding what depth of tissue is being probed by the detected light . by calibrating the system to a particular sensor strip , the user can allow the software to take into account ordinary variations in the sizes and shapes of sensor strips . such variations could result from differences within manufacturing tolerances , deformation ( e . g ., stretching ) of the sensor strip over time , or other causes and need not be representative of any sort of defect . any of a calibration pad , a sensor strip , a data acquisition module , and relevant software can be combined in a kit . the kit can then be used as explained above to calibrate the response of the sensor strip , data acquisition module and / or software package . it should be understood that the device of the present disclosure is applicable to all limbs and anywhere where a cast or dressings are placed . this is in addition to other applications mentioned previously ( e . g ., tissue flaps , vascular surgery , etc .). the invention now being generally described , it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention , and are not intended to limit the invention . a light - weight multi - channel multi - wavelength ultra - low power near infrared spectroscopy ( nirs ) system was designed and tested . the nirs system was designed for clinical use to emit low power ( maximum 5 mw ) red and near - infrared ( nir ) light into human tissue and acquire , record , and display reflected light from various tissue depths . as described below , results of initial functional tests of the system are presented . potential clinical applications of the nirs system include long - term non - invasive monitoring of functional activity in tissues , oxygen consumption in skeletal muscles , and tissue blood perfusion . near infrared spectroscopy ( nirs ) is a non - invasive , non - ionizing imaging technique that uses light in the 650 nm to 2 , 500 nm region of the electromagnetic spectrum . in medical applications , optical devices utilize what is known as the biologic window ( i . e ., “ therapeutic window ”). this window encompasses the light from 600 nm to approximately 1400 nm . the reason why many medical optical devices exploit light sources within this spectrum is that tissue proteins are relatively transparent at these wavelengths with the exception of certain chromophores such as oxygenated and deoxygenated hemoglobin , melanin , fat , and water . light is highly scattered by the cells and organelles in tissues , as well as absorbed by certain chromophores . understanding scattering , absorption , and penetration of light in tissue allows extraction of information from different tissue depths . modeling tissue scattering and absorption helps analyze light being detected at the surface . since their introduction , medical nirs devices have been used in many physiologic monitoring applications , including , pulse oximetry , functional nir for measuring the neuronal activity in the brain , measurement of oxygen consumption in skeletal muscles , and more recently the measurement of tissue blood perfusion . below , initial functional testing results of a novel multi - channel multi - wavelength ultra - low power portable nirs system ( fig7 ) are presented . to the best of our knowledge , the capabilities of this device , such as its ability to obtain optical information from multiple depths in tissue from a portable battery powered system for extended periods of time , has not been previously reported . this noninvasive system is designed to emit low - level red and nir light into human tissue and acquire , record , and display the reflected light from various tissue depths . the level of reflected red and nir light will vary , primarily , due to absorption by the chromophores of interest and the scattering coefficient of the tissue . the chromophores of interest include hbo 2 and hb hemoglobin , melanin , fat , water , and lipids . in preparation for human clinical trials , the objective of this study was to verify several design parameters , including power consumption , sampling rate , total system weight , and real - time multi - channel data display . the nirs system consists of an optical sensor module , data acquisition and processing module , and a pc computer used for real - time data display , analysis , and storage ( fig8 ). these components are described in further detail next . the system consists of a custom - made optical sensor module , data acquisition unit , and a laptop pc . at the heart of the system is an ultra - low power microcontroller , msp430 - family by texas instruments . the msp430 family was selected because of its ultra - low power requirements and processing capabilities . based on project requirements and microcontroller capabilities , the msp430g461x was selected for the initial prototype . this msp430 device features a 16 - bit risc cpu , a high performance 12 channel 12 - bit a / d converter ( with 610 μv lsb ) and one universal synchronous / asynchronous communication interface ( usart ). digitized data is sent to the pc in binary format using the serial communication protocol . serial communication protocol ( i . e ., serial port profile , spp ) is one of the most common protocols used for bluetooth ® wireless interface . finally , the msp430fg461x series supports a liquid crystal display ( lcd ) option with its integrated lcd driver . the system was designed to obtain information about various tissue chromophores at varying tissue depths . this has been achieved by using multiple source - detector distances to collect reflected light . light obtained from a near source - detector pair samples tissue closer to the surface , while the light obtained from the source - detector pairs several centimeters apart is able to sample deeper sections of tissue . understanding the results from these optodes requires careful modeling and algorithm development to interpret the data ( see below ). the optical sensor module contains light sources , leds , and a photodetector , pd . the optical signal strength at the detector position on the surface of the skin is expected to be on the order of pico - to micro - watts , which depends on the actual radiant intensity of the source . in our system , we set a goal of generating maximum 5 mw radiant power from leds . this value was chosen because it is considered to be a safe optical and thermal level for medical devices . the system utilizes silicone pin diodes for reflected light detection . the pin diodes have wide bandwidth , low capacitance , and low bias voltage . their optical sensitivity is approximately two orders of magnitude smaller than avalanche photo diodes ( apds ). preliminary tests , however , have shown that these detectors have sufficient sensitivity for our applications . the initial system requirements were based on a need for a fully portable ( i . e . light weight ), compact multi - channel system capable of 36 hours standby time , 12 hours of continuous nirs data acquisition at 20 samples per second using 700 mah rechargeable lithium - polymer battery . the sampling rate was based on the work by saager , who found that 20 hz offers more than sufficient sampling rate for characterizing hemodynamic fluctuations , which mostly occur in single - to sub - hz range . based on these requirements , the current consumption in the ready ( i . e ., standby ) mode would need to be 19 ma and 58 ma in the active mode . in addition , the system would need to display multi - channel real - time acquired data and save it to the pc hard drive for offline analysis . the initial version of the pc software for nirs data acquisition , display , and storage utilizes custom - designed application developed with microsoft ® directx ® technology . the application is capable of displaying up to 64 channels of data with various user - configurable parameters such as display scale , signal grouping , and displayed data color . presently , the acquired data is saved to a local hard drive for off - line analysis . initial signal processing algorithms have been developed and will be optimized pending the results of our clinical trials . four bench - top tests were conducted to evaluate initial performance of the nirs system . first , the system current was measured using the ampere meter in the agilent e3631a triple power supply . the voltage was set to 7 . 6v dc , and the current was measured in “ ready ” mode and then in “ active ” mode . in ready mode , system is set to acquire data with the sensor strip disabled . in active mode , the system is acquiring and sending ntrs data to pc for display and storage . the design goal for the ready mode current was set to 19 ma and was measured to be 16 . 5 ma , which is approximately 15 percent improvement over the design goal . active mode current goal was set to 58 ma but was measured to be 60 . 3 ma . second , in order to be able to monitor certain physiologic parameters , the system needed to be able to sample acquired optical signals at 20 samples per second ( sps ). we used agilent 33120a arbitrary function generator , agilent dso1024a oscilloscope , and pc application to test the accuracy of our analog - to - digital conversion , as well as to verify our maximum data sampling rate . the current version of the system is able to acquire nirs data at a rate of 50 samples per second . third , total system weight was measured to be 95 grams , which is five grams below design goal . finally , the last major design goal was achieved by successfully displaying 64 channels of data in real - time . the summary of initial nirs prototype test results is shown in table 1 . the system succeeded in accomplishing four of the five main goals for this stage of system development . the one parameter that requires further optimization is the active mode current consumption , which exceeded our goal by four percent . the 12 hour continuous active mode operation of the nirs system will be achieved by making improvements to the embedded control software . the details above describe initial design and functional testing results of a novel multichannel multi - wavelength ultra - low power portable nirs system . the nirs technology works by quantifying light absorption by chromophores of interest and the scattering coefficients of the tissue . the clinical applications of this lightweight , multi - channel nirs system includes long - term non - invasive monitoring of functional activity in tissues , oxygen consumption in skeletal muscles , and tissue blood perfusion . all publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference . in case of conflict , the present application , including any definitions herein , will control . those skilled in the art will recognize , or be able to ascertain using no more than routine experimentation , numerous equivalents to the devices , systems and methods described herein . such equivalents are considered to be within the scope of this invention and are covered by the following claims . those skilled in the art will also recognize that all combinations of the various embodiments described herein are within the scope of the invention .

the properties inside a human tissue as well as how those properties vary over time can include information of great importance to a healthcare provider . in some cases , the tissue of interest may not be easily accessible , as a tissue that is under a cast or beneath a bandage , or may be beneath a layer of skin that makes it difficult to evaluate the tissue visually or in a non - invasive manner . the systems and methods described herein relate to monitoring tissue at a plurality of depths .

the pharmacologically active drug used in the present invention includes all medicinal compounds capable of being converted into ions . preferable compounds in the present invention are , for example , codeine , dihydrocodeine , dextromethorphan , phenylpropanolamine , methylephedrine , hydrocodone and pilocarpine . as an ion exchange resin used in the present invention , a cation exchange resin is used for a basic drug , while an anion exchange resin is used for a acid drug . in the examples described below , amberlite irp - 69 ( 45 - 150 μm ) which is a gel type divinylbenezene sulfonic acid cation exchange resin supplied from rohm and hass was used . the impregnating agent used in the present invention includes polyethyleneglycol , polypropylene glycol , mannitol , lactose , methylcellulose , glycerol and the like . polyethylene glycol is preferable , and polyethyleneglycol 4000 was used in the example . the amount of the impregnating agent is usually up to 30 parts by weight per 100 parts by weight of drug - resin complex . a material for the diffusion barrier film is ethylcellulose having the content of ethoxyl group from 44 . 0 to 47 . 5 %, preferably from 45 . 0 to 46 . 5 %. a plasticizer such as durkex 500 vegetable oil may also be incorporated to improve the film forming property . although the amount of ethylcellulose coating based on the drug - resin complex treated with the impregnating agent varies depending on the profile of drug release desired once the liquid formulation was administered , it should be within such a range that maintains the controlled release of the drug when admixed with a preservative while does not retard the release excessively . thus , when the release of the drug is excessively retarded , then the drug is excreted before clinically effective dose is released and availability of the formulation is reduced . a preferable amount of ethylcellulose is usually 5 . 0 to 30 . 0 parts by weight per 100 parts by weight of impregnating agent - treated complex . the concentration of the diffusion barrier - coated complex in the liquid formulation varies from 0 . 1 to 45 . 0 w / v % depending on the types of drug and solvent employed and the efficacy desired . the preservative usually used in this field are various p - hydroxybenzoates , invert soaps , alcohol derivatives , organic acids and salts thereof , phenols , organic mercury compounds and the like . however , in the present invention , the preservative is preferably one or more p - hydroxybenzoates and sodium benzoate . the maximum concentration of the preservative in the liquid formulation was selected so that the release of the drug does not change significantly when the drug is stored under the condition for aging at 60 ° c ., while the minimum concentration was selected so that the antiseptic ability is maintained . thus , the concentration of the preservative employed in the present invention is , for example , 0 . 05 to 0 . 15 w / v % when methyl p - hydroxybenzoate ( methylparaben ) is used , 0 . 05 to 0 . 075 w / v % when ethyl p - hydroxybenzoate ( ethylparaben ) is used , 0 . 03 to 0 . 05 w / v % when propyl p - hydroxybenzoate ( propylparaben ) is used , 0 . 01 to 0 . 015 w / v % when butyl p - hydroxybenzoate ( butylparaben ) is used , 0 . 05 to 0 . 10 w / v % and 0 . 01 to 0 . 02 w / v % when a mixture of methylparaben and propylparaben is used , and 0 . 1 to 0 . 5 w / v % when sodium benzoate is used . when a preservative other than listed above is employed , the concentration may be selected experimentally as shown in the examples according to the requirements mentioned above . the solvent used to prepare the liquid formulation of the present invention may be an aqueous solvent . in addition to the preservative , a viscosity - increasing agent , a ph - adjusting agent , a sweetening agent and a flavoring agent may also be added to the solvent . as solvents other than the aqueous solvent , oily solvent such as vegetable oil , paraffin and glycols may also be employed , the formulation of the present invention can be prepared as follows . a pharmaceutical compound and an ion exchange resin are admixed in deionized water with stirring , washed thoroughly with deionized water in a buchner funnel , and then dried in a fluidized - bed dryer to yield a drug - resin complex . then the drug - resin complex is treated with an impregnating agent . the treatment may be conducted according to the method disclosed in u . s . pat . no . 4 , 221 , 778 . in the examples of the present invention , polyethyleneglycol 4000 was used as the impregnating agent and dissolved in deionized water . the aqueous solution thus obtained was added to the drug - resin complex while stirring , and dried in a fluidized - bed dryer to yield an impregnating agent - treated drug - resin complex . the complex thus obtained is then coated with a diffusion barrier film . the coating material listed above is dissolved in a suitable solvent ( for example , ethanol , methylene chloride / acetone ) and the solution is coated in an amount providing desired control of the release of the active ingredient onto the complex using a suitable coating method . in the examples of the present invention , methylene chloride : acetone ( 10 : 1 ) was used as the solvent and the solution was sprayed onto the complex using wurster type coating apparatus to form a diffusion barrier film . finally , the coated complex thus obtained is suspended in a solvent containing a preservative to obtain a prolonged - release liquid formation of the present invention . the formulation of the present invention has an excellent stability of the diffusion barrier film on the drug - resin complex , which is not broken even when stored for a long time . accordingly it ensures the controlled release of the drug for a long time , providing a prolonged release of the drug after administration while keeping sufficient antiseptic property . the present invention is further described in the following comparative , experiments and examples , which are not intended to limit the scope of the invention . preparation of coated codeine - resin complex using ethylcellulose having the content of ethoxyl group from 48 . 0 to 49 . 5 %. 95 . 0 g of codeine phosphate was dissolved in 950 ml of deionized water , and 359 . 9 g of amberlite irp 69 was added while stirring . the mixture was stirred for 1 hour . the codeine - resin complex was washed thoroughly in a buchner funnel , and then dried in a fluidized bed drier for 1 hour at the inlet air temperature of 60 ° c . to yield a codeine - resin complex . b . preparation of codeine - resin complex treated with polyethyleneglycol 82 . 5 g of polyethylene glycol ( peg ) 4000 was dissolved in 104 . 8 ml of deionized water to form a peg solution , which was added slowly to 350 g of the codeine - resin complex with stirring . after mixing for 15 minutes , the mixture was dried in a fluidized bed drier at the inlet air temperature of 40 ° c . for 1 hour to yield a peg - treated codeine - resin complex . 45 . 0 g of ethylcellulose having the content of ethoxyl group from 48 . 0 to 49 . 5 % and 21 . 2 g of durkex 500 were dissolved in 130 . 4 g of acetone and 1304 . 0 g of methylene chloride to obtain a coating solution . using wurster type coater at the inlet air temperature of 40 ° c ., 998 g of the coating solution was sprayed continuously at the rate of 8 g / minute onto 400 g of the complex in such a manner that the coating amount of ethylcellulose + durkex 500 based on the peg - treated codeine - resin complex was 11 . 0 w / v %. 180 mg of the coated codeine - resin complex prepared in comparative 1 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes . 12 ml of a solution of any one of methylparaben , ethylparaben , propylparaben and butylparaben , or 12 ml of a solution of the mixture of methylparaben and propylparaben was added to obtain the samples , which were allowed to stand overnight at 30 ° c . the samples were subjected to the dissolution test using a sample containing no preservatives as the control . according to the dissolution test ( paddle method ) under japanese pharmacopeia of the 11th amendment ( jpxi ), 0 . 1 n hcl solution at 37 ° c . was used as the test solution to examine the effect of each preservative in the condition of the rotation of 100 rpm . codeine was quantified by hplc . dissolution rate of codeine when the coated codeine - resin complex prepared in comparative 1 was stored in the solution of methylparaben or in the solution of propylparaben is shown in table 1 , while that when the complex was stored in the solution of the mixture of the both is shown in fig1 . although the concentrations of the preservative in the solutions were antiseptically - effective concentrations , the controlled release of the drug of the complex which had been observed previously in the absence of the preservative was lost once stored overnight at 30 ° c . when the coated codeine - resin complex stored in the solution of the mixture of methylparaben and propylparaben was observed by an electron microscope , the diffusion barrier film was broken ( fig2 ), indicating the loss of the controlled drug release . the controlled release of the drug from the coated codeine - resin complex was lost similarly when the complex was stored in the solution of ethylparaben and in the solution of butylparaben . table 1______________________________________change in % dissolution of drug from coated codeine - resincomplex of the reference after storage in solution ofmethylparaben or in solution of propylparaben ( 30 ° c . for 1 day ) preservativeconcen - tration timetype ( w / v %) 0 . 5 hour 1 . 0 hour 3 . 0 hours 6 . 0 hours______________________________________without -- 25 . 9 34 . 6 49 . 6 61 . 6preserva - tivemethyl - 0 . 04 29 . 8 39 . 8 58 . 9 70 . 7paraben 0 . 08 31 . 0 40 . 7 60 . 5 71 . 0 0 . 12 29 . 9 42 . 2 61 . 2 71 . 4 0 . 16 31 . 0 43 . 7 61 . 6 70 . 5 0 . 20 44 . 0 53 . 9 69 . 9 74 . 5propylpar - 0 . 010 28 . 9 41 . 5 57 . 4 69 . 0aben 0 . 015 28 . 1 40 . 3 58 . 2 68 . 8 0 . 020 28 . 8 41 . 2 59 . 0 69 . 3 0 . 025 29 . 8 41 . 7 60 . 5 72 . 5 0 . 030 30 . 4 43 . 1 60 . 1 71 . 1______________________________________ 180 mg of the coated codeine - resin complex prepared in comparative 1 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes . 12 ml of the solution of sodium benzoate was added and the mixture was allowed to stand at 30 ° c . overnight to obtain a sample , which was subjected to the dissolution test in the condition similar as in experiment 1 . dissolution rate of codeine when the coated codeine - resin complex prepared in comparative 1 was stored in the solution of sodium benzoate at an effective concentration as a preservative is shown in table 2 . the results indicated that the controlled release of the drug from the complex which had been observed previously in the absence of the preservative was lost also when sodium benzoate was used as a preservative . table 2______________________________________change in % dissolution of drug from coated codeine - resincomplex of the reference after storage in solution ofsodium benzoate ( 30 ° c . for 1 day ) preservativeconcen - tration timetype ( w / v %) 0 . 5 hour 1 . 0 hour 3 . 0 hours 6 . 0 hours______________________________________without -- 25 . 9 34 . 6 49 . 6 61 . 6preserva - tivesodium 0 . 1 32 . 4 43 . 6 60 . 0 71 . 1benzoate 0 . 2 34 . 5 45 . 7 63 . 6 72 . 0 0 . 3 37 . 1 47 . 2 64 . 7 73 . 5 0 . 4 46 . 0 58 . 1 71 . 9 74 . 1 0 . 5 70 . 5 75 . 1 80 . 4 86 . 2______________________________________ preparation of coated codeine - resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 %. 95 . 0 g of codeine phosphate was dissolved in 950 ml of deionized water , and 359 . 9 g of amberlite irp 69 was added while stirring . the mixture was stirred for 1 hour . the codeine - resin complex was obtained by the procedure similar as in comparative 1 . 82 . 5 g of peg 4000 was dissolved in 104 . 8 ml of deionized water to form a peg solution , which was added slowly to 350 g of the codeine - resin complex with stirring . after mixing for 15 minutes , the mixture was subjected to the procedure similar as in comparative 1 to yield a peg - treated codeine resin complex . 45 . 0 g of ethylcellulose having the content of ethoxyl group from 45 . 0 to 46 . 5 % and 21 . 2 g of durkex 500 were dissolved in 130 . 4 g of acetone and 1304 . 0 g of methylene chloride to obtain a coating solution . using wurster type coater at the inlet air temperature of 40 ° c ., 998 g of the coating solution was sprayed continuously at the rate of 8 g / minute onto 400 g of the complex in such a manner that the coating amount of ethylcellulose + durkex 500 based on the peg - treated codeine - resin complex was 11 . 0 w / v %. 180 mg of the coated codeine - resin complex prepared in example 1 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes . 12 ml of any one of 0 . 30 w / v % methylparaben , 0 . 075 w / v % ethylparaben , 0 . 05 w / v % propylparaben and 0 . 015 w / v % butylparaben , or , 12 ml of the mixture of 0 . 15 w / v % methylparaben and 0 . 03 w / v % propylparaben was added . after allowed to stand at 30 ° c . overnight , the samples were subjected to the dissolution test in the condition similar as in experiment 1 . dissolution rate of codeine when the coated codeine - resin complex prepared in example 1 was stored in the solution of any one of parabens in shown in table 3 , while that when the complex was stored in the solution of the mixture of the methylparaben and propylparaben is shown in fig3 . the results indicated that the dissolution rate of codeine in any of the solutions of the preservatives tested was similar to that observed in the sample containing no preservatives , showing that the controlled release of the drug from the complex was maintained . when the coated codeine - resin complex stored in the solution of the mixture of methylparaben and propylparaben was observed by an electron microscope , the diffusion barrier film coated the complex completely ( fig4 ). table 3______________________________________change in % dissolution of drug from coated codeine - resincomplex of example 1 after storage in solution of any oneof various parabens ( 30 ° c . for 1 day ) preservative time concentration 0 . 5 1 . 0 3 . 0 6 . 0type ( w / v %) hour hour hours hours______________________________________without -- 23 . 3 31 . 1 45 . 3 53 . 8preservativemethylparaben 0 . 30 26 . 6 34 . 9 47 . 7 56 . 3ethylparaben 0 . 075 24 . 5 31 . 5 47 . 4 53 . 8propylparaben 0 . 05 25 . 0 33 . 7 46 . 3 54 . 6butylparaben 0 . 015 25 . 4 33 . 1 47 . 4 51 . 0______________________________________ 180 mg of the coated codeine - resin complex prepared in example 1 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes . 12 ml of 0 . 9 w / v % solution of sodium benzoate was added and the mixture was allowed to stand at 30 ° c . overnight to obtain a sample , which was subjected to the dissolution test in the condition similar as in experiment 1 . dissolution rate of codeine when the coated codeine - resin complex prepared in example 1 after storage in 0 . 9 w / v % solution of sodium benzoate was almost similar to that observed in the sample containing no preservatives , showing that the controlled release of the drug was maintained ( table 4 ). table 4______________________________________change in % dissolution of drug from coated codeine - resincomplex of example 1 after storage in solution of sodiumbenzoate ( 30 ° c . for 1 day ) preservative time concentration 3 . 0 6 . 0type ( w / v %) 0 . 5 hour 1 . 0 hour hours hours______________________________________without -- 26 . 1 33 . 8 44 . 8 52 . 5preserva - tivesodium 0 . 90 30 . 4 37 . 2 46 . 4 52 . 4benzoate______________________________________ the controlled release of the drug from the coated codeine - resin complex prepared in example 1 was proved in example 2 to be maintained even after the storage in aqueous solutions of various p - hydroxybenzoates overnight at 30 ° c . in this example , change in controlled release of the drug from the complex after storage in an aging condition was examined and the ranges of the concentrations of the preservatives were selected for the purpose of providing prolonged - release liquid type of pharmaceutical preparations exhibiting the controlled release of the drug which is not fluctuated over a long period . thus , 180 mg of the coated codeine - resin complex prepared in example 1 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes . 12 ml of any one of the solutions of various p - hydroxybenzoate at various concentrations , namely , 0 . 05 to 0 . 30 w / v % methylparaben , 0 . 05 to 0 . 075 w / v % ethylparaben , 0 . 03 to 0 . 05 w / v % propylparaben and 0 . 01 to 0 . 015 w / v % butylparaben , or , 12 ml of the mixture of 0 . 05 to 0 . 20 w / v % methylparaben and 0 . 01 to 0 . 04 w / v % propylparaben was added . after allowed to stand at 60 ° c . for 5 days , the samples were subjected to the dissolution test in the condition similar as in experiment 1 . dissolution rate of codeine when the coated codeine - resin complex prepared in example 1 was stored in the solution of any one of various parabens is shown in table 5 , while that when the complex was stored in the solution of the mixture of the methylparaben and propylparaben is shown in table 6 . based on the results , the maximum concentrations of the preservatives were so selected that the release of the drug was not changed markedly , while the minimum concentrations were so selected that the antiseptic effect could be maintained . thus , 0 . 05 to 0 . 15 w / v % when methylparaben is used , 0 . 05 to 0 . 075 w / v % when ethylparaben is used , 0 . 03 to 0 . 05 w / v % when propylparaben is used and 0 . 01 to 0 . 015 w / v % when butylparaben is used were selected . when the mixture of methylparaben and propylparaben is used , the concentrations of 0 . 05 to 0 . 10 w / v % and 0 . 01 to 0 . 02 w / v %, respectively , were selected . it was confirmed that there was almost no change in % dissolution of the drug when the complex was stored in the solutions of the preservatives at the concentrations within the ranges specified above at 25 ° c . for a long period . table 5______________________________________change in % dissolution of drug from coated codeine - resincomplex of example 1 after storage in solution of any oneof various parabens ( 60 ° c . for 5 days ) preservative time concentration 0 . 5 1 3 . 0 6 . 0type ( w / v %) hour hour hours hours______________________________________without -- 23 . 3 31 . 1 45 . 3 53 . 8preservativemethyparaben 0 . 05 25 . 0 33 . 2 47 . 0 55 . 8 0 . 10 26 . 4 34 . 0 47 . 3 55 . 5 0 . 15 28 . 7 37 . 8 50 . 4 59 . 2 0 . 20 33 . 7 42 . 3 53 . 8 60 . 6 0 . 25 37 . 7 47 . 8 60 . 4 68 . 5 0 . 30 43 . 7 53 . 2 67 . 1 73 . 8ethylparaben 0 . 05 27 . 8 35 . 9 47 . 6 57 . 4 0 . 06 25 . 7 33 . 6 46 . 5 56 . 0 0 . 07 25 . 7 34 . 4 46 . 3 55 . 7 0 . 075 26 . 6 34 . 9 49 . 6 57 . 1propylparaben 0 . 03 25 . 0 34 . 4 45 . 2 55 . 9 0 . 04 27 . 1 34 . 2 47 . 6 55 . 7 0 . 05 28 . 6 35 . 6 50 . 4 59 . 5butylparaben 0 . 010 25 . 0 33 . 0 45 . 2 55 . 0 0 . 013 25 . 0 32 . 9 44 . 8 54 . 8 0 . 015 26 . 0 34 . 8 47 . 9 56 . 9______________________________________ table 6______________________________________change in % dissolution of drug from coated codeine - resincomplex of example 1 after storage in solution ofmixture of methylparaben and propylparaben ( 60 ° c . for 5 days ) preservative timemethylparaben propylparaben 0 . 5 1 . 0 3 . 0 6 . 0 ( w / v %) ( w / v %) hour hour hours hours______________________________________0 ( without 0 ( without 26 . 1 33 . 8 44 . 8 52 . 5preservative ) preservative ) 0 . 05 0 . 01 25 . 8 33 . 1 43 . 8 49 . 60 . 10 0 . 02 29 . 5 35 . 4 46 . 5 52 . 60 . 15 0 . 03 35 . 5 41 . 9 52 . 3 58 . 60 . 20 0 . 04 39 . 5 48 . 8 61 . 5 65 . 1______________________________________ the controlled release of the drug from the coated codeine - resin complex prepared in example 1 was proved in example 3 to be maintained even after the storage in the solution of sodium benzoate overnight at 30 ° c . in this example , in order to select the range of concentration of sodium benzoate , 180 mg of the coated codeine - resin complex prepared in example 1 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes , and then 12 ml of the solution of sodium benzoate at various concentrations ( 0 . 1 to 1 . 3 w / v %) was added and , after storage for 5 days at 60 ° c ., subjected to the dissolution test in the condition similar as in experiment 1 . increase in % dissolution was observed with dependency on the concentration of sodium benzoate ( table 7 ). based on the results , the range of the concentration of sodium benzoate from 0 . 1 to 0 . 5 w / v % was selected . the results of the long term storage test at 25 ° c . revealed that there was no change in % dissolution at the concentrations of the preservative within the range specified above . table 7______________________________________change in % dissolution of drug from coated codeine - resincomplex of example 1 after storage in solution of sodiumbenzoate ( 60 ° c . for 5 days ) preservative time concentration 0 . 5 1 . 0type ( w / v %) hour hour 3 . 0 hours 6 . 0 hours______________________________________without -- 26 . 1 33 . 8 44 . 8 52 . 5preservativesodium 0 . 1 27 . 5 34 . 2 43 . 9 49 . 5benzoate 0 . 5 33 . 9 39 . 1 47 . 5 55 . 6 0 . 9 39 . 6 44 . 2 51 . 9 57 . 3 1 . 3 44 . 1 48 . 1 54 . 4 60 . 4______________________________________ preparation of coated phenylpropanolamine ( ppa )- resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 % 12 . 0 kg of ppa hydrochloride was dissolved in 120 . 0 kg of deionized water , and 45 . 0 kg of amberlite irp69 was added while stirring . the mixture was stirred for 1 hour . the ppa - resin complex was washed thoroughly in a buchner funnel , and then dried in a fluidized - bed dryer for 1 hour at the inlet air temperature of 60 ° c . to yield a ppa - resin complex . 13 . 65 kg of peg 4000 was dissolved in 21 . 8 kg of deionized water to form an aqueous solution of peg , which was added slowly to 54 . 5 kg of ppa - resin complex with stirring . after mixing for 15 minutes , the mixture was dried in a fluidized - bed dryer at the inlet air temperature of 40 ° c . for 1 hour to yield a peg - treated ppa - resin complex . 6 . 0 kg of ethylecellulose described above and 2 . 82 kg of durkex 500 were dissolved in 17 . 38 kg of acetone and 173 . 8 kg of methylene chloride to obtain a coating solution . using wurster type coating at the inlet air temperature of 40 ° c ., 190 kg of the coating solution was sprayed continuously at the rate of 580 g / minute onto 60 . 0 kg of the complex in such a manner that the coating amount of ethylcellulose + durkex 500 based on the peg - treated ppa - resin complex was 14 . 0 w / w %. 750 mg of the coated ppa - resin complex prepared in example 6 was admixed with 1 . 0 ml of 1 . 3 % polysorbate 80 in water , and the mixture was allowed to stand for 30 minutes . 12 ml of the solution of the mixture of 0 . 10 w / v % methylparaben and 0 . 02 w / v % propylparaben was added and the mixture was allowed to stand at 30 ° c . overnight to obtain a sample , which was subjected to the dissolution test . a sample containing no parabens was used as a control . dissolution rate of ppa from the coated ppa - resin complex is shown in table 8 . the dissolution rate of the drug when the complex was stored in the solution of the mixed parabens was almost similar to that observed in the sample containing no parabens , showing that the controlled release of the drug was maintained . when the complex was after storage with parabens was observed by an electron microscope , the diffusion barrier film coated the complex completely . table 8______________________________________change in % dissolution of drug from coated ppa - resin complexof example 6 after storage in solution of mixture ofmethylparaben and propylparaben ( 30 ° c . for 1 day ) preservative timeconcentration 5 15 30 1 . 0 2 . 0 ( w / v %) minutes minutes minutes hour hours______________________________________without preserva - 24 . 2 36 . 8 50 . 5 59 . 6 67 . 9tive0 . 10 % methyl - 22 . 6 39 . 4 50 . 6 61 . 8 69 . 3paraben + 0 . 02 % propylparaben______________________________________ preparation of coated dihydrocodeine - resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 % 60 . 0 g of dihydrocodeine phosphate was dissolved in 600 ml of deionized water , and 378 . 8 g of amberlite irp 69 was added while stirring . the mixture was stirred for 1 hour to yield a dihydrocodeine - resin complex . then , the complex was treated with peg and coated with the diffusion barrier material similarly as in example 1 to obtain a coated dihydrocodeine - resin complex . preparation of coated dextromethorphan - resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 % 90 . 0 g of dextromethorphan hydrobromide was dissolved in 900 ml of deionized water , and 378 . 8 g of amberlite irp69 was added while stirring . the mixture was stirred for 1 hour to yield a dextromethorphan - resin complex . then , the complex was treated with peg and coated with the diffusion barrier material similarly as in example 1 to obtain a coated dextromethorphan - resin complex . preparation of coated methylephedrine - resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 % 75 . 0 g of methylephedrine hydrochloride was dissolved in 750 ml of deionized water , and 378 . 8 g of amberlite irp69 was added while stirring . the mixture was stirred for 1 hour to yield a methylephedrine - resin complex . then , the complex was treated with peg and coated with the diffusion barrier material similarly as in example 1 to obtain a coated methylephedrine - resin complex . preparation of coated hydrocodone - resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 % 20 . 0 g of hydrocodone bitartarate was dissolved in 800 ml of deionized water , and 378 . 8 g of amberlite irp69 was added while stirring . the mixture was stirred for 1 hour to yield a hydrocodone - resin complex . then , the complex was treated with peg and coated with the diffusion barrier material similarly as in example 1 to obtain a coated hydrocodone - resin complex . preparation of coated pilocarpine - resin complex using ethylcellulose having content of ethoxyl group from 45 . 0 to 46 . 5 % 100 . 0 g of pilocarpine hydrochloride was dissolved in 900 ml of deionized water , and 300 . 0 g of amberlite irp69 was added while stirring . the mixture was stirred for 1 hour to yield a pilocarpine - resin complex . then , the complex was treated with peg and coated with the diffusion barrier material similarly as in example 1 to obtain a coated pilocarpine - resin complex . ______________________________________coated codeine - resin complex of example 1 1 . 57 gmethylparaben 0 . 10 gpropylene glycol alginate 1 . 40 gpropylene glycol 1 . 0 gcorn syrup 30 . 0 gcitric acid 0 . 1 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________ ______________________________________coated ppa - resin complex of example 6 3 . 22 gethylparaben 0 . 06 gtragacanth gum 1 . 0 gpropylene glycol 1 . 0 gcorn syrup 30 . 0 gcitric acid 0 . 1 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________ ______________________________________coated dihydrocodeine - resin complex of 1 . 45 gexample 8propylparaben 0 . 04 gtragacanth gum 1 . 0 gpropylene glycol 1 . 0 gcorn syrup 30 . 0 gcitric acid 0 . 1 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________ ______________________________________coated dextromethorphan - resin complex of 2 . 03 gexample 9butylparaben 0 . 013 gxanthane gum 0 . 3 gpropylene glycol 1 . 0 ghigh - maltose syrup 40 . 0 gsorbitol 20 . 0 gcitric acid 0 . 1 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________ ______________________________________coated methylephedrine - resin complex of 4 . 84 gexample 10methylparaben 0 . 10 gpropylparaben 0 . 02 ghydroxypropylmethylcellulose 2 . 0 gpropylene glycol 1 . 0 ghigh - maltose syrup 40 . 0 gsorbitol 20 . 0 gcitric acid 0 . 1 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________ ______________________________________coated hydrocodone - resin complex of example 2 . 02 g11sodium benzoate 0 . 3 gtragacanth gum 0 . 68 gxanthane gum 0 . 18 gpropylene glycol 1 . 0 ghigh - maltose syrup 40 . 0 gsorbitol 20 . 0 gcitric acid 0 . 1 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________ a nasal spray formulation was prepared using the ingredients shown below . ______________________________________coated ppa - resin complex of example 6 6 . 45 gethylparaben 0 . 05 ghydroxypropylcellulose 1 . 0 gpolysorbate 80 0 . 1 gsodium chloride 0 . 9 gdeionized water q . s . to 100 ml______________________________________ an eye drop formulation for instillation was prepared using the ingredients shown below . ______________________________________coated pilocarpine - resin complex of example 12 6 . 50 gmethylparaben 0 . 10 gpropylparaben 0 . 02 gcarbopol 0 . 50 gmannitol 4 . 0 gpolysorbate 80 0 . 1 gdeionized water q . s . to 100 ml______________________________________

the present invention provides a prolonged - release liquid type of pharmaceutical preparation prepared by coating a pharmaceutically active drug - ion exchange resin complex which was treated previously with an impregnating agent , with a water permeable diffusion barrier material , followed by suspending the coated complex in a solution containing preservatives . the formulation of the present invention does not develop the rupture of the diffusion barrier film even in a solution containing preservatives . therefore the formulation of the present invention is a prolonged - release liquid type of pharmaceutical preparation which is stable and does not lose the controlled release of the active ingredient .

this invention utilizes a video disc player which incorporates the feature of a frame jump system with a fairy large range such as from n :± 50 to n :± 300 . the jump range has no specific significance to the present invention . it is simply a matter of compromise between software and hardware considerations with respect to cost . a jump range of n :± 100 has been found to be the most economical and suitable range . accordingly , all game examples explained hereinafter are based on a jump range of about n :± 100 . in the n :± 100 mode , if frame scanning is started from the 0 frame , the crt will display the frames in linear memory in the following order . at every 1 / 30 of a second : no . 0 , ( blank ), no . 100 , ( blank ), no . 200 , ( blank ), no . 400 , ( blank ) . . . . in this jump mode it will take about 36 seconds to scan the frames from 0 to 54 , 000 , which is the normal volume of frames on a video disc . referring now to fig1 an example of a coordinate map which includes the n :± 100 mode is illustrated . the map locates the serial frame numbers on the horizontal from 0 to no . 15 , 000 , for example , starting from the right top at 0 and extending to the left to 15 , 000 . the horizontal axis illustrates the n :± 100 mode . in this manner , all frame numbers are equivalent to its coordinate point , for example , arbitrary point p is equivalent to frame no . 8763 . the adjoining point to its left according to the jump sequence is 8863 ( n : 100 ). the adjoining point to its right is 8663 ( n :- 100 ). in other words , the n : 100 mode scans frames to the left , while the n :- 100 mode scans frames to the right . in the same manner , the scanning of frames in a n :± 1 mode is illustrated on the vertical axis starting at the upper right - hand corner from frame 0 and going down to frame 100 . referring again to a reference point p , scanning in the n - 1 mode would be upwards from this point , and scanning in the n : 1 mode would be downwards from this point . for the example shown , point p would be frame 63 . the adjacent point next to it in the n :- 1 mode would be 62 . the adjacent point next to it in the n : 1 mode would be 64 . in this manner , if the series of the scanned frames which contain the graphic information are systematically arranged so that they look natural and in a normal order of time flow , the viewer is able to select any one of four modes at any time by operating the manually - manipulatable mode switches . the ability to select four different modes according to the invention allows two different relative relations to be controlled by the vertical scan ( n :± 1 ) and two more different relative relations to be controlled by the horizontal scan ( n :± 100 ). for example , for horizontal scan , the distance between a viewer and an object in front of the viewer can be controlled . for vertical scan , left and right relation of the viewer and the object can be controlled . the horizontal and vertical relations can be exchanged if frame volume of the gradual changes of both scenes is within 100 frames . other instances of combinations that can be controlled are : ( 1 ) up and down relation of viewer and objects / distances between the two ; referring now to fig2 a block diagram of a system for video game display which employs the invention is illustrated . the game controls are illustrated as being a joystick 1 which has four switches ( not shown ) and a pushbutton switch 2 which may be used as a firing button . the four switches of joystick 1 may correspond to the four scanning modes n : 1 , n : 1 , n : 100 and n :- 100 . the pushbutton 2 may be utilized to produce firing trajectories such as ah and bh shown in fig6 and fig9 for example . such trajectories of bullets or missiles are ejected from a gun or missile launcher , a and b shown ( fig6 fig9 ) of the player &# 39 ; s ship . the memory disc storage device 3 is activated by the disc player / controller 4 . the frames retrieved from the memory disc are displayed on crt 5 through the action of the interface control circuitry of crt display controller 6 . the memory disc and disc player / controller circuitry are devices of the type manufactured by pioneer electronics company . the crt display controller 6 is a microprocessor - based device that provides timing and interface control between the crt circuitry and the disc player / controller 4 and the fixed image producer 7 . the fixed image producer 7 generates images that are frequently and intermittently used in the viewing sequence , such as bullet trajectories or scenes of an explosion , for example . the circuitry for the fixed image producer provides for the storage of such frames and movement of the stored frames pursuant to game control . the fixed image producer is activated either by a control device such as pushbutton 2 or a signal from the disc player / controller 4 . the trajectories ah and bh shown in fig6 and fig9 are examples of images which are produced at a fixed position on the crt by the fixed image producer 7 . the organization of the frame sequence stored on the memory disc 3 is systematic , and according to this invention , in a manner that permits them to be accessed in one of four modes at any time , complying to the operation of the joystick 1 . fig3 is an example of a coordinate map of the frames stored on the video disc of fig2 for a space war game having scenes of the type shown in fig4 through 6 . the object of the game is to have a player in a space vehicle 9 voyage through space where many planets 10 , 11 , 12 and 13 , for example , are floating or moving slowly . in addition , the player is looking for an enemy ship 8 hiding behind one of the planets for the purpose of shooting it and destroying it . the player can pilot his ship 9 to move left , right , backward and forward by operating the joystick 1 which has four switch positions . in this particular game , the vertical scan ( n :± 1 ) on the map of fig3 is illustrated by the vertical axis which is labeled no . 0 through no . 80 . the vertical scan produces the left and right movement of the player &# 39 ; s ship . the horizontal scan ( n :± 100 ) is illustrated by the horizontal axis on fig3 . this is labeled no . 0 through no . 10k . the horizontal scan provides for the back and forth movement of the ship . thus , when the joystick 1 is pushed forward , the planets 10 , 11 , 12 and 13 , for example , making up the front scene come closer to the player as if the player &# 39 ; s ship 9 is advancing forward . when the joystick is pulled backward , the front scene backs up as if the player &# 39 ; s ship 9 is backing up . when the joystick is pushed to the left , the whole front scene moves to the right as if the ship 9 is moving to the left . when the joystick is pushed to the right the whole front scene made up of the planets 10 , 11 , 12 and 13 moves to the left as if the ship 9 is moving to the right . if a player keeps pushing the joystick forward in spite of the closing in of a planet in front of the ship , the result will be scenes of collision and the consequent explosion . if a player finds an enemy ship 8 ( fig6 ) behind a planet he will want to bring its figure to the center h of the crt screen by piloting his ship left or right . when the trajectories of the firing beams cross at the enemy ship 8 location there will be an explosion of the enemy ship 8 when the firing button 2 is pushed . these trajectories cross only at the center h of the crt screen . a total of 10 , 000 frames of game scenes are utilized and arranged as shown in the coordinate map of fig3 . each block in fig3 represents a relative position between the player &# 39 ; s ship 9 and the planets 10 , 11 , 12 and 13 of the frame number coincident with the upper right - hand corner of the block . for instance , block a of fig3 shows relative position between the player &# 39 ; s ship 9 and the various planets 10 , 11 , 12 and 13 of frame no . 3590 . that is the frame number at point 14 . on the column of frame 4500 ( two columns to the left of the 3590 ) ten frames are shown vertically . these frames indicate the gradual changes of the relative positions between the player &# 39 ; s ship 9 and the four main planets 10 , 11 , 12 and 13 . these four planets happen to be the largest planets in the scene . the n - shaped link 31 represents the relative position between these four main planets which are shown in block a of fig3 and in addition are shown in fig4 and 6 in pictorial form . looking at the ten representative frames in frame column 4500 , the relative position of the player &# 39 ; s ship 9 with respect to the group of planets changes gradually from right to left during the display of 100 frames from frame 4500 at the top of the column to frame 4599 at the bottom of the column . in other words , on the crt screen the center position of the four planets 10 , 11 , 12 and 13 moves 1 % per frame from the farthest left to the farthest right . meanwhile , in the group the four planets 10 , 11 , 12 and 13 also change mutual positions gradually . on the row of frame nos . 40 , 540 , 1040 . . . ), 9540 and so on , the player &# 39 ; s ship 9 is always almost on the center line of the group of the four planets 10 , 11 , 12 and 13 . however , the distance between the two gradually changes , starting from the middle of one group , frame 40 , to where it almost passes over the next advancing group , frame 9540 . in this kind of layout of frame scenes , the scenes or frames with the last two numbers 99 and the following 00 do not continue because in all frames at the top of the map the player &# 39 ; s ship 9 is at the farthest right , and in all frames at the bottom of the map the player &# 39 ; s ship 9 is at the farthest left with respect to the group of planets 10 , 11 , 12 and 13 . the top and bottom of the frame map must be fenced in to stop overscan . also , both sides of the map must be fenced in to limit the memory of the game . for these reasons , all the frames bordering on all four sides have a collision scene to stop the scan at these frames . when the frame of the collison scene is accessed and displayed , a half collision scene is produced by the fixed image producer 7 ( fig2 ) and displayed until the access to the memory jumps to the nearest one of the explosion frames e1 , e2 and e3 shown in fig1 on the memory disc . after that the game goes to the next scene . the small square symbol 15 indicates a collision between the player &# 39 ; s ship and one of the various planets . this triggers the explosion sequence , starting with the half collision scene produced by the fixed image producer 7 . a second example of a game that may be illustrated according to the present invention is a space war shooting game , scenes of which are pictorially illustrated in fig8 and 10 . in this game fire ball - like rockets 21 are ejected from any enemy ship 18 one by one at random to attack the player &# 39 ; s ship 19 . the distance between the enemy ship 18 and the player &# 39 ; s ship 19 is constant . the player &# 39 ; s ship 19 , however , can move to the left and to the right to avoid the rockets . fig7 is the frame map for this game . the horizontal axis represents the horizontal scan from frame no . 0 to frame no . 4000 . scanning horizontally creates the left and right movement of the player &# 39 ; s ship . the vertical scan is illustrated on the vertical axis labelled as frames no . 0 through 80 . the vertical scan simply provides a time flow . according to this game , the time flow is beyond the player &# 39 ; s control . in other words , the flow of the game in the n : 1 mode is automatic and it proceeds regardless of the player &# 39 ; s control . the n :- 1 mode , wherein the frames are scanned in reverse , is not utilized at all . in this instance the joystick has an effect on the display only when it is moved to the right and left . backward and forward movement will have no effect on the display . the objective of this game is to shoot down the enemy ship 18 , as shown in fig9 in a manner similar to that illustrated in fig6 of the previous game , while at the same time avoiding the fire ball rockets 21 . the memory volume for this game is 4000 frames . each frame or block illustrated in fig7 represents the relative relation among or between the player &# 39 ; s ship 19 , the enemy ship 18 and the fire ball rockets 21 ejected from the enemy ship 18 . in fig7 the enemy &# 39 ; s ship symbol 18 is shown placed at the center of each frame block , but in display scenes fig8 through 10 , the player &# 39 ; s ship 19 is always in the center at the bottom . like the example for the previous game , each block represents the relative position of the frame number coincident with the upper right corner of the block where the horizontal and vertical lines meet . in the frame sequences , the distance between the player &# 39 ; s ship 19 and the enemy ship 18 is kept constant . during the time flow of the vertical scan , fire ball rockets 21 move along five trajectories 20 . one fire ball rocket is on each trajectory line . a particular one of these fire ball rockets has a flying cycle of 100 frames . in other words , on the same row of the map the flying phase of the fire ball rockets are all the same , and in each column they fly 1 % of the distance per frame from the enemy ship to the player &# 39 ; s ship . the five - digit member in frame no . 200 means that the five fire ball rockets traveled 70 %, 30 %, 90 %, 50 % and 10 % on their respective trajectories in this frame . in the next frame on the vertical axis , the number 84062 means the fire ball rockets traveled 80 %, 40 %, 0 %, 60 % and 20 % on the respective trajectories in this frame . therefore all these figures in the frames of the row from 0 to 4000 are the same , while the figures in the column , such as frame no . 210 becomes 84062 because the travel distance has advanced 10 % from frame no . 200 . thus the time flow continues and from the bottom of the map to the top , it continues also . frame 0 means the rocket is at the end of the travel line and also the start of the next rocket cycle , and if the player &# 39 ; s ship 19 is at this position , they will collide and explode as shown by the explosion symbol 17 . as shown in fig1 in the scene just before the collision , the fire ball rocket 21 is displayed almost full size on the screen when it is closest to the player &# 39 ; s ship . this visual image has great appeal to a player . by horizontally scanning the memory the relative position of the player &# 39 ; s ship 19 with respect to the enemy ship 18 changes from the farthest right to the farthest left . to prevent overscan in this mode , fences of many asteroids 22 on both right and left sides are used to block the scenes . the horizontal scan will be in the n : 102 and n :- 98 mode instead of n :± 100 to keep the time flow of the rocket travel during horizontal scan . fig1 is a pictorial illustration of the frame allocation in gross of all the scenes for each of the games on a disc . for example , the 4k block 39 depicting the scenes for game no . 1 is for the space game explained in connection with the memory map of fig7 and the pictorial illustrations of fig8 through 10 . the 10k memory block 37 for the scenes of game 2 are for the space war game illustrated with respect to fig3 and the pictorial illustrations of fig4 through 6 . likewise , a series of scenes for a third game ( not illustrated ) having for example , a 30k frame requirement 41 is illustrated , as well as an 8k block 43 for a smaller game . the explosion scenes e1 , e2 and e3 each take up 0 . 5k of frame space and are allocated on the memory disc at the end of each game frame sequence . the entire storage utilized for scene frames in this example is 53 . 5k . fig1 is a flow chart illustration of the space games described above . however , this particular game procedure is not limiting on the invention . many other applications on the invention described herein are possible . many other types of games may be played and illustrated according to the present invention . for example , car racing games as well as various sports games and shooting games may utilize the present invention to great advantage . all these games may utilize realistic movie excerpts as actual scenes , for example . an example of a racing game display is shown in fig1 through 16 . in this game , the player drives his car in the foreground steering left and right to avoid colliding with several cars in a group 23 . when near a collision with a car in front of him ( fig1 ) a huge figure of the other car appears , which the player finds very impressive . this particular game , for example , can be laid out in the same manner that the space war game illustrated in the memory map of fig7 was laid out . in the racing game , however , the rocket travel of fig7 is simply replaced with a racing group of many cars 23 . thus the relative positions of the cars in the group change gradually , like the planet positions 10 , 11 , 12 and 13 of fig7 changed . in addition , the race course can be changed to a curved one as shown in fig1 , or an up and down one as shown in fig1 . an example of another application of the present invention to illustrate a video game is shown in fig1 and 18 . this game relates to the game of baseball in which the game player can participate by being the batter 26 . as illustrated in fig1 , the frames are organized in a typical televised baseball sequence for a variety of pitches coming from the pitcher 24 . the player as the batter 26 uses a swing button to swing his bat at a time when the ball 25 , thrown by a famous pitcher 24 , is in the strike zone . the player can let the pitch go by if he thinks it will not be a strike . from the moment that the button to swing the bat is pushed , the display scene changes according to the combination of swing time and the nature of the pitch . a variety of pitches may be used , such as a fast ball , screw ball , slow ball , fork ball , knuckle ball , etc ., which may result in either a strike or a ball . this particular game may be implemented in accordance with the invention by using the swing button to generate scanning in a horizontal direction in an n : 102 mode . vertical scan in the n : 1 mode is for the pitcher &# 39 ; s pitching motion and the ball &# 39 ; s travel . scanning in the n : 100 and the n :- 1 mode are not used . this game is able to be organized in a 45k frame volume , which provides fifteen kinds of different pitches and 2 seconds of scene after the swing . what has been described is a memory mapping technique for linear memories which provides a very realistic and interactive visual display on a crt screen . the organization of the scenes can be accomplished through a computer sorting process to provide just about any relative motion between the player &# 39 ; s symbol and the objects in the scene . thus , it should be understood that the foregoing disclosure relates only to preferred embodiments of the invention and that modifications may be made therein without departing from the spirit and scope of the invention as set forth in the appended claims .

a one - dimensional memory storage device , such as a video disc , is utilized to store graphic image symbols for video game displays . the storage device is organized so that the graphic symbols may be retrieved rapidly enough to give the visual impression that the entire display , including background or scene depiction , is changing in response to the player - manipulated controls . the memory organization scheme utilized establishes a plurality of jump sequences . the particular sequence being utilized to withdraw graphic symbol information from memory is determined by the physical movement of a player - operated control device , i . e ., a joystick . certain frequently used scenes , such as explosions , or bullet or rocket trajectories , for example , are generated separately by a fixed image producer . the graphic image symbols that reproduce such a scene on the crt screen are stored in a memory in the fixed image producer which is triggered by the information contained on the video disc or by a player - manipulated control device , such as a pushbutton , for example .

the inventor of the present application synthesizes a hydrophobic compound , triphenylboroxin ( c 18 h 15 b 3 o 3 ), having the following structure ( i ), and is the first person using it as a boron - containing drug in bnct : lipiodol has been used as x - ray contrast medium and lymphography contrast medium . the present inventor and her co - workers in their previously study clearly demonstrated that hepatoma cells in culture are capable of rapidly active uptake of a large quantity of lipiodol by endocytosis with prolonged retention of the lipiodol intracellularly as long as the life span of the cells [ chou f i , fang k c , chung c , lui w y , chi c w , liu r s , and chan w k . lipiodol uptake and retention by human hepatoma cells . nucl med biol ( 1995 ) 22 ( 3 ): 379 – 386 ]. in this invention , the present inventor employs lipiodol as a boron - containing drug carrier in view of its capability of achieving selective and high retention in hepatoma cells . it is found that triphenylboroxin as the boron - containing drug has a property of uniform dispersion in lipiodol and is stable in lipiodol . this inventor further utilizes lecithin to enhance uptake of lipiodol by hepatoma cells , and linoleic acid to increase the solubility of lecithin in lipiodol . as a result , the pharmaceutical composition prepared in the present invention is suitable for use in bnct on hepatoma . it is apparent that the pharmaceutical composition prepared in the present invention has a great potential for use in bnct on other cancers such as breast cancer or malignant melanoma . to a round - bottom flask 3 g of phenylboronic acid and 1 ml of ethanolamine catalyst were added , and the mixture was heated with an oil bath at 130 ° c . for 24 hours while stirring by a magnetic stirrer . a red - brown solution was thus obtained . a portion of the red - brown solution was taken for thin - layer chromatography analysis ( tlc ), wherein a mixed solvent of hexane and ethyl acetate ( hexane : ethyl acetate = 5 : 2 , v / v ) was used as a mobile phase to develop the solution drop . after the silica gel tlc film being colored by i 2 vapor , a dark point was found at rf of 0 . 5 . in order to remove the remaining ethanolamine , the red - brown solution was introduced into a column packed with aluminum oxide , and eluted with ethyl acetate ( eluent ). the eluate collected in the beginning section , after the solvent therein being evaporated , was subjected to another elution in a column packed with silica gel by using a mixed solvent of hexane and ethyl acetate ( hexane : ethyl acetate = 8 : 1 , v / v ) as an eluent . the cluate was collected in consecutive separate portions , each of which was dropped on a silica gel tlc film and developed by a mixed solvent of hexane and ethyl acetate ( hexane : ethyl acetate = 5 : 2 , v / v ) for carrying out tlc analysis . the silica gel tlc films were colored by i 2 vapor , and the one with a rf of 0 . 5 was the target . the collected eluate portion having rf of 0 . 5 was evaporated in vacuo to remove solvents contained therein , and a liquid product having hydrophobic triphenylboroxin as a major portion was obtained . the liquid product purified by the aforesaid liquid chromatography was dropped on a thick silica gel tlc film ( 2 mm ), and developed with a mixed solvent of hexane and ethyl acetate ( hexane : ethyl acetate = 5 : 2 , v / v ). the product at rf of 0 . 5 was scrapped . the resulting powder was placed in a tube and dissolved by ethyl acetate . the solution was subjected to gas chromatography - mass spectrum ( gc - ms ) analysis , where a major product having a molecular weight of 312 was observed . 5 μl of the triphenylboroxin liquid product prepared above was dropped on an α track detectable film ( koda , lr - 115 film ). after being allowed to dry overnight , the film was placed in tsing hua open - pool reactor ( thor ), where it was irradiated by a thermal neutron beam for a predetermined period of time . the irradiated film was removed from the thor , and developed by etching in 10 % naoh aqueous solution at 60 ° c . with sonication for 50 minutes . the etched film was washed with distilled water to remove residual naoh , dried , and observed with phase - contrast microscope . α tracks were found in the area of the drop of the triphenylboroxin liquid product on the developed film . to lipiodol , linoleic acid and lecithin in a round - bottom , anhydrous ethanol was added , and then heated at 70 ° c . for 20 minutes while stirring . until the solution became completely clear , the triphenylboroxin liquid product prepared in preparation example was added , and the stirring and heating was maintained for another 10 minutes . the resulting mixture was placed in a rotary evaporator at 50 ° c . to remove the ethanol therefrom thoroughly , so that a triphenylboroxin entrapped lipiodol ( tel ) was obtained in the form of an oily light yellow - brown clear liquid . an appropriate ratio of the components for preparing tel was : triphenylboroxin liquid product : lipiodol : lecithinlinoleic acid : anhydrous ethanol = 0 . 03ml : 1 ml : 20 mg : 0 . 06 ml : about 30 ml . the procedures of α track of triphenylboroxin after neutron irradiation in preparation example were repeated except that the triphenylboroxin liquid product was replaced by tel . the observation results of the developed film show that there are α tracks uniformly distributed in the area of the drop of tel on the developed film , and no α track found outside the drop . to a teflon ® high pressure digestion vessel 0 . 5 ml of tel , 3 ml of nitric acid solution ( 14 n , 65 %) and 0 . 5 ml of hydrogen peroxide solution ( 30 – 35 %) were added . the vessel was sealed with a cap and placed in a microwave digestion oven ( mls 1200 miesfone , italia ) for the following digestions : 300 w for 15 minutes and 600 w for 10 minutes . after cooling for 60 minutes to reduce pressure in the vessel , the cap was turned off and the mixture in the vessel became a clear solution indicating a complete digestion . the digested solution was pour out , diluted with distill water , and assayed by inductively coupled plasma - atomic spectroscopy ( icp - aes , optima 2000 dv , perkin elmer instruments ). the boron content of tel is 12000 ppm . the boron content of tel varies with the formulation of preparing tel . an appropriate range of the boron concentration based on the weight of tel is from 1 × 10 3 ppm to 3 × 10 4 ppm . for testing the stability of tel in human serum , 0 . 1 ml of b - lipiodol having 12000 ppm boron was mixed with 5 ml human serum , and then incubated at 37 ° c . under 75 rpm to form a suspension of tel vesicles in the serum . for quantitatively testing the release of boron from the oily preparation into the aqueous serum , 2 ml of serum was regularly sampled from each test tube which was maintained at 37 ° c . and rotated with 75 rpm . the boron contents of the samples were measured by icp - aes , and the results show that the boron content of the tel vesicles gradually reduced to 88 % in the first four hours and stabilized thereafter , and 85 % of the boron content was still retained in the tel vesicles after 96 hours , indicating that triphenylboroxin was stably retain in lipiodol . 0 . 15 ml of tel was added to 100 ml of the complete dulbecco &# 39 ; s modified eagle medium ( cdmem ), and then homogenized by sonication of 75 w power under sterile condition so that a tel - cdmem liquid was formed . 7 ml of the tel - cdmem was added to hepg2 cells which were cultured in cdmem to 70 % confluence , and the absolute boron content in the culture after the addition was 16 μg . when hepg2 cells were incubated with tel - cdmem , tel globules were detected on the cell membrane by inverted light microscopic examination . after 1 h , the tel on the cell membrane was found to be emulsified to form smaller globules . after 8 h of incubation with tel - cmem , most of the hepg2 cells had intracellular tel globules in the cytoplasm , as confirmed by inverted light microscope . the intracellular b - lipiodol globules appeared to be larger in size and quantity as time increased . by 48 h , large numbers of tel globules accumulated in the cytoplasm , causing the cell size to enlarge and the plasma membrane to bulge . 7 ml of the tel - cdmem was added to hepg2 cells which were cultured in cdmem to 70 % confluence , and the absolute boron content in the culture after the addition was 16 μg . after exposing of the hepg2 cells to tel - cdmem for predetermined periods of time , cells were washed twice with 5 ml of phosphate buffer ( ph 7 . 4 ) to remove any loosely attached tel . cell were collected by centrifugation , and digested . the boron contents of the collected and digested cells were assayed by icp - aes . the results reveal that the boron content of the collected and digested cells increase as the culture time of tel - cdmem increases , the boron contents at the culture time of 12 and 24 hours are 58 and 118 ppm respectively , and by 48 hours it reaches 214 ppm , which is sufficient high for bnct .

a pharmaceutical composition for boron neutron capture therapy , and in particular for bnct on hepatoma is disclosed . the pharmaceutical composition contains a therapeutically effective amount of triphenylboroxin as a boron source and a pharmaceutically acceptable carrier , such as lipiodol .

while the cooker in accordance with the present invention is useful in cooking many different kinds of particulate foodstuffs , it will be described by way of example as a cooker for cooking individual portions of spaghetti or other pasta to order . as shown by way of example in the drawings , the cooker comprises a cabinet 1 having a base 2 and a top 3 . a control and indicator panel 4 projects upwardly above the top 3 at the rear of the cabinet . in an upper portion of the cabinet there is a tank 5 which drains into a reservoir 6 which is located at one side of the cabinet and extends downwardly from the tank 5 . the reservoir 6 is adapted to contain water the level of which is controlled by a ball switch 7 . the water in the reservoir 6 is heated to a predetermined temperature by electrical heating elements 8 . the tank 5 is adapted to receiving a plurality of cooking pots 10 each of which is of a size to receive a single individual serving of pasta or other foodstuff . each of the pots 10 has a cylindrical side wall 10a in which there are provided spaced apertures 11 and a bottom 10b having small holes 10c central opening . a removable cover 12 is provided for each of the pots . each pot is individually supported by a cone 13 which extends up through the central aperture in the bottom of the pot and has an annular flange 13a on which the pot rests . the upper end 13b of the cone is tapered . an annular grommet 14 of heat resisting rubber or plastic material provides a seal between the pot and the cone . near its lower end and just inside the pot , the cone is provided with holes 15 for injection of hot water into the pots as will be described below . the pots extend up through holes in the top 3 of the cabinet and can be lifted off the supporting cones 13 for removal from the cooker , for example to empty the cooked pasta . in the embodiment of the invention shown by way of example in the drawings , means is provided for raising and lowering the pots 10 and for supplying hot water to the pots for cooking the pasta or other foodstuff therein . to provide for vertical movement of the pots , each of the cones 13 is supported by a rod 16 which extends down through the bottom 5b of the tank 5 and is connected at its lower end with a rack 17 . the rack 17 meshes with a pinion 18 of a reversible gear reduction electric motor 19 . a pot 10 supported on the flange 13a of the cone 13 can thus be lowered from the raised position shown in fig3 to the lowered position shown in fig4 by rotation of the motor pinion 18 in one direction and raised from the lower position to the upper position by rotation of the motor pinion in the opposite direction . hot water is supplied to each of the pots 10 by a spindle 20 which is received inside the hollow cone 13 on which the pot is supported . the spindle 20 has holes 21 which register with the holes 15 of the cone 13 when the cone and pot are in lower position as illustrated in fig4 . an upper portion 20a of the spindle is of reduced diameter and is surrounded by a cylindrical mesh 22 which is retained by a nut 23 . when the pot 10 and supporting cone 13 are in raised position as shown in fig3 water can drain from the pot through the holes 15 and past the mesh 22 . water is supplied to each of the spindles 20 by a pipe 25 provided with a t - fitting 26 connected with the nipple by an adaptor 27 which extends through the bottom 5b of the tank 5 . a watertight seal is provided by a gasket 28 and nut 29 screwed onto a threaded portion of the adaptor 27 . the rod 16 by which the cone 13 and pot 10 are supported extend up through the t - fitting 26 , adaptor 27 and spindle 20 . a watertight seal with the t - fitting 26 is provided by a gland 30 and gland nut 31 . at the upper end of the spindle , a seal is provided by an o - ring 24 . hot water under pressure is supplied to the spindles 20 when the pots are in lowered position by a pump 33 through the water circuit shown schematically in fig5 . the pump 33 takes water from the reservoir 6 through a line 34 and strainer 35 . when solenoid valves 36 and 37 are open , hot water under pressure is delivered by the pump 33 through a line 38 , filter 39 and booster heater 40 to a header line 41 to which the supply pipes 25 of the spindle are individually connected through solenoid valves 42 . when a pot is in lowered position , the corresponding solenoid valve 42 is open to supply hot water to the pot . when a pot is in raised position , the valve 42 is closed and a corresponding return valve 43 is opened to permit water to return to the reservoir 6 through a return line 44 . a temperature gauge 9 on the panel 4 indicates the temperature of water in the header line 41 . the filter 39 is designed to remove starch and other solid particles from the recirculated water . in order to prolong the useful life of the filter , provision is made for backwashing the filter to remove accumulated solids . backwash is effected by closing solenoid valves 36 and 37 and opening solenoid valves 45 and 46 so that water flows through the filter 39 in reverse direction and is discharged through a waste line 47 . pressure in the deliver line of the pump 33 is indicated by a pressure gauge 48 on the panel 4 . a pressure responsive switch 49 shuts off the pump 33 in the event the pressure exceeds a predetermined value . moreover , a safety valve 50 is provided on the filter 39 . water is supplied to the reservoir 6 from a supply line 51 through a solenoid valve 52 controlled by the ball switch 7 in the reservoir . water is thus supplied to the reservoir 6 for initially filling the reservoir to a desired level when the cooker is put into operation and for supplying make - up water to replace water lost through evaporation and absorption by the foodstuff or through backwashing of the filter 39 . in order to simplify the drawing , only four pots are shown in fig5 . however , it will be understood that the number of pots can be increased or decreased according to the desired capacity of the cooker . electric circuitry of the cooker is shown in fig6 and 7 . while circuitry is shown for only four pots , it will be understood that the number of pots can be increased or decreased as desired . a power supply 54 provides lower voltage -- for example 110 volts ac -- between a ground line g and a low voltage line v 1 for control circuits and a higher voltage -- for example 220 volts ac -- between the ground line g and a high voltage line v 2 for a power circuit for operating the pump 33 and water heaters 8 and 40 . as seen in fig6 each of the gear reduction motors 19 for lowering and raising the corresponding pot 10 is controlled by upper and lower limit switches 55 and 56 and by a timer 57 which may be mechanical , electrical or combined mechanical and electrical . the timer 57 is designed to provide two different cooking times and is controlled by push button switches 58 , 59 and 60 on the panel 4 . the desired cooking time is selected by pushing either push button 58 or 59 . after the pasta has been put in the corresponding pot and the cover 12 has been placed on the pot , push button 60 is pushed to initiate the cooking process . as upper limit switch 55 is open and lower limit switch 56 is closed , the motor 19 is energized to run in a direction to lower the cone 13 and the pot supported thereby . when the pot reaches the lower limit of its travel , lower limit switch 56 is opened to stop the motor 19 . the lower limit switch 56 is a double throw switch . when the pot reaches the lower limit of its travel , the switch 56 is actuated to energize a relay 53 which operates to open solenoid valve 42 ( see fig5 ) and close solenoid valve 43 thereby supplying hot water from the header line 41 to the lowered pot . indicator lights 61 on the panel 4 indicate the operation of the several push buttons 58 - 60 . at the end of the cooking time , the timer operates to energize the motor 19 to raise the pot . when the pot is raised , the relay 50 is deenergized so as to close solenoid valve 42 and open solenoid valve 43 . water is thereby cut off from the spindle 20 and instead is returned to the reservoir 7 through the return line 41 . a fourth push button 62 is provided on the panel 4 for raising a pot prior to its being raised under control of the timer 57 . when the push button 62 is operated , the pot is raised , solenoid valve 42 is closed and solenoid valve 43 is opened to return the water to the reservoir . fuses 63 protect the control circuitry . during the cooking cycle , hot water under pressure supplied by the pump 33 is injected into a lower portion of each of the lowered pots through holes 21 in the spindle 20 which registered with holes 15 in the cones 13 . the pasta is thereby cooked by action of the hot water and at the same time is stirred by the jets of water entering through the holes 15 so as to keep the pasta from sticking to the pot or to itself . the water is discharged through the openings 11 in the side wall of the pot which in cooperation with the rate of flow of the injected water determine the water level in the pot . when the pot is raised at the end of the cooking cycle , the water in the pot drains out through holes 10c and 15 and through the mesh 22 . water discharged into the tank 5 drains back into the reservoir 6 . controls for the water circuit shown in fig5 including pump , heater and valve controls are shown in fig7 . when it is desired to put the cooker into operation -- starting with the reservoir 6 empty -- a push button switch 65 on the panel 4 is depressed to close a circuit which activates a timer 66 and to provide power for the float switch 7 . the float , being in lower position , activates a relay 67 so that solenoid valve 52 is opened to permit water to enter the reservoir from the supply line 51 . when the proper water level is reached , the float switch 7 opens and permits power to flow to relays 68 to supply power to heating elements 8 in the reservoir 6 if thermostats 69 are closed . when the proper temperature is reached , thermostat 69 open to shut off power to the heating elements . a light 70 on the panel 4 indicates operation of the push button 65 . in the event no water enters the reservoir 6 or the water level does not reach a predetermined level within a predetermined time , the timer 66 will open so that no power can be supplied to the pump 33 or the booster heater 40 . if the required water level in the reservoir is reached within the prescribed time , depressing a push button 71 will provide power for a relay 72 so that relay 73 can be activated to start the pump 33 , provided the pressure is within the limit of pressure switch 49 . relay 74 is also operated to supply current to the booster heater 40 provided that a thermostat 75 controlling water temperature is closed . power is also supplied for operating the solenoid valves 36 , 37 , 45 and 46 under control of a push button switch 76 on the panel 4 . when switch 76 is in opened position as shown , solenoid valves 36 and 37 are open to provide hot water to the pots 10 ( when in lowered position ) as described above . when the push button switch 76 is depressed , solenoid valves 36 and 37 are closed and solenoid valves 45 and 46 are opened to provide backwashing of the filter 39 as described above . lights 77 and 78 on the panel 4 indicate the operation of push button switches 71 and 76 respectively . the circuitry shown in fig7 is protected by fuses 79 . a clock 80 connected in parallel with the pump 33 records the time the pump is in operation and thus gives an indication as to when the filter should be backwashed or replaced or other servicing should be carried out on the equipment . the operation of the cooker in accordance with the invention will be readily understood from the foregoing description . starting up of the cooker is effected by pushing push button switch 65 to fill the reservoir 6 with water to the desired level and to energize heating elements 8 to bring the water up to the desired temperature which may be for example about 190 °. push button switch 71 is then depressed to start the pump 33 , energize the booster heater 40 and to supply current to open solenoid valves 36 and 37 . with the machine thus readied for operation and with the pots 10 in raised position , pasta or other foodstuff to be cooked is then placed in one or more of the pots 10 and the cover 12 is put on . for the pots into which foodstuff has been placed , push button 58 or push button 59 is depressed to provide the desired cooking time and then push button 60 is depressed to start the cooking cycle under control of the timer 57 . in the cooking cycle , the pot is lowered to its lower position and water is supplied through the spindle 20 to cook the foodstuff while keeping it in a continual state of circulation . the water is continually filtered by the filter 39 and its temperature is raised to the desired cooking temperature , e . g . 205 ° f ., by the booster heater 40 . at the end of the cooking time as selected by the push button 58 or 59 and controlled by the timer 57 , the water is shut off and the pot is raised , whereupon any water remaining in the pot is drained off through the holes 10c in the bottom of the pot and the holes 15 in the cone 13 . the pot can then be lifted off the cone 13 for emptying the cooked foodstuff from the pot . the pots are preferably teflon coated so that the contents can easily be removed by inverting the pot . it will be noted that the pots are operable individually and independently from one another so that one , some or all of the pots can be used . moreover , the cooking time for each pot is selected individually so that the foodstuff in different pots can be cooked different periods of time as desired . it will be noted that the water for cooking the foodstuff is recirculated so that the energy required for heating the water is conserved . during recirculation of the water , starch and other solid material is removed by the filter 39 . when it is desired periodically to backwash the filter to remove the material collected , this is accomplished by depressing push button 76 whereupon solenoid switches 36 and 37 are closed and solenoid switches 45 and 46 are opened so as to cause water to flow in reverse direction through the filter 39 and be discharged through the waste conduit 47 . while a preferred embodiment of the invention is illustrated in the drawings and is herein particularly described , it will be understood that many variations and modifications may be made and that the invention is thus in no way limited to the illustrated embodiment .

a cooker for foodstuff in particulate form , in particular pasta , comprises a plurality of perforate pots , each of which is of a size to cook an individual portion . the pots are individually movable vertically in a tank between a raised position and a lower position . the foodstuff is put in the pot when in raised position . when the pot is lowered , boiling water pumped from a reservoir is injected into the pot to cook the foodstuff while stirring it to prevent its sticking to the pot or to itself . the water drains into the tank and is returned to a hot water reservoir . after a preset time interval the pot is returned to its raised position for discharge of the cooked foodstuff .

referring generally to the drawings , wherein common reference numerals are used to refer to like elements , there is shown a nasal mask 10 . mask 10 generally consists of an air tube connector 12 , a mask frame 14 , a compliant face engaging mask portion 16 , and means 18 for securing the mask to a patient &# 39 ; s head , and a variable orifice member 20 . the apparatus may be secured to the head of the user in a known manner , such as by a head band . as will be explained in greater detail below , in use the nasal mask is mounted over the patient &# 39 ; s nose to deliver pressurized air to effect treatment . fig1 is a front perspective view of a mask constructed in accordance with the disclosure . air tube connector 12 preferably is made of a suitable medical grade plastic material with sufficient rigidity to retain its shape during use . air tube connector 12 has an inlet port 22 configured to be connected to a source of pressurized gas , such as by a flexible air tube connected , in turn , to a source of pressurized air in a known manner . the source of pressurized gas may be any source suitable for treating sleep apnea , and may be a source of pressurize air with or without supplements such as oxygen . the source of gas may provide continuous pressure as used in ncpap treatment , or may provide varied levels of pressure such as used in bipap ™ treatment . in either case , the maximum gas pressure typically is in the range of about 5 to about 15 centimeters of water . air tube connector 12 is connected in sealing engagement to mask frame 14 . preferably , air tube connector 12 is rotatably mounted to the mask frame for adjustability . most preferably , air tube connector 12 also is rotatably connected to an air tube at inlet port 22 to provide maximum adjustability between the air tube and the mask . mask frame 14 is substantially rigid to provide support for the air tube connector and the face engaging mask portion 16 . mask frame 14 may be of any suitable plastic or metal material to provide such support , and has apertures to receive air tube connector 12 and variable orifice member 20 . preferably , the aperture in mask frame 14 to receive variable orifice member 20 is configured as a cylindrical wall projecting outward from the mask frame to engage a variable orifice member cap , as described in greater detail below . the means 18 for securing the mask to a patient &# 39 ; s head is attached to mask frame 14 . as shown , means 18 may be a head strap holder and a head band or strap . alternative devices are also contemplated , such as a harness or plurality of strap engaging members disposed at various positions on the mask . accordingly , as used herein , &# 34 ; means for securing the mask to a patient &# 39 ; s head &# 34 ; is broadly intended to include all of the foregoing structures , equivalent structures and all other suitable structures for mounting the mask to the patient &# 39 ; s head . also attached to mask frame 14 is face engaging mask portion 16 . face engaging mask portion 16 preferably is made of a soft synthetic material which is comfortable to wear in contact with the face , and which can form a substantially airtight seal to the face around the nose . one suitable material is a soft , medical grade silicone . the face engaging portion is sealingly mounted to the mask frame by any suitable method , such as by gluing , welding , lip seal frictional engagement , etc . referring now to fig2 a side view of the mask of fig1 mounted to a patient &# 39 ; s face , the air tube connector is connected to an air tube 24 at inlet port 22 . air tube 24 is , in turn , connected to a source of pressurized air , as schematically illustrated in fig2 . a head band 26 holds the device in place relative to the user &# 39 ; s head , preferably by engaging the strap holder attached to the mask frame . as shown , a foam or other cushioned pad 30 may be placed between the strap holder and the forehead of the user for added comfort . as will be appreciated , pad 30 may be pre - attached to the strap holder for ease of use . headband 26 preferably is a cloth or plastic strap with a simple fastening structure such as a hook and loop fastener , e . g ., a velcro ™ fastener . as shown in fig1 and 2 , and described in greater detail below , a variable orifice member 20 is provided on the mask . as shown in fig1 and 2 , variable orifice member 20 preferably is mounted to the mask frame . fig3 is a front perspective view of an alternative configuration wherein the variable orifice member 20 is mounted to the air tube connector 12 . as shown throughout the figures , the device includes a variable orifice vent aperture member 20 . variable orifice vent aperture member 20 preferably is mounted to the mask frame , as shown in fig1 - 2 , although it is contemplated that the variable orifice member may be mounted to the primary tube , nasal tube , or other similar conduits or connectors adjacent the patient &# 39 ; s nose . one such configuration is illustrated in fig3 wherein the variable orifice member is mounted to the air tube connector . in one construction , variable orifice vent aperture member 20 is configured as a cap to mount onto and engage projecting walls of a cylindrical opening in the mask frame or other associated structure ( not shown ). this is just one method of mounting the variable orifice vent aperture member to the device , and other structures and methods will occur to those skilled in the art with practice . referring now to fig4 a - 4d , the variable orifice cap 20 is shown in greater detail . fig4 a is a perspective view of the variable orifice cap having vertical side walls 30 and an aperture defining surface 32 . the variable orifice cap is shown in fig4 a in the first , unexpanded state defining aperture 34 &# 39 ; having a first , reduced diameter . referring now to fig4 b , aperture defining surface 32 is shown in a second , expanded state defining an expanded aperture 34 &# 34 ; having a second diameter which is larger than the diameter of 34 &# 39 ;. fig4 c is a perspective sectional view of the variable orifice cap of fig4 a shown in the unexpanded state . as shown , side walls 30 have a first thickness sufficient to give rigidity to the cap and frictionally engage a cylindrical projecting wall on the device . aperture defining surface 32 is of substantially reduced thickness compared to side wall 30 , and may taper from a first thickness at a point 36 adjacent side wall 30 to a very thin , flexible thickness 38 immediately adjacent aperture 34 &# 39 ;. referring now to fig4 d , a perspective section view of the variable orifice cap of fig4 b showing aperture defining surface 32 in the expanded state , the aperture defining surface 32 is expanded in the area adjacent the aperture to define larger expanded aperture 34 &# 34 ;. more particularly , the reduced thickness portion 38 of surface 32 stretches under pressure to expand the diameter of the aperture . at least the aperture defining surface 32 of variable orifice cap 20 is made of a flexible material capable of expanding and contracting , such as latex rubber . in use , the variable orifice cap is mounted over and onto the projecting wall of the mask . the mask is placed against the patient &# 39 ; s face over the nose and the source of pressurized air is activated . during inhalation the pressure at the orifice cap is at a minimum level and the aperture defining surface 32 is in the unexpanded state shown in fig4 a , 4c . during exhalation the gas pressure at orifice cap increases and exerts pressure upon orifice defining surface 32 to cause the surface to stretch and expand , creating expanded orifice 34 &# 34 ; as shown in fig4 b and 4d . the variable orifice cap is an improvement over fixed aperture devices because the first , unexpanded aperture state allows efficient transfer of pressurized gas to the nose of the patient at relatively low pressure during inhalation . conversely , during exhalation the gas pressure adjacent variable orifice cap substantially increases and the increased pressure causes orifice defining surface 32 to stretch and expand , resulting in the aperture assuming a larger diameter expanded state . this allows more exhaled gas to exit the device through the aperture than a fixed orifice device , which typically has an opening on the order of the unexpanded state of the variable orifice . with a fixed orifice device much of the exhaled gas backs up into the source tube , and may be re - inhaled by the patient during subsequent inhalation . advantageously , the variable orifice cap may be used with any form of positive nasal airway pressure therapy , e . g . ncpap or bipap ™ therapy . of course , numerous modifications and alterations to the variable orifice will occur to those skilled in the art . by way of example only , the stretchable orifice defining surface could be mounted to the mask in a variety of ways , such as by mounting the stretchable membrane directly to a surface of the device across an opening , such as by gluing a latex rubber membrane defining the variable orifice to an inside surface of the mask over an opening . similarly , a substantially flat variable orifice defining member could be placed over aperture 34 , with a substantially rigid open - centered cap placed over the orifice defining member to capture the orifice defining member under the cap . in addition , it will be understood that the variable orifice member can be positioned at other locations than shown in the figs ., as long as the variable orifice member is placed reasonably close to the patient &# 39 ; s nose along the path of the gas supply . these and other modifications will occur to those skilled in the art after learning of and practicing the apparatus disclosed herein . the device may be fabricated in whole or in part from disposable or reusable plastics such as abs plastic , polystyrene , polyethylene terathalate , polycarbonate , polyurethanes , polyesters , polypropylene , polyethylene , acrylics , steel , aluminum , titanium , tantalum , alloys of the foregoing , etc . and may be fabricated by any suitable techniques such as blow or injection molding , extrusion , grinding , cutting , etc . the entire device may be disposable , or only parts of the instrument may be disposable . for example , all parts other than the face engaging portion of the mask might be relatively permanent with only the face engaging portion being periodically replaced . the foregoing description contains many specifics and numerous alternative structures and combinations will occur to those skilled in the art . as previously stated , for example , it is contemplated that a plurality of variable orifice members may be provided at various locations on the device to achieve substantially the same results . these and numerous other changes , variations and improvements will occur to those skilled in the art with practice of the invention claimed in the accompanying claims .

a nasal positive airway pressure mask is provided having a variable orifice venting aperture member . the variable orifice venting aperture member preferably is mounted to the mask frame , but may be mounted at other locations . the variable orifice vent aperture member expands under increased pressure , e . g ., during exhalation , and contracts to its original diameter at lower pressures , e . g ., during inhalation , to provide variable venting capacity during positive airway pressure treatment .

fig1 illustrates an introducer 10 which includes a sheath 12 having a lumen 14 . the sheath 10 is approximately 80 centimeters in length and is formed of a polymer material with a durometer in the range of about 50 d and 70 d . the sheath 10 has a diameter of approximately 0 . 1 centimeters , and the lumen 14 of the sheath 12 has a diameter slightly greater than an outside diameter of a deployment catheter 44 . the sheath 12 includes a longitudinal slit 34 in the wall of the sheath 12 . the slit 34 is approximately 60 centimeters in length and extends from the proximal end of the sheath 12 to a position intermediate the proximal and distal ends of the sheath 12 . the sheath 12 also includes an integral tab 24 at the proximal end of the sheath 12 . the integral tab 24 is made of a polymer material and is approximately 2 centimeters in length . finally , the sheath 12 includes purge holes 36 at the distal end of the sheath 12 . the purge holes 36 can vary in diameter but preferably the holes 36 have a diameter of approximately 0 . 02 centimeters . the introducer 10 also includes a holder 16 having a lumen 22 . the holder 16 is slideably disposed about the proximal end of the sheath 12 . the holder 22 is made from polyethylene but can be formed from other material like plastic or a polymer . the holder 16 is generally cylindrical in shape , but the proximal section 18 is tapered . the outside diameter of the proximal section 18 is approximately 0 . 07 centimeters while the diameter of the distal section 20 is approximately 0 . 1 centimeters . the holder 16 has a length of approximately 11 . 5 centimeters . a stop 30 is attached to the periphery of the sheath 12 at an intermediate position along the sheath 12 . the stop 30 is cylindrical in shape and is made of nylon but can also be formed from plastic or a polymer . the length of the stop 30 is approximately 1 . 3 centimeters while the diameter of the stop 30 can vary but the preferred diameter is 0 . 18 centimeters . a zipper 26 is slideably disposed about the sheath 12 and is approximately 4 . 5 centimeters in length . the zipper 26 is generally cylindrical in shape and has a lumen 28 . the zipper 26 is formed of polyethylene but can also be made from plastic or a polymer . the lumen 28 of the zipper 26 has a diameter slightly greater than the outside diameter of the sheath 12 . the outside diameter of the zipper 26 can vary but the preferred diameter is 0 . 18 centimeters . fig2 illustrates a cross sectional view of the sheath 12 between the holder 16 and the zipper 26 . the longitudinal slit 34 runs completely through the wall of the sheath 12 . the zipper 26 is slideably disposed about the sheath 12 . fig3 illustrates a cross sectioned view of the sheath 12 between the stop 30 and the distal end of the sheath 12 . purge holes 36 extend through the wall of the sheath 12 . fig4 illustrates an introducer system 38 which includes the introducer 10 slideably disposed about a deployment catheter 42 . the deployment catheter 42 is an elongated tube with a lumen 48 . preferably , the proximal section 44 of the deployment catheter 42 is formed of pellethane material having a durometer in a range of about 60 d to 75 d . the proximal section 44 is sufficiently flexible to transverse the vasculature of the human body , but is sufficiently rigid so that it can be pushed distally through the sheath 12 . the distal section 46 of the deployment catheter 42 is preferably formed of a pellethane material having a durometer of between 25d and 55d with a durometer of 40d being the preferred durometer . the introducer system 38 also includes a winged hub 40 coupled to the proximal section 44 of a deployment catheter 42 . the winged hub 40 is made from plastic and aids in the insertion of the deployment catheter 42 into the vascular of the body . furthermore , the system 38 includes an embolic coil 50 attached to the deployment catheter 42 and disposed within the sheath 12 of the introducer 10 . the embolic coil 50 may take various forms and configurations and may even take the form of a randomly wound coil , however , a helically wound flexible embolic coil 50 is illustrated in fig4 . fig5 illustrates the holder 16 being moved proximally to expose the integral tab 24 . the integral tab 24 is raised slightly , forcing the proximal end of the sheath 12 to separate from the deployment catheter 42 through the longitudinal slit 36 . fig6 illustrates the winged hub 40 , the deployment catheter 42 , and the holder 16 being moved distally , forcing the sheath 12 to separate from the deployment catheter 42 through the longitudinal slit 36 and pushing the embolic coil 50 out the distal end of the sheath 12 . fig7 illustrates the winged hub 40 , the deployment catheter 42 , and the holder 16 being moved proximally , pulling the embolic coil 50 back into the distal end of the sheath 12 . fig8 illustrates the zipper 26 being moved proximally over the sheath 12 causing the sheath to reattach about the deployment catheter 42 through the longitudinal slit 36 . the embolic coil introducer system operates to introduce a deployment catheter and embolic coil into the vasculature of the human body . with the introducer slideably disposed over the deployment catheter , the holder is positioned over the integral tab causing the introducer to be held to the deployment catheter . in this configuration , the system can be inserted into a delivery catheter . the sheath of the introducer protects the embolic coil as the distal end of the system is inserted into the patient . the system is introduced until the stop generally reaches the proximal end of the delivery catheter . at this point , the holder is moved proximally to expose the integral tab . then , the integral tab is raised slightly to begin separating the sheath from the deployment catheter through the longitudinal slit . to continue separating the sheath , the deployment catheter and holder are moved distally which forces the remaining part of the sheath off the deployment catheter . the sheath allows the deployment catheter to enter the vasculature more easily ; otherwise , the flexible deployment catheter would bend as it was being pushed distally . at the same time the sheath is separating from the deployment catheter , the embolic coil attached to the distal end of the catheter exits the sheath . from this position , the physician can deploy the embolic coil at a preselected position within a vessel . once the coil is no longer attached to the deployment catheter , the system is removed from the vasculature and another system is introduced in the same manner when more coils are required . if , before the embolic coil is deployed , the physician decides to retrieve the coil , the sheath can be reattached , and the system can be reused . to do this , the deployment catheter is pulled proximally until the coil is again disposed within the sheath . then , the zipper is slid from the stop to the holder , reattaching the sheath onto the deployment catheter through the longitudinal slit . the holder is then slid over the integral tab to hold the sheath to the deployment catheter . finally , the system is removed from the patient . a novel system has been disclosed in which a deployment catheter and embolic coil are introduced into the vasculature of the body . although a preferred embodiment of the invention has been described , it is to be understood that various modifications may be made by those skilled in the art without departing from the scope of the present invention . for example , there are many variations and modifications of the embolic coil , including numerous coil winding configurations , or alternatively , other types of vascular occlusive devices may be utilized , such as dilation balloons , radiopaque fluids , and liquid medications . these and other modifications would be apparent to those having ordinary skill in the art to which this invention relates and are intended to be within the scope of the claims which follow .

an apparatus and method for introducing a medical device deployment system into the vasculature of a human body and then using the deployment system for placing a medical device at a preselected position within a vessel , and an apparatus and method for introducing a medical device deployment system into the vasculature of a human body and then subsequently retrieving the deployment system , where the apparatus and method include an introducer having a detachable and reattachable sheath disposed about a deployment catheter .

the inventive system and methods disclosed herein comprise a simple - to - insert suture anchor which allows adjustment of suture or tissue tension prior to deployment , does not change the tension on the suture or tissue ( and as a result , the captured tissue ) when it is deployed , does not require a knot to secure the suture or tissue , and accepts multiple suture ends . referring now more particularly to the drawings , there is shown in fig1 - 6 a suture anchor 10 constructed in accordance with the principles of the present invention . the anchor 10 comprises a body 12 having a plurality of proximal suture barbs 14 , as well as bone barbs 16 . a portion of the outer surface of the body 12 comprises a suture recess 18 . an inner cavity 20 ( fig3 ) is provided for accommodating a suture pulley rod , to be described below . the distal end of the anchor body 12 includes bone displacement tabs 22 . within the suture recess 18 are disposed a suture pinch ramp 24 , a suture cleat 26 , and a suture eyelet 28 , which extends transversely through a width of the body 12 so that it is open to opposing sides of the body . now with reference to fig7 - 13 , the insertion system 30 for the anchor 10 will be described . the insertion system or inserter 30 comprises a suture pulley rod 32 ( fig7 ), suture cleat retainers 34 on the distal end of the pulley rod 32 ( also fig7 ), and an insertion tube 36 . in some embodiments , an optional metal distal tip 38 ( fig9 ) may be employed . a handle portion 40 of the insertion system 30 is illustrated in fig1 - 13 . the handle portion 40 comprises a knob release slide 42 and a proximal knob 44 . the anchor 10 has a number of features that are important to its innovative function . for example , the suture barbs 14 pinch the suture against the surrounding bone when the implant is deployed . the remaining barbs are the bone barbs 16 , distal to the suture barbs 14 , function to engage the bone during the initial and final deployment . the suture recess 18 , because of its recessed profile relative to remaining portions of the outer surface of the body 12 , allows the suture to slide between the anchor body and adjacent bone during the initial deployment . the inner cavity 20 for the suture pulley rod 32 , allows for the metal suture pulley rod 32 to support the anchor during initial deployment . the bone displacement tabs 22 displace the bone distal to the suture to allow for optimal suture sliding during initial deployment . the suture pinch ramp 24 helps to maintain tension during individual tensioning of the suture . it is configured to slope outwardly in a proximal direction , so that its distal end is at a depth approximating the depth of the suture recess 18 and its proximal end is at the outer surface of the implant body 12 , i . e . a depth of approximately zero . the suture cleat 26 pinches the suture to increase the suture pullout strength of the construct . the suture eyelet 28 allows for one or more suture ends to be placed in the implant . each suture end is individually tensionable , as well be described below . though the tip 46 of the anchor 10 is illustrated as being closed , as shown in fig9 , the optional metal tip 38 may be added to the anchor 10 to allow for the anchor to be inserted directly into bone without the requirement of a pilot hole . the insertion system 30 , as well , has several important features which contribute to the innovative function of applicant &# 39 ; s inventive system . in particular , the suture pulley rod 32 , in the initial deployment stage , allows the suture to move freely in the suture eyelet 28 , by preventing the suture from entering the suture cleat 26 . the pulley rod 32 also increases the strength of the anchor 10 by extending to the distal tip 46 of the anchor body 12 during initial deployment . the insertion tube 36 , as well as the pulley rod 32 , transmits the insertion force from a mallet to the anchor during initial deployment . rotation of the proximal knob 44 actuates a mechanism that retracts the pulley rod 32 between initial and final deployment stages . the knob release slide 42 releases the knob 44 to allow for removal of the inserter 30 after final deployment . the suture cleat retainers 34 maintain a set gap in the suture cleat 26 during final deployment . the remaining fig1 - 32 will now be referenced in connection with a description of methods of using the inventive system to deploy an anchor 10 in bone 48 . to deploy the anchor 10 in a suitable bone site , suture 50 is first passed through soft tissue ( not shown ) requiring repair . viewing , for example , fig1 , the suture loops 51 in the suture 50 would normally be occupied by the soft tissue to be approximated against the bone 48 , but that tissue is not shown , for clarity . alternatively , soft tissue itself may be anchored directly in place within the desired bone site 48 , rather than using suture 50 , in which case the tissue is manipulated in the same way as the suture to be described in this explanation . for this reason , though the term “ suture ” is used throughout this specification , for convenience , the term should be considered sufficiently broad to include other media having similar functional characteristics , including soft tissue itself . a pilot hole 52 ( fig9 and 28 ) is drilled or punched into the attachment site ( bone 48 ), through the cortical bone layer 54 and into the cancellous bone layer 56 . in some circumstances , the optional metal distal tip 38 may be employed ( fig9 ), in which case the step of drilling a pilot hole is unnecessary . the suture is then fed through the suture eyelet 28 , as shown in fig1 and 15 , directly or with a snare . one or more suture ends 58 , 60 ( fig1 ) may be placed through the eyelet 28 . with the anchor 10 and attached inserter 30 positioned at the desired bone site , as shown in fig1 and 15 , initial deployment of the anchor 10 can occur . it should be noted that fig1 and 17 , and fig2 , illustrate the same step as fig1 and 15 , with the suture 50 removed for clarity . to initiate this initial deployment , a mallet is driven against the proximal end of the handle portion 40 to drive the anchor 10 distally to its initial deployment position , as shown in fig1 and 19 , and also in fig2 and 21 , and 29 , with the suture again removed for clarity . at this juncture , the suture recess 18 is acting to apply pressure to the sutures or tissue 50 disposed between the outer surface of the anchor body 12 and the adjacent bone surface , as well as against the suture pinch ramp 24 . this pressure maintains the tension on the suture 50 . the free suture ends 58 , 60 may be individually tensioned around the suture pulley rod 32 to approximate the tissue within the suture loops 51 up against the anchor and repair site and its surrounding bone 48 . if the suture is over - tensioned , a probe may be used to loosen the tissue side of the suture . once the desired tension is achieved , the suture pulley rod 32 is pulled proximally into the insertion tube 36 , by rotating the threaded proximal knob 44 on the handle portion 40 until further rotation is prevented . when the tube 36 is retracted by the rotation of knob 44 , the gap of the suture cleat 26 is exposed . at this point , the suture cleat retainers 34 are in position on either side of the suture cleat 26 . this retracted pulley rod position is illustrated in fig2 and 27 , which is the position required prior to the final insertion step . as noted above , the suture cleat 26 is exposed and held open by the suture cleat retainers 34 , which thus allow the suture to pull into proper position during final insertion . at this juncture , the final deployment steps are initiated , as shown in fig2 and 23 , and also in fig2 and 25 , and 30 , wherein the suture 50 has been removed for clarity . with the gap of the suture cleat 26 maintained by the suture cleat retainers 34 , the inserter handle 40 is again malleted , directing insertion force into the insertion tube 36 until the anchor 10 rests below the surface of the bone , as shown in fig3 . because the suture 50 has maintained an equal distance from the surface of the bone , post - tensioning and post - final deployment , the tension in the suture 50 is maintained . if additional tension is required , the anchor can be malleted deeper into the bone , pulling the suture ends with it , thereby increasing tension . the suture 50 is now pinched between the suture barbs 14 and the bone on the tissue side of the anchor , as shown in fig2 . it is also pinched between the suture cleats 26 on both sides of the anchor body 12 . finally , the free suture ends 58 , 60 are pinched between the suture barbs 14 and the bone opposite to the tissued side of the anchor . the suture pulley rod 32 may now be pulled out of the anchor body 12 , as shown in fig3 , releasing the inserter 30 by actuating the knob release slide 42 to allow the threaded knob 44 to be free to rotate . the knob 44 is then rotated until the inserter is released from the implant . at this juncture , the free suture ends can be cut , as shown in fig3 , which completes the repair . accordingly , although an exemplary embodiment of the invention has been shown and described , it is to be understood that all the terms used herein are descriptive rather than limiting , and that many changes , modifications , and substitutions may be made by one having ordinary skill in the art without departing from the spirit and scope of the invention , which is to be limited only in accordance with the following claims .

an anchoring system for securing tissue to bone includes an implant having a body through which a suture eyelet extends transversely , a suture recess extending along a portion of a length of the body , having a predetermined depth below an outer surface of the body , and a suture pinch ramp disposed at a proximal end of the suture recess . the suture pinch ramp has a depth approximately equal to the predetermined depth at a distal end thereof and sloping outwardly in a proximal direction so that a depth of a proximal end of the suture pinch ramp approaches zero . an insertion member includes an insertion tube and a handle which is engageable with the anchor body to deploy the anchor in a selected bone site .

the following describes a preferred embodiment and rules for playing the game according to the present invention . it is noted that fig1 a - 1 g are not successive figures of a single game play or round , whereas fig3 a - 3 t show a single game play or round . the game according to the present invention is a computerized matching game played over a network , such as the internet . the game includes a graphical user interface ( gui ) 100 . the gui 100 includes an area 101 where a player can click or select for initiating game play . the gui 100 further includes clickable icons 130 for viewing the rules of the game , obtaining help , quitting the game , and for toggling the game sounds on and off . upon clicking the area 101 , the player can be offered the opportunity to register to set up an account and / or to make payment , such as paying to play a number of games and placing a bet of a possible outcome occurring . payment could be made by credit card or by using an online account , such as a prepaid player account . if the player is already registered , the player can enter a password or other identification in order for the game to determine the player &# 39 ; s identity and retrieve the player &# 39 ; s prepaid account . game play consists of three turns or spins , in an attempt to achieve a favorable outcome as indicated in a payout table 102 . a preferred game board 103 for the game consists of 27 positions organized into three rows 104 of nine squares each or nine columns 112 of three squares each ( see fig1 a and 1 b ). it is noted that the game is not limited to this particular configuration , but may contain more or less rows and positions and the positions may be any of a plurality of shapes . during the setup phase of the game , each of the positions is assigned a randomly selected number 105 ( see fig1 b ) and a “ spins ” indicator 107 is set to three to indicate the number of turns or spins remaining . the randomly selected and displayed number 105 for each position is preferably selected from a numerical range corresponding to the column the position belongs to . for example , the numbers selected and displayed in the leftmost column are selected from the numerical range of 1 - 10 , and the numerical ranges for the rest of the columns 112 , from left to right , are as follows : 11 - 20 , 21 - 30 , 31 - 40 , 41 - 50 , 51 - 60 , 61 - 70 , 71 - 80 and 81 - 90 . each game turn is initiated by the player clicking on the “ take spin ” icon 106 . spinners 108 then display randomly selected icons ( see fig1 c ) from a group of icons consisting of : numbers 109 , free spin 113 , jokers 110 , and other icons which represent bonuses or penalties to the player . points accumulated are indicated by a score indicator 115 . following the display of the icons , the effects are preferably prosecuted one icon at a time . numbers 109 which appear in the spinner 108 result in the matching number in the corresponding column being covered by a covering icon 111 . however , if no matching numbers exist in the corresponding column , then there is no action taken , other than one or more game sounds . the appearance of a joker 110 results in an entire corresponding column 112 being covered ( see fig1 c ). if in a turn a select number of jokers appear , then payouts are made according to the exemplary payout table 102 which is provided below : the appearance of a “ free spin ” 113 ( see fig1 d ) offers the player an additional turn beyond the standard three turns , in an attempt to achieve a favorable outcome . total number of free spins acquired by the player is indicated by a “ free spins ” indicator 114 . maximum number of free spins allowable per game can vary from one version of the game to the next . however , in the preferred embodiment , two free spins per game is the maximum allowed . any “ free spin ” beyond the two is disregarded and no action is performed on the game board 103 . additionally , some versions of the game may include penalties indicated by a particular icon , which may result in the uncovering one position or several positions of the game board , loss of a spin , loss of a predetermined number of points as indicated by the score indicator 115 , or any other penalty . occasionally , in the embodiment shown by the figures , when a position on the game board 103 is covered or marked , a “ gold coin ” or other icon 116 appears . this results in a predetermined number of coins or credits being instantly credited to the player &# 39 ; s account as indicated by graphic 117 . the coins or credits can then be redeemed for prizes or cash , or be used to play additional games . at the end of each turn , the player &# 39 ; s score is updated to reflect the results of the turn . the player &# 39 ; s score is indicated by the score indicator 115 . during the course of game play , the player may cover or mark an entire row 118 ( see fig1 f ) resulting in a payout as indicated in the payout table 102 . the corresponding payout will be added to the player &# 39 ; s game score as indicated by the score indicator 115 . upon completion of all three turns and any accumulated free spins , the game ends with a “ game over ” message 119 ( see fig1 g ). the winnings as indicated by the score indicator 115 are added to the player &# 39 ; s account 117 . after a predetermined number of games as indicated by a cash out indicator 120 , the winnings are automatically cashed out . the rules outlined above generally apply to all versions of the game according to the present invention . however , in some versions , the game is played by more than one player , or is incorporated in a slot machine device for installation at a casino . additionally , the basic rules may be further expanded to enhance game play , risk , and payouts with the addition of other spinner icons or with the incorporation of side bets — the ability for the player to place bets in addition to the standard pay - to - play bet — on such outcomes as the covering of a particular row or position during a turn or course of game play , i . e ., over a series of turns . if the outcome occurs , the player is awarded points based on the bet placed and / or the odds of the outcome occurring . in another embodiment in accordance with the present invention , the game is incorporated into a slot machine 210 for installation in gaming establishments . while game play remains essentially unchanged from the preferred embodiment described above , certain elements have been adapted to slot machine devices . a player initiates a game by first inserting a token , coin , prepaid account card or other means of payment through the appropriate slot 206 and 207 . the processor prepares the game board and displays it on a video screen 208 . the appearance of the game board is generally similar to that described above . during each turn , spinners 209 are activated by either pulling the spin arm 204 a or pressing a spin button 204 b , at which point the processor simulates the spinning reels of a conventional slot machine on screen along with the associated sounds . each spinner 209 eventually comes to a stop and spinner icons are displayed in each . as described above , the displayed icons on the spinners 209 are processed and results are posted in a score area 201 . payouts are then calculated by the processor based on the posted payout table 205 . the winnings are cashed out when the player presses a pay out button 202 , attains a predetermined maximum score , or after playing a predetermined number of games . the winnings can be deposited into a cash out bin 203 , credited to the player &# 39 ; s account card , or provided to the player in some other method . various support components are not shown , but understood to be part of conventional video slot machine devices of the type indicated here , and therefore components of this embodiment . these components include one or more processors to handle the task of managing the player &# 39 ; s account , winnings , and bets as well as overall game play , a means of providing winnings to the player , i . e . an internal cash out vault containing monies or tokens to be used to award the player , means for applying winnings to the player &# 39 ; s account , etc ., and a candle or other apparatus for signaling an attendant . additionally , this embodiment readily lends itself to the incorporation of side bet functionality with the inclusion of additional buttons , touch screen , or other such input method . the challenge , and resulting payout amounts , are increased with the inclusion of additional spinner icons which impart one or more penalties to the player or increasing the range of possible numbers from which the position numbers are randomly chosen . additionally the game as described may also take the form of a table game in which the means for conducting game play is provided by a dealer and the spinners are replaced with cards , dice or some other appropriate instruments . generally , the rules remiain the same as described herein , but like the slot version , such a table embodiment allows for modification and expansion of the rules to enhance game play . a further embodiment of the present invention is a computer - readable medium , such as a cd - rom , containing a set of computer executable instructions for display and prosecution of the game described herein . accordingly , it will be understood that various modifications may be made to the embodiments disclosed herein , and that the above descriptions should not be construed as limiting , but merely as illustrative of preferred embodiments . those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto

a system and method are provided for playing a single - or multi - player interactive bingo - style game . the system includes an input device for receiving a player &# 39 ; s inputs , a display for displaying a graphical user interface , and a processor for controlling the operations of the game according to a set of game rules . the system is preferably implemented as a combination of hardware and software . it is further contemplated that the system can also be implemented over a network , such as the internet , for allowing players in remote locations to play the game .

the following description is of the best mode presently contemplated for carrying out the invention . this description is not to be taken in a limiting sense , but is made merely for the purpose of describing the general principles of the invention . turning first to fig1 , there is shown a simple binaural interposer 23 that may be used as part of the present disclosure . the bte speech processor 22 is normally connected to a removable battery 24 . to insert the interposer 23 , the battery 24 is removed from the bte processor 22 , and the interposer 23 is inserted between the bte processor 22 and the battery 24 . the battery 24 may then be connected to the underneath side of the interposer 23 . the interposer 23 has a bte interface port 25 on the side thereof that is placed against the bte processor . such interface port allows electrical connections to be made with the circuits within the bte processor . a binaural communications port 26 is on one side of the interposer 23 . this port , used for a wired implementation , allows a cable to be attached thereto that connects with another bte processor , or to a programming device , such as a host fitting station . power connections or terminals are also provided on the interposer 23 so as to allow the power terminals on the battery 24 to make electrical connection with the power input terminals on the bte speech processor 22 . thus , power in terminals are located on a side 27 of the interposer 23 that is placed adjacent the battery terminals , and power out terminals are located on a side 28 of the interposer that is placed adjacent the bte processor , thereby allowing power to pass through the interposer from the battery to the bte processor . turning next to fig2 , an enhanced binaural interposer 30 is depicted that includes a binaural cpi programming cable 32 exiting from a bottom side thereof . the acronym cpi stands for “ clinician programming interface ”, and refers to a special interface unit that allows the clinician &# 39 ; s programmer ( usually a laptop computer ) to interface with the bte processor that is being programmed . the cpi programming cable 32 is an extension to an existing bte / cpi programming cable . on one end it is terminated with a standard db15 connector for connection to a standard cpi - 2 . on the other end , it is terminated with the enhanced binaural interposer 30 . the enhanced interposer 30 performs cpi signal level shifting , power distribution and bsp ( body speech processor ) interconnection between a master bte ( to which the interposer is attached ), a slave bte ( to which the interposer is tethered ) and the cpi ( host pc ). this is used for wired fitting of the system . multiple variations of the enhanced interposer 30 are possible , as described , e . g ., in fig5 and 7 , below . the fitting system is embodied in a “ wired binaural fitting mode ”. next , with reference to fig3 , a bionet bte interposer 40 is shown . the interposer 40 houses a wireless transceiver ( bluetooth , ism , medical band , fis itel , etc . . . ) for wireless communication between binaurally co - joined bte &# 39 ; s and / or a host fitting station . the interposer 40 includes the same or similar connectors , e . g ., power in , power out , bte interface port 25 , binaural cable port 26 ( optional ), and further includes an optional cpi programming cable port 42 . in a singular mode , the wireless link provided through the wireless transceiver can be used to fit a remote bte . a more powerful mode provided by the interposer 40 is simultaneous fitting of synchronized bte pairs . a block diagram of the control subsystem necessary to implement a bionet is shown in fig4 . that which is shown in fig4 functionally represents the circuitry contained within the interposer 40 . as seen in fig4 , a control module 44 interfaces with the local bte 22 and local battery 24 through the bte interface port 25 and power connections . internal to the interposer 40 , the control module 44 — typically realized from microprocessor circuitry — interfaces with both a wireless network interface module 43 and a wired network interface module 46 . the wireless network interface module 43 has an antenna coil 45 connected thereto . such antenna coil 45 is advantageously embedded within the housing of the interposer 40 so that it is not obtrusively visible to a user of the bionet , which bionet is made possible by the interposer 40 . the wireless network interface module 43 may connect to one or more remote bte &# 39 ; s . the wired network interface module 46 may connect to a remote bte through the binaural cable port 26 , or to a host fitting system through the cpi programming cable port 42 . fig5 illustrates a standalone wired interconnection of two bte &# 39 ; s , a master bte 22 , and a slave bte 22 ′, via simple binaural interposers 23 and 23 ′, and a binaural interface cable 21 . the wiring of the binaural interface cable 21 is illustrated in fig9 . fig6 and 8 respectively show variations of a master bte 22 connected to a slave bte 22 ′. in fig6 , an enhanced interposer 30 connects the master bte 22 to a cpi device 52 , while a binaural interface cable 21 connects the slave bte 22 ′ to both the cpi 52 and the master bte 22 through a simple interposer 23 ′. in fig7 , a bionet bte interposer 40 connects the master bte 22 to a cpi device 52 , while a binaural interface cable 21 connects the slave bte 22 ′ to both the cpi 52 and the master bte 22 through a simple interposer 23 ′. in fig8 , two enhanced interposers 30 and 30 ′ are used to respectively connect a primary bte 22 and a secondary bte 22 ′ to respective cpi &# 39 ; s 52 and 52 ′. dual port fitting software 54 interfaces with each of the respective cpi &# 39 ; s 52 and 52 ′. turning next to fig1 , a wired binaural fitting mode is illustrated . a slave bte 22 ′ is connected through , e . g ., a simple interposer 23 ′ and a synchronous binaural interface cable 21 to an enhanced interposer 30 . the enhanced interposer 30 is connected to a master bte 22 . the binaural fitting cable 32 that exits from the enhanced interposer 30 ( see fig2 ) is connected to a cpi device 52 . the cpi device 52 , in turn , is connected to a host programming system , e . g ., a laptop computer ( not shown ) loaded with the appropriate fitting software . next , with reference to fig1 , a bionet wireless fitting system is illustrated . fig1 embodies the operational modes for fitting and operating a wireless bte fitting system . as seen in fig1 , the system consists of two bionet bte interposers 40 , each connected to a respective bte 22 , and a bionet pc card 56 plugged into the host fitting station 58 . as thus configured , a bionet 60 is created that allows either bte to be coupled to the host fitting station 58 , and that further allows either bte to be coupled to the other bte . fig1 illustrates the preferred cascaded master / slave bootload operation relative to a cpi device , a master bte and a slave bte . as seen from fig1 , in keeping with the architecture of present day speech processors , a cascaded bootload scenario is presented whereby cable interconnection as per “ fitting cable configuration # 2 ”, fig6 , is employed . the “ command / response ” handshaking is defined in the serial link protocol and is presently controlled from the pc side by ppmif . dll ( or equivalent ). first , the need to utilize multiple target addresses ( destination field in the packet protocol ) is required . secondly , monitor functions running on the dsp require master & amp ; slave awareness with all incoming commands ( from the host ) delivered to the master for processing or forwarding ( based on destination address ) and all acknowledges to the pc delivered from the slave ( directly or by way of forwarding from the master ). the key to the startup is a double blind bootload . that is , bootloading is a blind process , the success of which cannot be determined until the operation is complete and a ping is received from the remote kernel . in one binaural configuration , this blind operation is cascaded . for the bte processor to become operational , a bootload to the master is performed ( identical to the present day single speech processor environment ). upon completing the master bootload sequence , the slave bootload sequence is forwarded by the now operational master bte to the slave bte . once both bte &# 39 ; s have been bootloaded , success can be determined by issuing a ping to the master bte . the ping response is routed through the slave bte and returned to the host pc through the cpi . receipt of this acknowledgment indicates success . once a bootload has been successfully made , application programs can be loaded as per an existing packet protocol with the caveat that destination addresses will determine which bte processor processes each command . fig1 illustrates how stimulation synchronization is obtained between the master bte and the slave bte . fig1 shows the manner in which audio synchronization is obtained between the master bte and the slave bte . fig1 depicts a fitting system platform . such platform allows operation with the various binaural speech processor configurations described above . the platform includes a host fitting station 58 , typically comprising a laptop computer loaded with the appropriate fitting software . also included in the platform is a bionet pc card 56 , or equivalent , that is plugged into the fitting station 58 , thereby allowing communications with two bte &# 39 ; s 22 , one bte being for the left ear and the other bte being for the right ear . each bte is coupled to a headpiece 21 . the headpiece 21 , in turn , is coupled to the bionic ear implant 18 , which implant includes an electrode array 19 . a multiplicity of electrode contacts , e . g ., 16 electrode contacts , are spaced apart along the length of the array 19 , thereby allowing stimulation of cochlea tissue to occur at various locations along the length of the array . fundamental to the platform shown in fig1 are means to perform bilateral pitch ranking and channel allocation . this process of pitch ranking is illustrated in fig1 , and is further explained in appendix a of the above - referenced provisional patent application , ser . no . 60 / 313 , 694 , filed aug . 20 , 2001 , previously incorporated herein by reference . while the invention herein disclosed has been described by means of specific embodiments and applications thereof , numerous modifications and variations could be made thereto by those skilled in the art without departing from the scope of the invention set forth in the claims .

a method for establishing a network to allow communications between plural bte units of a bilateral cochlear implant system . the bilateral cochlear network includes four main components : a communications interposer adapted to be inserted between the bte battery and the bte housing or modified bte devices ; a communication channel over which communication takes place between the connected devices , including the protocol governing access to such channel ; the synchronization mechanisms used to achieve synchronization between the connected devices ; and a bilateral fitting paradigm .

fig1 to 4 of the accompanying drawings shows a ride - on mower , which comprises a ride - on vehicle unit 1 having an engine 2 . the vehicle unit 1 is supported on four wheels 3 ( the front left wheel being omitted from fig1 for the sake of clarity ). the engine 2 , which may , for example , be a petrol - driven internal combustion engine , a battery - driven electric motor , or some combination of combustion engine and electric motor ( s ), provides power to drive at least one of the wheels 3 via a transmission assembly ( not shown ). the vehicle unit 1 also includes a seat or other operator station for supporting a seated or standing operator and one or more controls , such as a steering wheel for steering the vehicle , a pedal for actuating a clutch or a braking assembly , and / or other common controls . in the illustrated embodiment , the vehicle unit 1 is a rear - engine articulating lawn care vehicle that is steered by articulating a rear portion of the vehicle that contains the rear wheels relative to a front portion of the vehicle that contains the front wheels about the vertical axis of a hinge mechanism located between the two portions . in other embodiments , the vehicle unit 1 may have other configurations . for example , the vehicle unit 1 may be , for example , a stand - on or sit - on “ zero - turn ” lawn care vehicle where the vehicle is supported by two independently driven drive wheels and one or more caster wheels . in another example embodiment , the vehicle unit 1 may be a lawn tractor , where the engine is located forward of the operator and the vehicle is typically steered by the front wheels . in still another example , the vehicle unit 1 is a rear - engine non - articulated rider with front or rear steering . in the illustrated embodiment , the vehicle unit 1 is configured to support a removable front - mounted implement . the implement may be any powered or non - powered tool used to complete a particular task , such as a lawn care task . for example , the implement may be a cutting deck for mowing grass , a plough , a brush , a blower , a dethatcher , a brush cutter , an aerator , and / or the like . although the figures provided herein illustrate a front - mounted implement mounted forward of the vehicle unit &# 39 ; s front wheels , engine , and operator , other embodiments of the invention may be similarly used on rear , side , or mid - mounted implement assemblies . referring to the embodiment shown in fig1 , extending from the front of the vehicle unit 1 is an implement mounting arrangement 4 . the implement mounting arrangement 4 comprises at least one support member 5 movably coupled to the vehicle unit 1 and configured to support a front - mounted implement 9 , here a cutting deck assembly . a mounting 6 couples the support member 5 to the vehicle unit 1 so that the support member can lift the attached implement 9 upwards relative to the vehicle unit 1 . the mounting 6 may be a mounting assembly that is separate and distinct from , but capable of being couple to , the vehicle unit 1 and the support member ( s ) 5 ( e . g ., a hinge , a bearing , a slide , and / or other coupling mechanism ), or the mounting 6 may be integrally formed with the support member 5 and / or the frame or other component of the vehicle unit 1 ( e . g ., a protrusion , aperture , hook , tongue , groove , and / or other integrally formed feature ). a biasing member , such as a spring 7 , urges the support member 5 upwards so as to , for example , counteract the downward force generated by the weight of the implement 9 during operation and / or to assist with lifting the implement 9 into a maintenance position . more particularly , in the illustrated embodiment , the one or more support members comprise a pair of pivoting arms 5 mounted on the mounting 6 fixed to the vehicle unit 1 , so that the pivoting arms 5 can pivot about a lateral horizontal axis . the mounting 6 is provided with the spring 7 which acts to bias the pivoting arms upwards towards the underside 17 of the vehicle unit 1 . a mounting assembly coupled to the implement 9 removably mounts the implement 9 to the support member . in the illustrated embodiment , the mounting assembly comprises a mounting arm 8 that is telescopically received on the end of each pivoting arm 5 . the mounting arms 8 carry the implement 9 . in this case the implement is a cutting deck configured for the mowing of grass . in this regard , the cutting deck comprises a shroud covering two rotary cutting blades ; however other cutting deck configurations known in the art may be used . the cutting deck is driven by a transmission system , such as an assembly of belts , pulleys , shafts , gears , clutches , and / or electronics , that transmits power from the engine 2 to the cutting deck to be used to move the blades . in other to perform maintenance on the implement 9 and / or change the combination of the mounting arms 5 and implement 9 , the mounting assembly can be detached from the support member by , in this example , sliding the mounting arms 8 off of the pivoting arms 5 . in some embodiments , the transmission system that may provide power to some implements 9 must be disconnected in order to slide the mounting arms 8 from the pivoting arms 5 and / or remove the mounting arms 8 and implement 9 from the vehicle unit 1 . in order to make installation or removal of the combination of the mounting arms 5 and the implement 9 , a locking mechanism 10 is provided , mounted on support member , here the pivoting arms 8 . as explained in more detail below , the locking mechanism 10 has two states : ( i ) a locked state ( shown in fig4 of the accompanying drawings ) when it restricts upward motion of the support member relative to the vehicle unit at least beyond a particular point by , in the illustrated embodiment , restricting the pivoting motion of the pivoting arms 5 at least beyond a particular point ; and ( ii ) an unlocked state ( shown in fig3 of the accompanying drawings ) when the upward motion of the support members ( e . g ., the pivoting motion of the pivoting arms 5 ) is permitted beyond the particular point . in one embodiment , the locking mechanism comprises a rotating member 11 pivotally mounted on the pivoting arms 5 about an axis through and perpendicular to the pivoting arms 5 . this can lay in two positions : a first unlocked position shown in fig3 of the accompanying drawings , when it lays flat in a plane containing the generally parallel pivoting arms 5 , and a second locked position shown in fig4 of the accompanying drawings , when it protrudes upwards towards the underside 17 of the vehicle unit 1 , generally perpendicular to the plane containing the pivoting arms 5 . in the locked position , the rotating member 11 acts as a spacer , preventing the pivoting arms 5 from moving closer than the length l of the rotating member 11 to the underside 17 of the vehicle unit 1 . the spring 7 will tend to bias the pivoting arms 5 so that , in the locked position , the rotating member 11 comes into contact with the underside 17 of the vehicle unit 1 ( e . g ., with a frame / chassis member , body panel , or other vehicle component ). in order to drive the rotating member between the locked an unlocked states , and vice versa , a pushrod 12 is provided . one captive cranked end 13 of this pushrod is pivotally mounted on the rotating member 11 , about an axis offset from the axis about which the rotating member 11 is mounted relative to the pivoting arms 5 . the other end 14 , also cranked but free , of the pushrod , is received within an aperture 16 provided on one of the mounting arms 8 , and secured by means of a clip 15 . thus , relative linear movement of the mounting arms 8 and the pivoting arms 5 will cause linear movement of the pushrod 12 relative to the pivoting arm 5 , which will , in turn , cause rotational motion of the rotating member 11 . this rotational motion is such that , when the mounting arms 8 are disengaged from the pivoting arms 5 ( and so moved in the direction of the arrow in fig4 ), the rotating member 11 is moved into the locked position . furthermore , the length of the pushrod 12 is such that the movement into the locked position is completed before the mounting arms 8 are completely disengaged from the pivoting arms 5 . conversely , when the mounting arms 8 are reengaged with the pivoting arms 5 ( and so moved in the direction of the arrow in fig3 ), the rotating member is moved into the unlocked position . thus , when it is desired to remove the implement 9 , the mounting arms 8 are slid forwards until the locking mechanism 10 is in the locked position shown in fig4 . the pushrod is then removed from the aperture 16 , and the combination of the mounting arms 8 and the implement 9 can be lifted off of the pivoting arms 5 without fear of the pivoting arms unpredictably springing upwards and hitting the underside 17 of the vehicle unit 1 , as the rotating member 11 is acting to space the pivoting arms 55 from the underside 17 of the vehicle unit 1 . when it is desired to replace the implement 9 ( whether it be the same or a different implement ), the mounting arms 8 are offered up to the pivoting arms 5 , and slid along the pivoting arms 5 until in the position of fig4 , when the free cranked end 14 of the pushrod 12 is engaged into the aperture 16 . the mounting arms 8 can then be slid to the fully engaged position shown in fig3 , which will drive the rotating member 11 back into the unlocked position and allow the full range of pivotal movement of the pivoting arms 5 . furthermore , once the load of the combination of the mounting arms 8 and the implement 9 have been removed from the pivoting arms 5 , the spring 7 will be sufficiently strong to hold the pivoting arms 5 in the position with the locking member contacting the underside 17 of the vehicle unit 1 . this means that the pivoting arms will be a constant distance 1 from the underside 17 of the vehicle unit 1 , and so a constant distance d above the ground ( or other flat surface on which it is resting ). this is shown schematically in fig5 of the accompanying drawings . this constant height above ground d allows for the easy interchange of different implements 9 with their respective mounting arms 8 . in fig5 , the vehicle unit 1 is provided with four different implements , being a mower 9 a , plough 9 b , snow thrower 9 c and aerator 9 d with respective mounting arms 8 a , 8 b , 8 c , 8 d . for each of the implements 9 a , 9 b , 9 c , 9 d , the respective mounting arms 8 a , 8 b , 8 c , 8 d are also the same distance d above ground . because , with no implement 9 engaged , the pivoting arms 5 are held at the distance d above ground , all the operator of vehicle unit 1 has to do for the pivoting arms 5 to engage any of the mounting arms 8 a , 8 b , 8 c , 8 d is to carefully drive the vehicle unit 1 up to the desired implement 9 a , 9 b , 9 c , 9 d , whereupon they will both be at the correct , consistent height to engage correctly . by providing the mounting arms at a consistent height d , a set of implements can be provided that can easily be engaged by the operator of a vehicle unit 1 . friction washers or another source of friction can be added to the rotating mounting of the rotating member 11 to add some friction to the motion of the rotating member 11 . this means that the rotating member 11 will not fall into the unlocked position when engaging or disengaging the mounting arms 8 .

an implement coupling arrangement , typically for use with a lawn care vehicle , comprising a first part arranged to be coupled to a vehicle and a second part arranged to be selectively mounted on the first part , in which the first part comprises a support arm configured to support the second part , a mounting for moveably mounting the support arm relative to the vehicle , and a biasing member arranged so as to bias the support arm upwards relative to the vehicle , in which the second part comprises an implement and a mounting assembly , the mounting assembly and the support arm being interengageable so as to mount the second part on the first part ; and in which the arrangement further comprises a locking mechanism , which has a locked state which inhibits movement of the support arm upwards relative to the vehicle beyond a point , and an unlocked state which allows upward movement of the support arm relative to the vehicle beyond the point ; in which disengagement of the mounting assembly from the support arm causes the locking mechanism to enter the locked state .

referring to fig1 and 2 of the drawings , a shower door assembly is shown having the improved mounting structure of the invention . the assembly comprises a flexible slidable shower door 10 mounted on the outside of a bathtub 11 to form a closed compartment therewith . the door 10 is mounted in a frame or casing composed of upright frame members 12 and 13 on opposite sides of the door , and parallel upper and lower horizontal rails 14 and 15 at the upper and lower ends of the door . the door is constructed of alternate ridged and flexible vertically extending elongated panels , commencing at each end with a leading edge panel 16 . a flexible panel 17 of plastic or other suitable material is joined to each leading edge panel 16 along one edge thereof . the opposite edge of the flexible panel is joined to a rigid divider panel 18 . the divider panel 18 is in turn joined to another flexible panel 17 followed by another rigid divider panel 18 . the door thus illustrated is constructed of two outer leading edge panels 16 and four flexible panels 17 alternating with three rigid divider panels 18 therebetween . a handle 21 is mounted on each leading edge panel , and a latch 22 is mounted on each of the uprights 12 and 13 , for opening and closing the door 10 from either side . referring to fig3 , 5 , 6 , 7 , 8 and 9 , the rigid divider panels 18 are preferably constructed of relatively thin sheet or strip material which in the illustrative embodiments is extruded metal such as an aluminum alloy . the back side of the panel 16 is provided with pairs of spaced parallel longitudinal walls 28 , 29 , 30 and 31 . which extend laterally outwardly from the panel and provide channels therebetween . walls 32 and 33 are provided on the rigid divider panel 18 for defining channels for restraining the flexible panels 17 of the present invention . a retaining groove 100 engages a bead 101 provided on the flexible panel 17 . the mounting structure of the invention includes lower glides 40 and upper glides 41 mounted on the leading edge panels 16 , and lower glides 42 and upper glides 43 mounted on the rigid divider panels 18 . the glides 40 and 41 as shown particularly in fig5 and 11 have a generally rectangular body 45 , an integral shank 46 , and a roller 47 . the glide body 45 is mounted for reciprocal sliding movement on the front surface of the leading edge panel 16 . the shank 46 is rectangular and extends laterally outwardly from the glide body 45 . the roller 47 includes an integral hub 48 which serves as a spacer to project the wheel portion of the roller forwardly from the body . the roller 47 is rotatably mounted on the body 45 by a rivet 49 extending through the hub . the glide body 45 , the integral shank 46 , and the roller 47 preferrably are constructed of a suitable plastic material such as acetal , delrin or celcon , the latter two being registered trademarks . such construction is tough and resilient and has good bearing properties . the glide is resistant to the physical and chemical forces encountered including temperature and humidity conditions , frictional forces , and corrosive influences . referring to fig5 - 11 , the glides 40 and 41 are mounted in the various panels 16 and 18 by providing a longitudinally extending rectangular slot 53 provided with a tab 54 at one end , as shown particularly in fig1 . the glides are mounted with the shanks of each extending through the rectangular slots 53 and being received loosely therein . a longitudinal bore 55 is provided in each shank . the bore is also formed partly in the adjoining glide body portion 45 . the bore 55 receives one end of a coiled compression spring 56 therein , and the other end of the spring engages the tab 54 therearound and may abutt on the adjoining outer margin of the panel opening 53 . the springs urge the glides 40 - 43 inwardly of the respective ends of the panel with the shanks normally seated on the ledges . from this position , each glide may be moved longitudinally outwardly against the force of the spring . the glide may move outwardly until its shank abutts on the outer margin of the panel opening , at which time the spring 56 is compressed , and the end of the tab 54 is received within the shank bore 55 . the body 45 is provided with glide retainer grooves 57 and 58 at its ends . the glides 40 - 43 are retained in place by means of glide retainers 61 , each of which has an arched body member 62 with latching teeth 63 and 64 at its ends . glide surfaces 65 are provided for slidably engaging the panel . terminal recesses 66 are provided for permitting a screwdriver to be inserted therein for prying the glide retainers from the glides for removal of the glide assemblies . spring - receiving recesses 67 and 68 are provided for receiving the springs and for preventing lateral movement of the glide retainers 61 . the embodiments of the glide retainers shown in the lower portions of fig5 and 7 , and in 11 may be utilized for mounting glides both in the lower and upper margins of the shower doors . the shower door . in the upper portion of fig5 - 9 and in fig1 - 17 , glide retainers are shown in an embodiment which is particularly suitable for mounting at either the upper margins or the lower margins of the shower door , since they facilitate the application and removal of the retainers . in the embodiment shown , the glide 41 has a structure similar to that shown and described above . the glide retainer 69 also has a basic structure similar to that of the glide retainer 61 . however , the retainer is additionally provided with a web or strap - form extension handle 72 provided with a transverse grip 73 . the grip 73 may be engaged and the handle 72 moved to disengage the glide retainer 69 from the glide retainer grooves of the glide 41 and subsequently reengage the retainer without the use of an external tool . in contrast , in the embodiment shown in the lower portions of fig5 and 11 , it is necessary to insert the end of a tool such as a screwdriver into the terminal recesses 66 for disengaging the glide retainer . fig8 - 10 illustrate still another embodiment which is particularly useful for mounting on the rigid divider panel 18 . the glide structure 76 comprises a generally rectangular body 77 , integral shanks 78 , a pair of rollers 79 and 80 mounted in tandem . the rollers have integral hubs 81 and 82 and are maintained in place by rivets 83 and 84 . a glide retainer 69 similar to that shown in fig1 - 17 engages latching recesses provided in the shank , in a manner identical to that of the embodiments previously discussed . the glide structure having tandem rollers is especially adapted for suspending certain portions of the door panels between rails 14 and 15 ( fig7 ). the rails preferrably are formed of extruded corrosion - resistent metal and are adapted for holding the rollers on the respective tracks and preventing them from becoming dislodged . an outer or upper track 87 is formed within the top rail 14 and it is boarded by a guard flange 88 . an inner or lower track 89 is provided parallel to the outer track and is boarded by a guard flange 90 . the opposite sides of the tracks are closed by a rail wall 91 . similarly , adjoining guard flange 92 , inner track 93 , and adjoining flange 94 together with a closure wall 95 form the lower rail . the glides 40 - 43 are tensioned or pulled into engagement with the rails 14 and 15 so that the glides and the panels are suspended therefrom . the rollers 47 , 79 and 80 bear against the respective inner tracks 89 and 93 , and the rollers roll along the tracks in opening and closing the sliding door 10 . the mounting structure of the invention provides a door mounting which is virtually trouble - free , notably in the case of flexible doors . not only are the rollers prevented from being removed from the rails , but they are not bound or jammed when an off - center pulling or pushing force is exerted . when this happens the glides move outwardly against the springs , which absorb the forces that would otherwise tend to cause binding . when the leading edge panels are moved out of alignment , which is more often the case , the individually mounted glides at each end move individually according to the force at each point , preserving the two point suspension on the rollers . the rollers at each end of the panel continue to roll on the rail tracks . when the force is altered or released , the structure automatically rights itself . the invention provides the further advantage that variations of spacing between the top and bottom rails are accommodated by the resilient mounting , as are irregularities and possible foreign substances on the individual tracks . the door panels with the mounting structure thereon present a very pleasing appearance when viewed from the front . the springs are enclosed by the glide body on the front and the retainer on the back , so that they are protected from fouling and are only visible from the rear . a particular advantage of the invention is that the glide retainers are easily prepared from plastic materials and easily engaged and disengaged with the detent structure of the shanks of the glides . the retaining structure is strong and does not fail even after extended periods of use . further the plastic is not subject to corrosion or attack by atmospheric conditions . it is to be understood that the invention is not to be limited to the exact details of operation or materials shown and described , as obvious modifications and equivalents will be apparent to one skilled in the art .

a structure comprising a door panel having an elongated opening therein , and resilient mounting means on the panel engageable with a rail for moving the panel along the rail , the mounting means comprising a glide including a body disposed on one side of the panel , a roller rotatably mounted on the body engageable with the rail for movement of the glide thereon , a shank on the body extending through the panel opening and moveable therein for relative movement of the glide and the panel , detent flanges provided at both ends of the shank , and a c - shaped glide retainer mounted on the reverse side of the panel having flanges adapted to engage and clamp the detent flanges of the shank , and means for restraining the retainer against transverse movement .

with reference now to the drawings , and in particular to fig1 through 5 thereof , a new tool device embodying the principles and concepts of an embodiment of the disclosure and generally designated by the reference numeral 10 will be described . as best illustrated in fig1 through 5 , the garden tool device 10 generally comprises a head 12 and a handle 14 . the head 12 has a perimeter edge 16 . the perimeter edge 16 defines a rectangular parallelogram . long sides of the perimeter edge may be between 10 and 15 centimeters and the short sides of the perimeter edge 16 may be between 15 and 25 centimeters . the head 12 may be formed from a plate having a thickness between 2 and 5 millimeters . the perimeter edge 16 of the head 12 is beveled such that a peripheral edge 18 of a top surface 20 of the head 12 is inset from a peripheral edge 22 of a bottom surface 24 of the head 12 . each of a plurality of grooves 26 extends into the perimeter edge 16 of the head 12 . the grooves 26 are spaced along the perimeter edge 16 of the head 12 . each of the grooves 26 has a semi - circular shape and is positioned entirely between the peripheral edge 18 of the top surface 20 and the peripheral edge 22 of the bottom surface 24 . the grooves 26 are arranged into a respective central groove 28 and a respective pair of outer grooves 30 positioned on each side 32 of the perimeter edge 16 of the head 12 . the handle 14 is coupled to and extends from the head 12 . the handle 14 extends from the top surface 20 of the head 12 such that the handle 14 forms an acute angle 36 with the top surface 20 of the head 12 . the handle 14 extends outwardly from the top surface 20 of the head 12 and aligns with one of a plurality of corners 38 of the head 12 where adjacent sections 40 of the perimeter edge 16 define an obtuse angle 42 of the rectangular parallelogram . the handle 14 has a first section 44 and a second section 46 . the first section 44 is coupled to the head 12 and may have a straight distal portion 48 relative to the head and a curved portion 50 adjacent to the head 12 . the second section 46 is coplanar with the first section 44 . the second section 46 extends from the first section 44 at an obtuse angle 52 within a transverse plane relative to the top surface 20 of the head 12 . the second section 46 extends away from the head 12 at an angle between 35 and 45 degrees . each of a pair of cutouts 54 extends through the head 12 . each cutout 54 is triangular having a pair of outer edges 56 . each of the outer edges 56 extends parallel to an associated straight side 32 of the perimeter edge 16 of the head 12 . the cutouts 54 define an elongated strip 58 of the head 12 extending between opposite corners 60 of the head 12 . the opposite corners 60 each define an obtuse angle . the handle 14 is coupled to and extends from the elongated strip 58 . the handle 14 may have a length between 20 and 30 centimeters wherein the handle 14 is suitable as a hand tool usable by a single hand while in a kneeling position similar to a conventional trowel . an extension 62 is removably coupled to the handle 14 to allow the head 12 to be manipulated while in a standing position . the extension 62 is elongated . the extension 62 is linearly aligned with the second section 46 of the handle 14 when the extension 62 is coupled to the handle 14 . each of a pair of mounting holes 64 extends into the second section 46 of the handle 14 . each of a pair of fasteners 66 is insertable through the extension 62 and an associated one of the mounting holes 64 . each fastener 66 engages the handle 14 wherein the extension 62 is secured to the handle 14 . in use , the head 12 is manipulated to agitate , break up , shape , or otherwise work with soil to achieve a desired result . the grooves 26 may be positioned to receive a root allowing the root to be pulled on instead of cut by the peripheral edge 22 of the bottom surface 24 . the handle 14 , with or without the extension 62 , is used to manipulate the head 12 to perform the desired gardening and landscaping tasks . with respect to the above description then , it is to be realized that the optimum dimensional relationships for the parts of an embodiment enabled by the disclosure , to include variations in size , materials , shape , form , function and manner of operation , assembly and use , are deemed readily apparent and obvious to one skilled in the art , and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by an embodiment of the disclosure . therefore , the foregoing is considered as illustrative only of the principles of the disclosure . further , since numerous modifications and changes will readily occur to those skilled in the art , it is not desired to limit the disclosure 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 disclosure . in this patent document , the word “ comprising ” is used in its non - limiting sense to mean that items following the word are included , but items not specifically mentioned are not excluded . a reference to an element by the indefinite article “ a ” does not exclude the possibility that more than one of the element is present , unless the context clearly requires that there be only one of the elements .

a garden tool device facilitates manipulation of soil , removal or cutting of weeds , cleaning joints between concrete , landscape design and the like . the device includes a head and a handle . a perimeter edge of the head defines a rectangular parallelogram . each of a plurality of grooves extends into the perimeter edge of the head . the grooves are spaced along the perimeter edge of the head . the handle is coupled to and extends from the head .

the subject of this application is a protective plastic shell , preferably transparent , which may be mounted upon a fishing : rod ( 100 ) and within which barbed lures or fish - hooks ( 101 ) may be emplaced to avert injury to an operator or for stowage in general . the shell comprises in part a semi - tubularly configured body ( 1 ), comprising enclosed longitudinally opposing ends ( 13 ) and , extending along its ( 1 ) longitudinal dimension , first and second laterally opposing edges ( 11 , 12 , respectively ), the latter of which ( 12 ) comprises flanged configuration . the shell further comprises an enclamping id ( 2 ), itself semi - tubularly configured in having a degree of longitudinal concavity , comprising open longitudinally opposing open ends ( 23 ) and first and second laterally opposing edges ( 21 , 22 , respectively ). the first edge ( 21 ). is disposed by hinged connection to the body &# 39 ; s first ridge ( 11 ). preferably , an integrally hinged connection ( 4 )— one of true attachment — comprises this connection , wherein the lid &# 39 ; s first edge ( 21 ) and the body &# 39 ; s first ridge ( 11 ) are molded together by extrusion or by infusion . for reasons mentioned ante , the lid may comprise trapezoidal configuration with the sides joining the first and second edges ( 21 , 22 , respectively ) angled toward one another so that the second edge ( 22 ) is shorter than the first ( 21 ). the enclamping lid ( 2 ) comprises an enclamping lip ( 24 ) disposed along its second laterally opposing edge ( 22 ), the lip &# 39 ; s ( 24 ) configuration is such as to , co - engage the semi - tubular body &# 39 ; s flanged second ridge ( 12 ) at what is herein identified as an enclampment sector ( 14 ) to form an enclosure . while the sector ( 14 ) may extends substantially along the entirety of the body &# 39 ; s ( 1 ) longitudinal aspect . the semi - tubular body ( 1 ) is configured to comprise an encompassing notch ( 15 ) disposed upon the upper portion of each of the body &# 39 ; s ends ( 13 ). the notches ( 15 ) are , thus , oppositely disposed in the longitudinal sense and when the shell is closed by mutual enclampment of the lid ( 2 ) and semi - tubular body ( 1 ) along the enclampment sector ( 14 ), a longitudinally disposed caddying tunnel ( 3 ) is formed proximate the lid ( 2 ). the tunnel ( 3 ) provides a longitudinal opening through which a portion of a fishing rod ( 100 ) reposes when the shell is by such means ( 3 ) axially connected to it ( 100 ). preferably , the notches ( 15 ) comprise size sufficient to permit the shell to rotate loosely upon the rod ( 100 ) so that when the latter ( 100 ) is held in its usual operable orientation , the shell pends — that is , hangs freely — to facilitate its use by the operator ( 200 ). co - engagement of the enclamping lip ( 24 ) and the body &# 39 ; s flanged second laterally opposing ridge ( 12 ) would not , of course , be possible but for the shell &# 39 ; s plastic , resilient composition and its configuration , supra . closing and opening the shell is accomplished by the operator &# 39 ; s ( 200 ) gently squeezing downward or inward at one point or another along the length of the lid ( 2 ) and is made possible by what is herein characterized as pop - open and pop - shut capability . to facilitate this operation , the semi - tubular body ( 1 ) additionally comprises notch shoulders ( 16 )— sturdy peaked structures extending upwards a short distance along the sides of each encompassing notch ( 15 )— and the enclamping lid ( 2 ), additionally comprises pop - shut and pop - open compression nodes ( 26 , 27 , respectively )— elongated protrusions longitudinally disposed along its ( 2 ) upward exterior or topside — the pop - shut compression node ( 26 ) proximate the lid &# 39 ; s second edge and one or more pop - open compression nodes ( 27 ) otherwise so disposed but distal the lid &# 39 ; s second edge ( 12 ). experience demonstrates that the configuration for the enclamping lid ( 2 ) which confers the best operability upon the pop - open , pop - shut feature is the trapezoidal one mentioned supra . in certain models , the sides of a strictly rectangular lid ( 2 ) do not clear the notch shoulders ( 16 ) nearest the body &# 39 ; s second ridge ( 12 ), preventing it ( 2 ) from responding with the flexibility desired upon the operator &# 39 ; s ( 200 ) fingered depression of the compression nodes ( 26 , 27 ). as the drawings illustrate , the inward slanting of the trapezoid &# 39 ; s sides permit the lid ( 2 ) to flex in a manner facilitating the operator &# 39 ; s ( 200 ) pop - open and pop - shut manipulations and without compromising the height of the shoulders ( 16 ) which as we have seen , themselves ( 16 ) contribute considerably to the operation . by reason of these embellishments ( 16 , 26 ), the operator ( 200 ) is able to flex an unengaged enclamping lip ( 24 ) inwards upon the body &# 39 ; s second ridge ( 12 ) at the enclampment sector ( 14 ) and thereby impinge it ( 24 ) into co - engagement with the ridge ( 12 ) in pop - shut fashion merely by depressing or gently forcing the pop - shut compression node ( 26 ) downward . indeed , the preferable disposition , configuration and composition of the two members ( 12 , 24 ) is such that by reason of mutual interference between the enclamping lip ( 24 ) and the body &# 39 ; s flanged second ridge ( 12 ), closure , though not impossible , occurs only with relative difficulty when attempted in any other manner such as , for example , by attempting to press the two ( 12 , 22 ) together directly . conversely , the operator ( 200 ) is able to flex the enclamping lip ( 24 ) outward and upward , undoing its ( 22 ) co - engagement with the body &# 39 ; s flanged second ridge ( 12 ) in pop - open fashion merely by depressing or gently forcing downward against the notch shoulders ( 16 ) any of the pop - open , more distally disposed , compression nodes ( 27 ). as a point of subtlety , it happens that opening the shell is not as restrictive in technique as closing it . as important as it is to make the pop - shut node ( 26 ) the precise situs of depression to attain closure , experience fairly well demonstrates that an operator ( 200 ) may snap the shell open , ignoring the presence or absence of pop - open nodes ( 27 ), by depressing any point within a substantial portion of the lid ( 2 ) remote its second edge ( 22 ). the lid &# 39 ; s ( 2 ) concavity provides sufficient flexing tension for the purpose . it is , therefore , appropriate to consider the distal pop - open nodes ( 27 ) more as convenient markers or manipulation sites for pop - open operation . mutual tensions within the body ( 1 ) and the lid ( 2 ) comprising such disposition , configuration and composition , thus , permit the co - engaging parts ( 12 , 24 ) to be snapped together or apart with a properly applied gentle squeeze . moreover , by reason of the shell &# 39 ; s pop - open , pop - shut feature — as distinguished , for instance , from one comprising pop - open , memory closed character , the shell may be conveniently mounted around a portion of the fishing rod ( 100 ) without having first to open it against the memory closed tension for the purpose .

a hinged flexible plastic shell in which barbed fishing lures and fish - hooks in general may be kept to avoid injury connects to a fishing rod merely by an operator &# 39 ; s closing of its lid upon the rod by pop - open and pop - shut manipulation of certain nodes atop the shell &# 39 ; s lid . to close , he or she depresses a pop - shut node against an enclosure ridge on the underlying storage portion . to open , either of the pop - open nodes may be depressed against notch shoulders to cause the lid to flex outward to position it for co - engagement with the lower portion .

the following is a description of exemplifying embodiments in accordance with the present invention . this description is intended for describing the general principles of the invention and is not to be taken in a limiting sense . thus , even though a suture sleeve comprising separable outer and inner portions is illustrated , the scope of the invention includes suture sleeves constituted by one tubular portion . furthermore , even though the illustrated locking arrangement comprises two means for performing the transitions between the three different modes of operation , a single means for performing the transitions , although in two different manners , is contemplated within the scope of the invention . referring first to fig1 , there is shown an implantable heart stimulator 4 ′ when implanted in a patient &# 39 ; s body . a lead 2 connects the heart stimulator 4 to the heart 1 , thereby allowing stimulation of the heart 1 and control of the heart rhythm . a suture sleeve 3 is provided at a position along the lead 2 in order to fixate the position of the lead 2 in the body . in fig2 , there is shown an enlarged view of a suture sleeve 3 arranged at a position along a lead 2 . it can be seen that the inner diameter of the suture sleeve is adapted to the outer diameter of the lead 2 . now referring to fig3 , there is presented a perspective view of the outer tubular portion or tube 9 , having a lumen 8 for receiving an inner tubular portion or tube 10 . the outer tubular portion 9 comprises , in this example , two circumferential grooves 5 , two actuation areas 6 , which are located on opposite sides of the outer tubular portion 9 , and a longitudinal slit 7 . the circumferential grooves 5 are intended for engagement with suture wires when suturing the sleeve 3 to body tissue . the grooves 5 improve the grip of the suture on the suture sleeve and prevents the suture from sliding off the sleeve during and after suture . the actuation areas 6 are provided with indentations acting as indicators and provide guiding for where pressure should be exerted in order to actuate the transition between the different modes of operation . the longitudinal slit 7 indicates where to cut , if or when the suture sleeve is to be removed . particularly , the outer portion is made of a flexible material , such as silicone or any other equivalent material , that allows the inner diameter of the outer portion to be expanded , while the inner portion , with a outer diameter that is slightly larger than the inner diameter of the outer portion , is inserted . the outer tubular portion may be used in conjunction with a variety of inner tubular or core portions , of which two examples are described . it is to be understood that other working examples of the inner core portions are contemplated . even though they are not described here , they nevertheless fall within the scope of the invention as claimed in the appended claims . in fig4 , there is indicated a perspective view of the outer tubular portion 9 and a first exemplifying illustration of an inner core portion 10 , wherein the inner core portion 10 is intended to be inserted into the lumen 8 of the outer tubular portion 9 according to arrow a . note that the inner diameter of the end portions of the flexible outer tubular portion 9 , respectively , is slightly smaller than the outer diameter of the inner core portion 10 . the inner core portion 10 , or inner tube , is made from two essentially semi - cylindrical portions which are connected via a hinge mechanism ( not shown ). the core portion 10 comprises a snap locking mechanism 11 for securing and closing the two semi - cylindrical portions into the general shape of a cylindrical tube . the inner core portion 10 further comprises a retaining mechanism for retaining the sleeve at a selected position along the lead . the retaining mechanism comprises a depressible manipulating portion 13 and engagement elements 12 , to be described in further detail below . the entire core portion 10 is made as a one - piece structure . with reference to fig5 , it is demonstrated how the diameter of the outer tubular portion fits to the diameter of the inner portion , such that a snug fit is provided . it can also be seen that the depression 6 of the outer tubular portion 9 is aligned with the depressible portion 13 of the inner portion 10 , as well as with the snap locking mechanism 11 . in particular , the locations of the circumferential grooves 5 matches the location of the engagement elements 12 of the inner portion 10 , such that , when sutured , the elements 12 are held against the lead even though a pressure would be exerted onto the depressible portion 13 . when the outer and inner portions are arranged according to fig5 , the suture sleeve has been completely assembled and is ready for operation . in fig6 , the snap lock 11 of the inner core portion 10 is depicted in a perspective view . as can be seen in the figure , the snap lock 11 is shown in an open state , whereby the entire inner core portion 10 may be opened such that the lead can be removed after the outer tubular portion has been cut open and removed . furthermore , following assembly of the inner and outer portions 9 , 10 , but prior to or during fitting of the suture sleeve 3 onto the implantable lead 2 , the snap locking mechanism 11 is in an open or a semi - open state . in the open state of the snap lock , the outer tube 9 prevents the inner tube 10 from opening up altogether . however , the snap lock 11 of the inner tube 10 is preferably in a semi - open state in which the opposing portions of the snap lock 11 are in engagement , but where the snap lock 11 may be further closed when pressure is applied to the suture sleeve . in other words , the snap lock 11 may be provided with a plurality snap catches , such that the inner tubular portion 10 may be closed in steps . then , the first step would provide the inner tubular portion 10 with such inner dimensions that it would still be freely movable along the lead . the retaining mechanism , as illustrated in fig6 and 7 , comprises engagement elements 12 having projections 14 , that protrude into the lumen of the inner core portion 10 , and a depressible portion 13 . the depressible portion 13 of the manipulating element is located centrally with regard to the longitudinal direction of the inner tubular portion 10 , and is connected to the engagement elements 12 via a respective pivot point . thus , the inner tubular portion is operable to loosen the grip on the lead by means of a leverage effect upon applying pressure on the depressible portion 13 . turning now to the cross - sectional view of the inner core portion and the outer tubular portion , as shown in fig7 , note how the depression of the outer tubular portion matches the depressible portion of the inner core portion . it can also be noted how the circumferential grooves 5 are aligned with the projections 14 , such that the engagement elements 12 , and the projections 14 thereof , can be displaced towards the lead when pressure is applied by a suture that is tied down in the suture grooves 5 . as readily understood from fig6 and 7 , the projections 12 can only be displaced a limited distance , due to the geometrical configuration of the retaining mechanism and the adjacent portion of the cylindrical tube . thereby , the lead is protected from tie down failure . fig8 a through 8c demonstrate in greater detail the function of the engagement elements 12 . in fig8 a , the situation when the suture sleeve is in the first mode is illustrated . then , the snap lock 11 is in the open state , wherein the suture sleeve is easily movable along the lead . in this first mode , the retaining mechanism is unbiased , and there is essentially no contact between the retaining elements and the surface of the lead . in fig8 b , a transition has been made such that the suture sleeve is in the second mode . here , the snap lock 11 is in the closed state and the retainer is in the engaged state , wherein the suture sleeve is fixed at a position along the lead . the projection of the retaining mechanism has been displaced radially inwardly and is pressed radially outwardly by the lead surface . thus , the engagement element is biased against the lead and the projection exerts a pressure onto said lead . in fig8 c , there is illustrated the situation when the suture sleeve is in the third mode . now , the snap lock is in the closed state and the retainer is in the temporarily released state , wherein the pressure exerted by the projection 12 is temporarily released from the lead such that the suture sleeve can be moved along the lead . for illustrative purposes , a gap has been provided between the projection and the lead . this is , however , not required . it may be sufficient to decrease the pressure exerted onto the lead by means of applying pressing onto the depressible area 13 , which by a leverage effect acts on the projection 12 , in order for the sleeve to be movable along the lead . in a second working example , shown in fig9 through 11 , there is provided another example of an inner core portion 20 and an outer tubular portion 18 . the inner core portion 20 operates according to the same basic principles as the previously described inner portion . the inner core portion 20 depicted in fig9 comprises a centrally arranged depressible area 23 and distally arranged engagement elements 22 , at a longitudinal end of the inner portion , respectively . projections 24 of the engagement elements 22 protrude into the lumen 21 of the inner portion 20 and are arranged to be brought into engagement with the outer surface of an implantable lead . in the described example , the cross sections of the projections 24 are in the form of circular arcs , such that a smooth and large contact surface can be obtained between the projections 24 and the surface of the lead . the engagement elements 22 are further connected to the depressible portion via pivot points , respectively , such that the depressible portion 23 is operable to loosen the grip on the lead by means of a leverage effect . the inner core portion according to this embodiment further comprises a snap locking mechanism ( not shown ) similar to that of the inner core portion 10 in the embodiment described above . the outer tubular portion 18 differs only with respect to the shape of the lumen 19 from the lumen 8 of the previously mentioned outer tubular portion 9 . the exterior of the outer tubular portions 9 , 18 are in these examples similar . in all other aspects , the outer tubular portion 9 of this embodiment is operated in a similar manner as described above . it is to be noted that the suture grooves may also in this working example match the position of the engagement point ( s ) of the projections . likewise , the snap lock 11 may be matched by the actuation areas , which provide guiding for the operator . referring to fig1 , there is provided a cross - sectional view of the inner portion 20 in its unbiased state . in this embodiment , the inner minimum diameter of the inner portion is less than the diameter of the lead , such that the inner portion 20 will be biased when a lead is inserted into the lumen of the inner portion 20 , as is depicted in fig1 . even though the invention has been described with reference to specific examples thereof , many different alterations , modifications and the like will become apparent for those skilled in the art . the described examples are therefore not intended to limit the scope of the invention , as defined by the appended claims .

a suture sleeve for securing an implantable lead to body tissue has a lumen that receives the lead and that includes a locking arrangement that secures the sleeve at a selected position along the lead . the locking arrangement provides the suture sleeve with three modes of operation . in the first mode , the size of the lumen exceeds the diameter of the lead , such that the suture sleeve is easily movable along the lead . in the second mode , the size of at least a portion of the lumen is reduced , causing the sleeve to apply pressure to the lead so that relative movement between the sleeve and the lead is prevented . in the third mode , the pressure is temporarily released , allowing the sleeve to again be movable along the lead .

referring to the drawings , the main components of the orthopedic instrument 22 are a handle 20 and an acetabular impactor 21 . the handle 20 is comprised of a shaft 9 , an impactor head 10 at the proximal end of the shaft 9 and a threaded portion at the distal end . the threaded portion of the handle is comprised of an axially disposed , internally threaded annular portion . the acetabular impactor 21 is comprised of threads 8 at the proximal end for removably affixing the acetabular impactor 21 to the handle 20 by screwing the acetabular impactor 21 and handle 20 together . the threads 8 are comprised of an axially disposed externally threaded portion . in a variation of the invention which is not illustrated in the drawings , the threads on the handle can be external and the threads on the acetabular impactor can be internal . other elements of the acetabular impactor 21 include recess 1 , hemispherical head 2 , proximal conical extension 11 , retaining tongues 5 , release levers 6 , hemi - circular retaining ring 7 and recesses 17 . the retaining ring 7 acts as a spring to allow the retaining tongues 5 to move laterally to removably engage the acetabular cup 14 . optional elements of the acetabular impactor include conical protective / supportive sheet 12 and channels 3 and 4 as drill guides and for screw insertion . the acetabular cup 14 has a stem 15 which is accommodated by recess 1 in acetabular impactor 21 . a circumferential groove 16 is located in the concave surface of the acetabular cup in proximity to the circumferential edge of the cup . as illustrated in fig3 , the retaining tongues 5 engage the circumferential groove 16 when the acetabular cup is releasably engaged with the orthopedic instrument 22 . in a variant of the invention , reference number 16 can designate diametrically opposed recesses for the retaining tongues 5 . surface 18 of the acetabular cup is adapted for secure attachment to the acetabular socket of a pelvis . in a preferred embodiment the surface 18 is convex but other shapes suitable for secure attachment to a pelvic bone can be used as will be apparent to those skilled in the art . referring to fig4 , the screw holes 25 are optionally threaded and preferably are threaded in a portion of the holes having a morse taper , the taper having a larger diameter on the concave surface 19 of the acetabular cup 14 and a smaller diameter on the opposite side 18 , said opposite side preferably having a convex shape . an orthopedic system is provided according to the invention when the acetabular cup 14 is removably engaged with the orthopedic instrument 22 or when the acetabular cup 14 is removably engaged with the acetabular impactor 21 . there are two methods according to the invention . the first method is employed when the surgeon does not use screws to affix the acetabular cup 14 in the pelvis . the second method is employed when the surgeon uses at least one screw to affix the acetabular cup 14 to the pelvis . in the first method , the acetabular cup 14 is releasably engaged with the distal end of the orthopedic instrument 22 by snap fitting the cup over the retaining tongues 5 to engage the circumferential groove 16 . then the acetabular cup 14 is positioned in the acetabular socket of the pelvis and the impactor head 10 is impacted , such as with a hammer , to affix the acetabular cup 14 in the acetabular socket . the orthopedic instrument 22 then is released from the acetabular cup by pressing release levers 6 inwardly . in the second method , the acetabular cup 14 is releasably engaged with the distal end of the orthopedic instrument 22 in the same manner as described above . then the acetabular cup 14 is positioned in the acetabular socket of the pelvis and the impactor head 10 is impacted to set the acetabular cup 14 in place . then the handle 20 is unscrewed from the acetabular impactor 21 and a sleeve 23 of fig5 is inserted into one or both of channels 3 or 4 . sleeve 23 is also optionally provided with threads 24 , preferably on a morse taper , to mate with the threads in screw holes 25 . when a sleeve 23 is threaded into a screw hole 25 , the sleeve will not spin during drilling and the engagement of the acetabular cup 14 with the acetabular impactor 21 is enhanced . the sleeve 23 is sized with suitable outer and inner diameters to prevent or minimize wobbling of the drill bit during drilling of the pelvic bone . the length of the sleeve 23 is sized to insure that the drill bit penetrates the bone to the appropriate depth without going too deep . after the hole is drilled , the sleeve 23 is removed , the screws are installed and the acetabular impactor 21 is released from the acetabular cup 14 as described above .

an orthopedic instrument for installing a new reverse hip prosthesis , particularly the acetabular cup thereof , wherein the cup can be affixed to the pelvis with or without screws . the acetabular cup is releasably attached to the instrument and the instrument is used to position the cup in the pelvis . optional screw guides are provided in the instrument in case the surgeon wishes to use screws to affix the cup to the pelvis .

unless otherwise stated , a reference to a compound or component includes the compound or component by itself , as well as in combination with other compounds or components , such as mixtures of compounds . as used herein , the singular forms “ a ,” “ an ,” and “ the ” include the plural reference unless the context clearly dictates otherwise . all publications , patents and patent applications cited herein , whether supra or infra , are hereby incorporated by reference in their entirety to the same extent as if each individual publication , patent or patent application was specifically and individually indicated to be incorporated by reference . medicament , “ active agent ” or pharmaceutical may be used interchangeably , and individually or collectively comprise any drug , solution , compound or composition which induces a desired pharmacologic and / or physiologic effect , when administered appropriately to the target organism ( human or animal ). reference herein to “ one embodiment ”, “ one version ” or “ one aspect ” shall include one or more such embodiments , versions or aspects , unless otherwise clear from the context . as an overview , the present invention comprises apparatus , systems , assemblies , components and ventilator circuits . in some embodiments , one or more components may be used independently of the other combinations and / or assemblies described herein . moreover , the various embodiments of the coupling apparatus are not limited to use with the ventilator circuits of the invention . thus the various embodiments of the coupling apparatus of the present invention may be used in a variety of fluid and / or gas flow applications where a device to atomize a fluid is to be incorporated into a fluid or gas supply system . this includes , without limitation , systems for distributing or supplying an aerosolized material within a gas or fluid manifold or distribution circuit , such as fuel supply systems , coating systems , biological test systems and the like . such systems can have aesthetic purposes , as for example , distributing a fragrance or other aesthetic component , or may be for functional purposes . one or more embodiments of the apparatus , systems , assemblies and components are configurable to administer aerosolized medicament to a patient on - ventilator or off - ventilator . on - ventilator treatment methods comprise administering the nebulized aerosol through a ventilator circuit to the patient . aerosol doses , containing an effective dose , such as about 1 to about 500 mg of a medicament , may be delivered through the ventilator circuit in a phasic or non - phasic manner . off - ventilator treatment methods comprise taking the patient off the ventilator before administering the nebulized aerosol . once the treatment session is completed the patient may be put back on the ventilator , or may breathe on his or her own without assistance . off - vent devices often are self - contained , for freely - breathing patients , and may comprise an aerosol generator ( e . g . a nebulizer ) and a mask , cannula , lipseal or mouthpiece to administer an aerosolized liquid or powder formulation , such as a medicament . administration may be continuous , phasic ( such as during inspiration ), and / or intermittent ( such as timed ). devices , especially off - vent devices , used to administer the aerosol formulations , such as medicaments , may comprise a reservoir or holding chamber to permit or allow continuous flow of aerosol . while one benefit of the apparatus , systems , assemblies , components of the present invention is in conjunction with positive pressure - type apparatus , the apparatus , systems assemblies and components of the present invention may also be useful in non - pressurized systems , neutral pressure systems , or negative pressure ( e . g . vacuum ) systems , as being rapidly and easily replaceable , exchangeable or interchangeable . referring to the drawings and initially to fig1 a thereof , there is illustrated a known aerosolized medicament delivery apparatus 100 that is suitable for coupling with a circuit of a pressure - assisted breathing system connected to the respiratory system of a patient , for example as described in detail in the aforementioned u . s . pat . no . 6 , 615 , 824 , incorporated by reference herein . in its most basic form , delivery apparatus 100 comprises a nebulizer 101 having an aerosol generator ( not shown ) for aerosolizing a liquid medicament , and a generally “ t ”- shaped hollow connector 102 for coupling nebulizer 101 to a circuit of a pressure - assisted breathing system . although reference is made herein for convenience to a “ t ”- shaped connector , or “ t ”- piece , it is understood that the connector 102 may have other shapes , for example , a “ y ” or other shape . connector 102 comprises an aerosol supply conduit 103 having inlet opening 105 into which barrel 104 of nebulizer 101 may be inserted , a gas conduit 106 having an inlet opening 109 , which may be attached to one tube of the pressure - assisted breathing system circuit , and outlet opening 107 , which may be attached to another tube of the circuit , thereby completing the circuit through gas conduit 106 . gas flow 108 flowing under positive pressure in the circuit enters inlet opening 109 and is conducted to the junction of aerosol supply conduit 103 and gas conduit 106 . an aerosol of medication generated by nebulizer 101 , preferably using a vibrating aperture - type aerosol generator , passes through barrel 104 into aerosol supply conduit 103 and into the junction , where it is entrained in gas flow 108 to form gas flow 110 comprising entrained aerosolized medicament . gas flow 110 exits gas conduit 106 through outlet opening 107 into the pressure - assisted breathing system circuit . the aerosol of medicine is then ultimately carried by the gas flow in the pressure - assisted breathing system to the patient &# 39 ; s respiratory system , e . g . through a patient interface device . when nebulizer 101 is withdrawn from connector 102 in the arrangement illustrated in fig1 a , gas flows 108 and 110 may be disrupted since they will be diverted into aerosol supply conduit 103 and out opening 105 to the atmosphere , thereby eliminating the positive airway pressure in the circuit . fig1 b illustrates one proposal that has been advanced to solve the above - described problem . as shown in fig1 b , a spring - loaded valve 112 is positioned in aerosol supply conduit 103 of connector 102 . the force of the spring holds valve 112 over inlet opening 105 when barrel 104 of nebulizer 101 is not present in aerosol supply conduit 103 , and therefore valve 112 seals off aerosol inlet opening 105 . as shown in fig1 c , when barrel 104 is inserted into aerosol supply conduit 103 , valve 112 is forced downwards by barrel 104 and inlet opening 105 is uncovered , thereby allowing aerosol 113 emitted by nebulizer 101 to be released into and entrained by air flow 108 . an example of a commercially available “ t ”- piece is provided by thayer medical and is designed to work with a pneumatic nebulizer . although this device may effectively seal the circuit when nebulizer 101 is withdrawn , the efficiency of delivery of aerosol to the pressure - assisted breathing system is drastically reduced since valve 112 is in the path of the aerosol and impedes its flow . as shown in fig1 c , aerosol 113 impacts valve 112 and is deflected from gas flow 108 through gas conduit 106 . fig2 , 3 , 4 a and 4 b illustrate embodiments of a connector according to the present invention wherein insertion and removal of a nebulizer from the aerosol supply conduit may be accomplished without interrupting the positive pressure gas flow in the circuit of the pressure - assisted breathing system with which it is coupled , while maintaining a high efficiency of aerosol delivery , and further without impeding flow of aerosol or gas . in one or more embodiments , there is provided a connector 200 , which comprises aerosol supply conduit 203 having inlet opening 205 into which a nebulizer barrel may be inserted , gas conduit 206 having inlet opening 209 for the entrance of gas from a circuit , and outlet opening 211 for the exit of entrained aerosol and gas into the circuit . in addition , connector 200 has a hinged lid 212 attached to aerosol supply conduit 203 by spring - loaded or otherwise biased hinge 213 . as shown in fig3 , lid 212 is held in a closed position over inlet opening 205 by the hinge 213 when the nebulizer barrel is not present , thereby sealing the circuit and maintaining positive pressure . lid 212 may be rotated upwards to uncover inlet opening 205 and accommodate the insertion of the nebulizer barrel when desired . this position provides an unimpeded path for aerosol to travel from the nebulizer to the gas conduit . upon removal of the nebulizer barrel , spring - loaded hinge 213 causes lid 212 to return to the closed position over inlet opening 205 to re - seal the circuit . in some embodiments , lid 212 may have an “ o ”- ring seal 214 around its lower periphery to aid in the sealing of inlet opening 205 . in some embodiments , a slotted flap seal or valve 215 may be positioned in inlet opening 205 , as shown in fig3 . slotted flap seal 215 is preferably made of a suitable sealing material , e . g . silicone , and may comprise a plurality of deformable flaps 216 defined by crossed slots 217 , as illustrated in fig4 a . fig4 b illustrates the deflection of flaps 216 when nebulizer barrel 104 of nebulizer 101 is inserted into inlet opening 205 . the deflection of flaps 216 allows unimpeded flow of aerosolized medicament 218 from nebulizer through aerosol conduit 203 . when nebulizer barrel 104 is removed from inlet opening 205 , flaps 216 return to their original position to re - seal the circuit before lid 212 is returned to the closed position shown in fig3 . closed flap seal 215 also aids in maintaining the seal when the nebulizer is removed . in some embodiments , the slotted flap seal 215 may be made sufficiently robust to function alone to seal the inlet opening 205 , yet permit insertion of the nebulizer barrel 104 . in such embodiments , the lid 212 and hinge 213 may be omitted . fig5 illustrates another embodiment of the apparatus of the present invention , represented by the reference character 500 . apparatus 500 comprises a nebulizer 501 , a rotatable disc adaptor 502 and a sleeve connector 503 . adapter 502 has an off - set opening 504 in planar surface 506 into which barrel 505 of nebulizer 501 may be inserted . the offset opening 504 is preferably off - set about a central axis of the adapter 502 . sleeve connector 503 comprises aerosol supply conduit 507 having off - set inlet opening 508 in planar surface 509 that is substantially equal in size and shape to opening 504 in adaptor 502 . the offset opening 508 is also preferably off - set about a central axis of the surface 509 . adaptor 502 is preferably mounted on connector 503 such that it can be rotated about a central axis as indicated by arrows 510 . accordingly , adapter 502 may be placed in the position shown in the overhead view of fig6 a during removal or insertion of nebulizer 501 into opening 504 . in the position illustrated by fig6 a , opening 504 in adapter 502 is not aligned with opening 508 in aerosol supply conduit 507 and therefore opening 508 is effectively blocked by planar surface 506 of adaptor 502 ( and opening 504 is effectively blocked by planar surface 509 of aerosol supply conduit 503 ). this position seals the circuit and allows barrel 505 of nebulizer 501 to be removed from opening 504 without interrupting gas flow through connector 503 or losing pressure in the pressure - assisted breathing system . when it is desired to connect nebulizer 501 to connector 503 , barrel 505 is inserted in opening 504 and adapter 502 is rotated in the direction of arrow 511 to the position illustrated in fig6 b . in this position , opening 504 is aligned with opening 508 , thereby providing an unimpeded path for aerosol emitted from nebulizer 501 to enter aerosol supply conduit 507 of connector 503 and become entrained in the gas flow of the system such as a pressure - assisted breathing system , as previously described . if required , it is contemplated that suitable sealing means ( such as o - rings , gaskets or the like ) may be placed between adapter 502 and planar surface 509 to further reduce the possibility of leaks . additionally , suitable detents , indents , tabs or indicators ( not shown ) may be provided on appropriate engaging surfaces of conduit 507 and adaptor 502 to positively identify engagement and disengagement of openings 504 and 508 . fig7 a and 7 b illustrate yet another embodiment of the invention designated by the general reference character 700 , and represent a cross - section view perpendicular to the longitudinal axis of the connector 700 . connector 700 has an aerosol supply conduit 702 having an inlet opening 703 at its distal end and an outlet opening 704 at its proximal end . outlet opening 704 communicates with gas conduit 705 running the length of the main body of connector 700 . hinged door 706 is attached to the internal wall of gas conduit 705 by spring - loaded or otherwise biased hinge 710 . in the position illustrated in fig7 a , door 706 is disposed over outlet opening 704 to seal aerosol supply conduit 702 and prevent the escape of the gas flow in gas conduit 705 . when nebulizer barrel 707 is inserted into aerosol supply conduit 702 through inlet opening 703 , nebulizer barrel 707 forces hinged door 706 downward , opening a pathway for the aerosol 708 . in some embodiments , there is provided a notch or recess 708 in the internal wall of gas conduit 705 to further facilitate insertion of the nebulizer barrel 707 and to provide an unimpeded path for aerosol 709 from the nebulizer into the gas flow in gas conduit 705 , as shown in fig7 b . the notch or recess 708 may cooperate with a mating structure ( not shown ) on the door 706 to assist in removably holding the door 706 in the open position , and / or aligning the door 706 . when nebulizer barrel 707 is withdrawn from aerosol supply conduit 702 , spring - loaded or biased hinge 710 acts to return hinged door 706 to the closed position shown in fig7 a , thereby re - sealing the circuit . the hinge or biasing means 710 may be configured to hold the door 706 between two positions , such as an open position as depicted in fig7 b and a closed position as depicted in fig7 a . another embodiment of the present invention is illustrated in fig8 a and 8 b , wherein connector 800 comprises gas conduit 801 and rotatable sleeve 802 , which may be rotatable about the conduit 801 . rotatable sleeve 802 comprises aerosol supply conduit 808 and lumen 804 , which is configured to receive gas conduit 801 so that aerosol supply conduit 808 can rotate around the longitudinal axis of gas conduit 801 . aerosol supply conduit 808 comprises inlet opening 803 configured to accommodate the barrel of a nebulizer , as previously described . gas conduit 801 comprises intermediate opening 805 , outlet opening 806 and inlet opening 807 . gas conduit 801 may be positioned within lumen 804 of sleeve 802 so that intermediate opening 805 in gas conduit 801 is aligned with aerosol supply conduit 803 , as shown in fig8 a . when a nebulizer is inserted in inlet opening 803 , the position shown in fig8 a allows an unimpeded path for aerosol emitted by the nebulizer into aerosol supply conduit 808 to travel through intermediate opening 805 into gas conduit 801 and be entrained in the gas flowing from inlet opening 807 to outlet opening 806 . when the nebulizer is to be removed from connector 800 , sleeve 802 may be rotated relative to conduit 801 in the direction indicated by the arrow in fig8 a to a position wherein aerosol supply conduit 803 is effectively blocked by the internal wall of lumen 804 . in this position , the aerosol supply conduit 808 is sealed off from gas conduit 801 and the nebulizer may be removed from connector 800 without the escape of gas from gas conduit 801 . when the nebulizer is re - inserted into aerosol supply conduit 808 through inlet opening 803 , sleeve 802 may be rotated to the position shown in fig8 a , thereby again opening up an unimpeded path for aerosol to pass through aerosol supply conduit 808 into the gas flow of gas conduit 808 . optionally a suitable sealing means 809 , such as an o - ring , gasket or the like , may be placed around opening 805 to further reduce the possibility of leakage . additionally , suitable detents , indents , tabs or indicators ( not shown ) may be provided on appropriate engaging surfaces of conduit 801 and sleeve 802 to positively identify engagement and disengagement of openings 803 and 805 . the aerosol generators or nebulizers contemplated for use herein may , for example , be a vibrating mesh nebulizer where the energy source is mechanical , such as wave energy , an ultrasonic nebulizer where the energy source is acoustic wave energy , a jet nebulizer where the energy source is compressed air , a metered dosing device where the energy source is a propellant , such as a composition that boils under preselected , such as ambient conditions , or a dry powder device where the energy source is compressed or flowing air or is a vibrating membrane or the like . some specific , non - limiting examples of technologies for producing fine liquid droplets comprise those which supply liquid to an aperture plate having a plurality of tapered apertures , and vibrate the aperture plate to eject liquid droplets through the apertures . such techniques are described generally in u . s . pat . nos . 5 , 164 , 740 ; 5 , 938 , 117 ; 5 , 586 , 550 ; 5 , 758 , 637 , 6 , 014 , 970 , and 6 , 085 , 740 , the complete disclosures of which are incorporated by reference . however , it should be appreciated that the present invention is not limited for use only with such devices . for example , in one or more embodiments , the aerosol generator is the commercially available aerogen ( aerogen , inc . mountain view , calif .) aerosol generator which comprises a vibrational element and dome - shaped aperture plate with tapered holes . when the plate vibrates ( at several thousand times per second ), a micro - pumping action causes liquid to be drawn through the tapered holes , creating a low - velocity aerosol with a precisely defined range of droplet sizes . the aerogen aerosol generator does not require propellant . jet nebulizers involve use of air pressure to break a liquid solution into aerosol droplets . in one or more embodiments , a jet nebulizer ( e . g ., aerojet , aeroeclipse , pan l . c ., the parijet , whisper jet , microneb ®, sidestream ®, acorn 11 ®, cirrus and upmist ®) generates droplets as a mist by shattering a liquid stream with fast moving air supplied by tubing from an air pump . in one or more embodiments , an ultrasonic nebulizer that uses a piezoelectric transducer to transform electrical current into mechanical oscillations is used to produce aerosol droplets . examples of ultrasonic nebulizers include , but are not limited to , the siemens 345 ultrasonic nebulizer ™ and ones commercially available from , for example , omron heathcare , inc . and devilbiss health care , inc . see , e . g ., ep 1 066 850 , which is incorporated by reference herein in its entirety . vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate . see , e . g ., u . s . pat . nos . 5 , 758 , 637 ; 5 , 938 , 117 ; 6 , 014 , 970 ; 6 , 085 , 740 ; and 6 , 205 , 999 , which are incorporated herein by reference in their entireties . in condensation aerosol generators , the aerosol is formed by pumping drug formulation through a small , electrically heated capillary . upon exiting the capillary , the formulation is rapidly cooled by ambient air , and a gentle aerosol is produced that is relatively invariant to ambient conditions and the user inhalation rate . see , e . g ., u . s . pat . no . 6 , 701 , 922 and wo 03 / 059413 , which are incorporated herein by reference in their entireties . in one or more embodiments , the condensation aerosol generator comprises one disclosed by alexza molecular delivery corporation . see , e . g ., u . s . published application no . 2004 / 0096402 , which is incorporated herein by reference in its entirety . it is understood that while the invention has been described above in connection with preferred embodiments , the description and drawings are intended to illustrate and not limit the scope of the invention , which is defined by the appended claims and their equivalents .

apparatus and components for coupling fluid or gas conducting elements , such as apparatus and components for connecting a nebulizer with a gas flow system . in particular , the apparatus and components are useful for connecting , in a gas - tight and quick release manner , a nebulizer to a pressure - assisted breathing system , such as a mechanical ventilator or a continuous positive airway pressure system .

referring now to the drawings in more detail in which like reference numerals refer to like or corresponding devices among the views , there is shown in fig1 and 2 a view of an embodiment of an infusion system 20 having a pump 22 , a medicament supply tube segment or pump - side tube segment 24 from the pump , a fluid flow rate restrictor 26 , a patient delivery tube segment or patient - side tube segment 28 , and a sharp cannula 30 for inserting into the patient to perform the infusion . in fig1 , it will be noted that the restrictor has been affixed to the patient 32 with tape 34 to stabilize the position of the cannula and control the temperature of fluid entering the restrictor assembly . this approach is meant to provide a broad illustration only and not meant to be restrictive of the use of the invention . other techniques well known to those skilled in the art for mounting pumps to or with a patient , puncturing the patient , and stabilizing a tube , restrictor , or other devices may be employed as needed . additionally , the size of the restrictor 26 has been exaggerated in this case for clarity of illustration . the fluid infusion system 20 can be used for a wide variety of therapies such as pain , spasticity , cancer , and other medical conditions . the fluid infusion system 20 operates to infuse a therapeutic substance at a pre - determined rate into the patient 32 . the therapeutic substance is a product or substance intended to have a therapeutic effect such as pharmaceutical compositions , genetic materials , biologics , and other substances . pharmaceutical compositions are chemical formulations intended to have a therapeutic effect such as intrathecal antispasmodics , pain medications , chemotherapeutic agents , and the like . pharmaceutical compositions are often configured to function in an implanted environment with characteristics such as stability at body temperature to retain therapeutic qualities , concentration to reduce the frequency of replenishment , and the like . genetic materials are substances intended to have a direct or indirect genetic therapeutic effect such as genetic vectors , genetic regulator elements , genetic structural elements , dna , and the like . biologics are substances that are living matter or derived from living matter intended to have a therapeutic effect such as stem cells , platelets , hormones , biologically produced chemicals , and the like . other substances are substances intended to have a therapeutic effect yet are not easily classified such as saline solution , fluoroscopy agents , and the like . referring now to fig3 , an embodiment of a fluid flow rate restrictor 26 in accordance with aspects of the invention is provided . the pump - side tube segment 24 is shown facing a capillary tube 40 that forms a part of the restrictor 26 . the pump - side tube segment includes a lumen opening 36 having a certain size ( i . e . dimension ) d 1 . fluid from the pump 22 will be received from the lumen opening of the pump - side tube segment 24 into a chamber 42 . the chamber is formed by the pump - side tube segment 24 at the proximal end , and the distal end of the chamber is formed by the proximal end 44 of a sleeve 46 that surrounds and mounts the capillary tube 40 . the outer wall of the chamber is provided by a housing 48 that tightly fits over the fluid supply tube segment 24 and the sleeve 46 of capillary tube 40 in a fluid - tight fashion . as will be described in more detail below , the chamber has a volume selected to cause medicament entering the chamber 42 from the pump through the pump - side tube segment 24 to decrease in instantaneous velocity to a level where contaminants in the medicament fall out of the solution of the medicament thereby separating from the medicament . those contaminants may then fall to the wall 48 provided by the housing . because the capillary tube projects into the chamber by a certain distance and is not flush with the proximal end 44 of the sleeve 46 , it is much less likely that those separated contaminants will find their way into the capillary tube opening . in this way , the chamber performs a filtering function . in addition , the capillary tube may be eccentrically or oddly shaped to further precipitate filtering of contaminants . turning now to fig4 , a partial cross - sectional side view of the restrictor of fig3 is shown . the fluid supply tube segment 24 has a distal end 25 that forms a part of the chamber 42 . as can perhaps more clearly be seen in fig4 , the contaminant - separating chamber 42 is formed by that distal end 25 of the fluid supply tube segment , the proximal end 44 of the capillary tube mounting sleeve 46 , and the housing 48 a . as illustrated , capillary tube 40 is preferably projected into the chamber to further aid filtering of contaminants . also illustrated in fig4 , the patient - side tube 28 is connected to the restrictor 26 by the housing 48 b . the housing consists of two parts , section 48 a on the proximal end 50 of the restrictor , and section 48 b on the distal end 52 . the sleeve 46 around the capillary tube 40 may be formed of polyvinylchloride ( pvc ). the capillary tube 40 is slid into the sleeve and located as desired . adhesive may be applied at one end of the sleeve at the capillary and will wick into the interface of the sleeve and capillary tube to permanently attach the sleeve to the capillary tube . in a preferred embodiment the capillary tube 40 is disposed within the sleeve 46 by adhesive bonding for example at its proximal end . rigidity of the sleeve will protect the capillary tube from breakage due to extreme inadvertent bending . as illustrated in fig4 , an optional mounting flange 60 may be mounted on the sleeve 46 . the mounting flange may be centered on the sleeve and may also be formed of pvc . in one embodiment , the mounting flange is a shorter sleeve ( e . g . 60 ) slid over the first sleeve ( e . g . 46 ) and held in position by adhesive or other means . the mounting flange provides distal 62 and proximal 64 abutment surfaces for the housing 48 b , 48 a to facilitate manufacture and assembly of the restrictor 26 . in one or more configurations ( not shown ), mounting flange 60 may be omitted . in such configurations , housing sections 48 a and 48 b may be configured such that the distal end of housing section 48 a and the proximal end of housing section 48 b are approximately abutting . in a further embodiment , the sleeve 46 comprises a hard - plastic housing that is formed by being over - molded around the capillary tube 40 . the amount of overlap of the housing over the pump - side tube segment 24 and the patient - side tube segment 28 is not to scale in fig4 and may actually be more than shown . although not shown , the housing may have stop shoulders located internally to receive the pump - side tube segment and patient - side tube segment and limit their length of insertion into the housing . referring now to fig5 , an alternate embodiment is shown in which the sleeve 70 of the capillary tube 40 differs from the embodiment of fig4 . in this case , the sleeve may be formed by overmolding of pvc of another plastic material on the capillary tube and is configured to provide not only protection for the capillary tube and to provide proximal 72 and distal 74 mounting surfaces for the housing 48 , but also proximal 76 and distal 78 abutment surfaces for the housing . as in all the other configurations , the capillary tube may be configured to project out of the sleeve in both the proximal and distal directions . also , flange 60 may be configured to extend outward to the distance similar to that of the housing outer surface to form a relatively smooth outer surface 66 . the patient will feel less discomfort with a smooth outer surface design than with other designs having an uneven outer surface . referring now to fig6 , another alternate embodiment is shown in which the sleeve 80 of the capillary tube 40 differs from the previous embodiments . in this embodiment , the sleeve 80 may also be formed by overmolding of pvc or another plastic material on the capillary tube . the sleeve is configured to provide protection for the capillary tube and to provide proximal 82 and distal 84 mounting surfaces for the housing ( 48 a , 48 b ). no abutment surfaces for the housing are provided and a gap may exist between the two housing components 48 a and 48 b . it should also be noted that this embodiment is configured such that the sleeve 80 has a length and location in relation to the capillary tube 40 so that both ends of the capillary tube project beyond the ends of the sleeve . this eliminates the possibility that the capillary tube could be improperly oriented when installed in the restrictor 26 . this will also reduce cost in the manufacturing process thus making it widely available to all patients with differing access to health care . turning now to fig7 , further information on the relative sizes of the components of the chamber 42 is provided . dimension d 1 is the inner surface dimension of the pump - side tube segment 24 . dimension d 2 is the inner surface dimension of the housing which surrounds both the pump - side tube segment and the sleeve 46 that in turn surrounds the capillary tube 40 . dimension d 3 is the inner surface dimension of the lumen 54 of the capillary tube 40 . d 2 is larger than d 1 which is larger than d 3 . the internal fluid passageway 90 of the pump - side tube segment with a first inner dimension d 1 is in fluid communication with a proximal end 92 of a chamber 42 . the chamber 42 has a length 94 and a chamber wall 96 . the chamber has a second inner dimension d 2 that is larger than the first inner dimension d 1 . a capillary tube 40 having a third inner dimension d 3 is provided . the capillary tube 40 is located at a distal end 98 of the chamber and has a length 100 projecting into the chamber . the third inner dimension d 3 is smaller than the first d 1 and the second d 2 inner dimensions . the inner dimensions d 1 , d 2 , d 3 along with the lengths 94 and 100 are selected to result in optimal filtering properties with minimal opportunity of damage to the capillary tube during manufacture or use . as used herein , 1 “ mil inch ” shall be equal to 1 / 1000 of an inch and “ mil - inches ” shall indicate more than one mil - inch . also , note that the flow restrictor , sleeve , and capillary may have circular cross - sectional areas thus , although their inner surface dimensions may be referred in terms of diameters , reference to diameters are not intended to limit the invention to circular / cylindrical objects . referring to the embodiments in fig4 through 7 , the sleeve ( i . e . 46 , 70 , 80 ) can be injection molded around the capillary tube 40 . alternatively , the sleeve ( i . e . 46 , 70 , 80 ) can be co - extruded around the capillary tube during its manufacturing process . previous flow restrictors had the end of the capillary tube 40 flush with the end of the sleeve . in accordance with an aspect of the present invention , the capillary tube 40 projects outward from the sleeve and into the chamber 42 . in operation , fluid flows from the pump - side tube 24 at relatively high velocity and into the chamber 42 having a much larger volume . once it reaches the chamber , the fluid velocity slows . any contaminants being carried in the fluid will leave solution and settle to the bottom of the chamber 42 , away from the opening 102 to the capillary tube 40 . the above - mentioned components of the restrictor 26 may be color coded to indicate the intended fluid flow rate of the restrictor . such color coding provides a visual indication that the correct restrictor is assembled in the correct model . the capillary tube 40 places a maximum limit on the flow rate of fluid out of the restrictor 26 . the capillary tube may be non - adjustable and thus pre - selected during manufacture to provide a given maximum fluid flow rate for fluid flowing out of the restrictor . in a preferred embodiment the capillary tube 40 is made of glass and defines a very small bore 102 in fluid communication with the chamber 42 . with the flow regulator near the connecting means , the restrictor 26 can be placed on the patient &# 39 ; s skin . the patient &# 39 ; s body heat maintains the liquid passing through the capillary lumen 54 at a relatively constant temperature , regardless of changes in the ambient air temperature . when the infusion site is near the subclavian vein for example , the temperature is about 92 degrees f . ( 33 . 3 degrees c .). this relatively constant temperature provides a relatively constant liquid viscosity in the restrictor 26 and thus a more constant fluid flow rate through the bore 54 . while several forms of the invention have been illustrated and described , it will also be apparent that various modifications can be made without departing from the spirit and scope of the invention . accordingly , it is not intended that the invention be limited except by the appended claims .

a fluid flow rate control system and method comprises a capillary tube having a proximal end that projects into a chamber with a cross - sectional area that is larger than or equal to the fluid supply tube &# 39 ; s cross - sectional area . the inner cross - sectional area of the capillary tube is configured less than the inner cross - sectional area of the chamber . the chamber has a volume large enough to slow the fluid conducted to it by the upstream fluid line to permit contaminants to fall out of solution . in another aspect , a sleeve is used to mount the capillary tube into the chamber . the sleeve provides a mounting surface for tube segments from the pump and downstream of the capillary restrictor .

embodiments to implement the food or drink of the present invention will be described in detail hereinbelow . the food or drink of the present invention contains an algae extract oil , an animal or plant protein , and an emulsifier . the algae extract oil is contained in an amount of 1 to 30 wt % in the food or drink of the present invention . the algae extract oil contains 30 to 50 wt % of docosahexaenoic acid ( dha ) and 1 to 20 wt % of docosapentaenoic acid ( dpa ). the algae extract oil preferably contains 35 to 45 wt % of dha and 10 to 15 wt % of dpa . the algae extract oil further contains 0 . 1 to 1 wt % of eicosapentaenoic acid ( epa ) in addition to dha and dpa . preferred algae extract oils are those extracted from aurantiochytrium sp ., schizochytrium sp . and the like of labyrinthulea of microalgae . extraction of an oil from these microalgae can provide an extract oil having a high content of docosahexaenoic acid ( dha ) and docosapentaenoic acid ( dpa ). a specific example of such algae extract oil includes an algae extract oil ( trade name : dha rich oil ) manufactured by vedan biotechnology corporation in taiwan . the animal or plant protein is contained in an amount of 2 to 50 wt % in the food or drink of the present invention . the animal or plant protein is preferably at least one selected from milk protein , soybean protein , and collagen peptide . examples of the milk protein that can be used in the food or drink of the present invention include , but are not particularly limited to , milk , skim milk , concentrated milk , concentrated skim milk , whole milk powder , skim milk powder , condensed milk , defatted condensed milk , soy milk , yogurt , cheese , butter , buttermilk , cream , cream powder , concentrated whey , and whey powder . examples of the soybean protein that can be used in the food or drink of the present invention may be any protein contained in soybeans , and include , but are not particularly limited to , soy milk , concentrated soybean protein , isolated soybean protein , and soybean peptide . examples of such soybean protein that can be used include those commercially available as supplement food and materials for food and drink . examples of the collagen peptide that can be used in the food or drink of the present invention include those provided by hydrolysis of collagen or gelatin with an enzyme or acid , without particular limitation , and preferably having an average molecular weight of the order of 100 to 300 , 000 . examples of such collagen peptide that can be used include those commercially available as materials for food and drink both in powder and liquid forms . the emulsifier is contained in an amount of 80 to 300 wt % relative to the algae extract oil . the emulsifier is preferably at least one selected from glycerin fatty acid esters , sucrose fatty acid esters , soy lecithin , yolk lecithin , and the like . the food or drink of the present invention may contain water , fragrance , a taste - masking agent , seasoning , an organic acid , a ph adjusting agent , and the like in addition to the algae extract oil , the animal or plant protein , and the emulsifier . examples of the fragrance include yogurt fragrance , lemon fragrance , pineapple fragrance , grapefruit fragrance , lemon lime fragrance , orange fragrance , and apple fragrance . examples of the taste - masking agent include green tea , black tea , oolong tea , coffee , almond oil , peppermint oil , spearmint oil , cinnamon oil , and menthol . examples of the seasoning include salt , sugar , sweet cooking rice wine , japanese sake , and wine . examples of the organic acid include lactic acid , malic acid , citric acid , tartaric acid , and ascorbic acid . examples of the ph adjusting agent include the organic acids and its salts , phosphoric acid and its salts , and carbonic acid and its salts . subsequently , a method for producing the food or drink of the present invention will be outlined . in a first step , an algae extract oil and an emulsifier are mixed . the mixture ratio between the algae extract oil and the emulsifier is 1 : 0 . 1 to 1 : 50 . in a second step , to the mixture of the algae extract oil and the emulsifier obtained in the first step , water or hot water is added and stirred until emulsification takes place . the mixture ratio may be any value , and the temperature of the water or hot water is 5 to 100 ° c . additionally , the stirring may be continued for any length of time , which is preferably between 5 minutes and 24 hours . in a third step , to the emulsion obtained in the second step , milk protein and / or soybean protein and / or collagen peptide , which is an animal or plant protein , is / are added , and additionally mixed and stirred . the mixture ratio between the emulsion and the animal or plant protein is 1 : 0 . 1 to 1 : 500 . any stirring temperature , stirring time , and stirring method may be used . to the emulsion mixture obtained via such steps , vitamin c , citric acid , tartaric acid , and the like are added to adjust the ph to 1 . 5 to 5 and make the mixture an acidic liquid . then , the acidic liquid may be added to milk or soy milk to provide a beverage . to the acidic liquid , as it is or diluted , fruit juice and the like may be added to provide a beverage . furthermore , the acidic liquid , as it is or diluted , may be blended to produce food such as retort food , baked confectionery such as cookies and rice crackers . alternatively , to the acidic liquid , as it is or diluted , a thickener and a polysaccharide may be added to produce gelled food or jelly - like semi - solidified or solidified food . subsequently , the food or drink of the present invention will be described in detail referring to examples , but the food or drink of the present invention are not intended to be limited by these examples . in order to evaluate suppression of offensive odor emission due to time - dependent changes using an algae extract oil used in the food or drink of the present invention and a commercially available fish oil , monitor test was carried out as described below ( for a period of about one month ) by 10 males and females . the algae extract oil used was an algae extract oil ( trade name : dha rich oil ) manufactured by vedan biotechnology corporation ( taiwan ). the fish oil used was a purified fish oil commonly used as food . ten males and females were asked to smell the odor of the algae extract oil and the fish oil once a week for four weeks . in accordance with the following evaluation criteria , the degree of the offensive odor emission was scored and the average was determined . the results are shown in fig1 . the evaluation criteria included three grades : “ 0 ”: no odor is noticed ; “ 1 ”: an odor is barely noticed ; “ 2 ”: an odor is slightly noticed ; and “ 3 ”: an odor is clearly noticed . as the results of the monitor test , after two weeks , the degree of the offensive odor emission from the algae extract oil was scored “ 1 ”, and the degree of the offensive odor emission from the fish oil was scored “ 2 ”. numerically , the degree of the offensive odor emission from the algae extract oil was 50 % of that from the fish oil . furthermore , after four weeks , the degree of the offensive odor emission from the algae extract oil was scored “ 1 . 7 ”, and the degree of the offensive odor emission from the fish oil was scored “ 3 ”. numerically , the degree of the offensive odor emission from the algae extract oil was about 57 % of that from the fish oil . one algae extract oil used in the food or drink of the present invention and two commercially available fish oils were used to prepare drinkable preparations , which were used to confirm the action of inhibiting platelet aggregation . the algae extract oil used to be contained in a drinkable preparation was dha rich oil ( dha : 38 wt % and epa : 0 . 4 wt %) manufactured by vedan biotechnology corporation ( taiwan ), and the fish oils to be contained in a drinkable preparation were a purified fish oil , dha 27 oil ( dha : 27 wt % and epa : 8 wt %) commonly used as food and a purified fish oil , dha 46 oil ( dha : 46 wt % and epa : 5 wt %) commonly used . in sample preparation , human blood was centrifuged to collect platelet - rich plasma ( prp ), which was centrifuged to collect platelet - poor plasma ( ppp ). in addition , blood coagulation factors ( adenosine diphosphate , an arachidonate salt , and platelet - activating factor ( paf )) were each added to the prp to aggregate platelets . each dha oil was added to each sample described above , and the light transmittance of prp was set at 0 % and the light transmittance of ppp was set at 100 % before addition of an aggregating agent . the maximum transmittance of prp after addition of the aggregating agent was taken as the maximum percentage of aggregation (%), i . e ., the percentage of platelet aggregation (%). the averaged results of testing in triplicate are shown in fig2 to 4 . the results of testing for confirmation of the action of inhibiting platelet aggregation are as follows . the percentage of platelet aggregation of the algae extract oil used in the food or drink of the present invention was 89 % for adenosine diphosphate , 88 % for the arachidonate , and 89 % for paf . the percentage of platelet aggregation of the two commercially available fish oils were 73 % and 60 % for adenosine diphosphate , 69 % and 49 % for the arachidonate , 67 % and 60 % for paf . examples of the food or drink of the present invention as a drinkable preparation or jelly - like food will be described hereinbelow . a drinkable preparation containing the ingredients described above was prepared in accordance with the production method aforementioned . the drinkable preparation was placed in a bottle , which was capped and stored in a refrigerator ( inner temperature : 10 ° c .) for one month , after which the bottle was opened and the odor was smelled . no odor other than the yogurt fragrance and vanilla flavor was felt at all . the drinkable preparation contains dha and epa , which have an excellent action of inhibiting platelet aggregation , derived from the algae extract oil . thus , drinking the preparation for a long period holds promise of prophylactic and therapeutic effects on arteriosclerotic diseases . jelly - like food containing the ingredients described above was prepared in accordance with the production method aforementioned . the jelly - like food was placed in a synthetic resin container , which was capped and stored in a refrigerator ( inner temperature : 10 ° c .) for one month , after which the container was opened and the odor was smelled . no odor other than the yogurt fragrance and pink grapefruit was felt at all . the jelly - like food contains dha and epa derived from the algae extract oil which has an excellent action of inhibiting platelet aggregation . thus , taking the food for a long period holds promise of prophylactic or therapeutic effect on arteriosclerotic disease .

the present invention provides a food or drink that emits no offensive odor typified by a fish odor in any form of the food or drink , such as liquid , gel , semi - solid , or solid form , and also suppresses emission of an offensive odor due to time - dependent changes . further , a food or drink is provided that has , particularly , a superior action of inhibiting platelet aggregation to that of conventional fish - derived epa and dha - containing food . the food or drink comprise an algae extract oil , an animal or plant protein , and an emulsifier .

fig1 and 2 are schematics of a functional electrical stimulation ( fes ) system . it consists of three basic parts : a hand - wrist orthosis 100 , a portable stimulation unit 102 and a docking station 101 . the fes interfaces with a computer 104 . the functional electrical stimulation system has two basic configurations . fig1 illustrates the first configuration , which is for training and parameter setup . fig2 illustrates the second configuration in which the portable stimulation unit works in standalone mode without connection to the docking station . these configurations will be described in more detail later . referring to fig3 to 6 , the hand - wrist orthosis 100 is made of plastic material moulded to fit the shape of the forearm of a stroke affected hand 21 of a patient . the orthosis 100 comprises three pieces . these are : a posterior portion 7 , anterior portion 8 , and a hand portion 9 . the hand portion 9 is connected with the anterior portion 8 by two joints 10 , 11 on the lateral sides . the joints 10 , 11 allow flexibility for wrist movement . a strap 15 is attached to one side of the anterior portion 8 and passes over the top part of the patients forearm to detachably connect with the other side of the anterior portion 8 by velcro ™ fasteners 18 , 19 . the posterior aspect 7 is mounted on the strap 15 for location on the top part of the patients forearm . the hand portion 9 includes two electrodes 5 , 6 . a thenar electrode 5 is for stimulating the thenar muscle group and a thumb electrode 6 is for stimulating the thumb abductor . the posterior portion 7 includes two electrodes 1 , 2 for stimulating the wrist extensor muscle group . the anterior portion 8 includes two electrodes 3 and 4 for stimulating the wrist flexor muscle group . the electrodes 1 , 2 , 3 , 4 , 5 , 6 are self - adhesive type electrodes located on the inner surface of the orthosis 100 to correspond to the above mentioned muscle groups . the electrodes are located by a clinician to suit the patient . for stimulating the thenar group electrode 5 is the active pole and electrode 4 is the indifferent pole . for stimulating the thumb abductor electrode 6 is the active pole and electrode 4 is the indifferent pole . for stimulating the wrist extensor electrode 1 is the active pole and electrode 2 is the indifferent pole . and for stimulating the wrist flexor electrode 3 is the active pole and electrode 4 is the indifferent pole . an active pole is the negative terminal and an indifferent pole is the positive terminal . a pressure sensor 12 , accelerometer 13 and gyroscope 14 are located on a strap 16 on the back of hand portion 9 . the sensors provide feedback of hand movement and position . signal wires from sensors and electrodes on the orthosis 100 are brought together at a connector 20 on the anterior portion 8 . the orthosis 100 is linked to the portable stimulation unit 102 or docking station 101 by signal cable 22 . referring to fig7 and 8 , the portable stimulation unit 102 generates a train of electrical pulse , which it transmits to selected electrodes to stimulate selected muscles and coordinate muscle contractions . the portable stimulation unit 102 is controlled by a microprocessor 28 . stimulation parameters are stored in random access memory ( ram ) 30 . an output channel selector 31 and electrode output connector 26 transmit the train of electrical pulse to the electrodes . feedback from the sensors is input to the microprocessor 28 via input connector 27 . manual control of the portable stimulation unit 102 is provided by a user interface means comprising a 12 × 2 liquid crystal display 23 , up / down / left / right input buttons 24 and a selection input button 25 on a front panel of the portable stimulation unit 102 . the lcd display 25 provides information about the stimulation patterns and the user can adjust parameters such as the stimulation frequency , stimulation amplitude levels , sensor - threshold values , pulse widths , duration time using the interface means . the portable stimulation unit b can interface with the computer 104 via a serial port 29 to facilitate download of simulation parameters obtained during setup and training . the docking station 101 comprises two microprocessors and input and output connectors for the sensors and electrodes . both the input and output connectors are connected to an input microprocessor for capture of real - time signals from the sensors and feedback of electrode output signal parameters . the output connector is connected to an output microprocessor for output of electrode control signals . the docking station 101 also includes a parallel connector for interface to the host computer 104 that facilitates graphical displays showing input and output signal parameters , parameter adjustment and data logging . the functional electrical stimulation system has two basic configurations . a first configuration is for training and parameter setup . in this first configuration the connector lead 22 from sensor and electrodes on the orthosis 100 are connected to the input / output connectors of the docking station 101 , and an extension cable 32 from the docking station 101 connect to the portable simulation unit 102 . the docking station 101 also includes a parallel connector 33 for interface to the host computer 104 that facilitates graphical displays showing input and output signal parameters , parameter adjustment and data logging . at the end of the training and parameter setup session the simulation parameters are uploaded from the computer 104 to the portable simulation unit 102 via a serial connection 34 . in a second configuration the orthosis 100 and portable stimulation unit 102 work in standalone mode without connection to the docking station 101 or computer 104 . in this second configuration the input / output cables 22 from the orthosis 100 connect directly to the portable stimulation unit 102 . this allows the patient to go home , or go about there daily routine , without the need to carry / wear bulky equipment . the portable simulation unit 102 responds to input signals to generate output signals according to the simulation parameters uploaded from the computer 104 . minor adjustment of simulation parameters and control of the portable simulation unit 102 are achieved via the user interface means . referring to fig9 , a layout of a graphical user interface on a computer is shown . a microsoft windows ® based graphical user interface can be programmed in visual basic ® or constructed using an application such as lab view ® available from national instruments ® ( www . ni . com ). the simulation parameters and their respective range are set out in the following table . the microprocessor may set the output on each channel to one of 256 levels within a range of 1 to 100 ma . the required level for each channel , to achieve the required muscle group stimulation , is determined during the setup mode ( configuration 1 ) where monitoring feedback of the output parameters is possible . this level is stored in the portable stimulation unit for recall during standalone use . the sensors is 0 to 5 volts with a resolution of 256 . the two input thresholds are set a one of 256 levels . a pressure sensor is also included on the orthotic . it provides an on / off switch to trigger the portable stimulator unit for mode 2 stimulation ( described below ). it is very thin for the pressure sensor , therefore the sensor can attached on the surface of the sensor cluster . the functional electrical stimulation system has 3 control modes selectable at the portable simulation unit . mode 1 is a simple exercise control . the patient chooses a muscle group to exercise and the simulation unit repeatedly stimulates that muscle group until the patient exits the mode . mode 2 is a manual mode in which the patient manually initiates a single stimulation of a selected muscle group . the pressure sensor on the orthotic can be used to initiate the stimulation . mode 3 is an automated stimulation mode in which the portable stimulation unit monitors feedback from the sensors and initiates a stimulation if the inputs exceed the input thresholds . the sensors capture the patients intention from their voluntary residual movement on the affected upper limb . this mode can initiate two different types of movement and then generate two different stimulation patterns controlling two different hand postures : hand opening for spastic hand , and lateral grasp for holding a pen . referring to fig1 , if the accelerometer sensor signal on input channel 1 is above threshold 1 the system enters stimulation a control . the microprocessor waits for the period set in the “ delay time ” parameter and then activates both channel 1 ( electrodes 6 ) and channel 3 ( electrodes 1 and 2 ) output signals to stimulate the respective muscles / muscle groups . the channels are closed again after the period of time set in the “ duration time ” parameter . the microprocessor enters an idle stage for the period of time set in the “ reset time ” parameter . this is to prevent the functional electrical stimulation system immediately repeating the stimulation if the input 1 signal is still above the threshold 1 value . a stimulation b is triggered by lateral wrist rotation followed by wrist extension . if the gyroscope sensor input on channel 2 is above the input 2 threshold the microprocessor will enter the waiting stage . if the accelerometer sensor signal on input channel 1 does not go above threshold 1 within the “ reset time ”, then the microprocessor will return back to idle stage . if the accelerometer sensor signal on input channel 1 goes above threshold 1 within the “ reset time ” the microprocessor enters stimulation b control . the microprocessor waits for the period set in the “ delay time ” parameter and then activates both channel 2 ( electrodes 5 ) and channel 3 ( electrodes 1 and 2 ). the channels are closed again after the period of time set in the “ duration time ” parameter . the microprocessor enters an idle stage for the period of time set in the “ reset time ” parameter . this is to prevent the functional electrical stimulation system immediately repeating the stimulation if the input signals is still above the threshold values . the functional electrical stimulation system triggers the stimulation pattern through the sensors to capture the patients intention from their voluntary residual movement on the affected upper limb . there are lots of patients after stoke who still have partially voluntary movement on hand and wrist . by encouraging their hand movement , the patients can gradually re - learn the function movement . the present invention could help the user to motor - relearn the functional movements . where in the foregoing description reference has been made to integers or elements having known equivalents then such are included as if individually set forth herein . embodiments of the invention have been described , however it is understood that variations , improvements or modifications can take place without departure from the spirit of the invention or scope of the appended claims .

an electrical stimulation device for a body part of a person comprises an orthotic with sensor and electrodes and a controller . the controller receives a sensor signal , compares the sensor signal to a threshold value and generates an electrical output from the electrodes if the sensor signal exceeds the threshold value . a docking station facilitates connection of the electrodes and sensors to a computer . the docking station including a first processor for measuring values of the sensor signal and the electrical outputs and a second processor for generating electrical outputs on the electrodes .

during the emulsification phase , of the wax paper recycling process used in practicing this invention , substantial quantities of wax are present from the waste waxed paper . however , this wax does not contaminate or coat the equipment even when slurries containing the emulsified product are cooled . when making waxed paper , very little wax penetrates below the surface of the un - waxed sheet of paper . however , during the emulsification phase of recycling , the paper is broken down into minute fiber filaments having irregularly shaped surfaces . each of these minute filaments has a substantial surface area . literally millions of fiber filaments are released from a relatively small piece of wax paper . consequently , a piece of waxed paper having a waxed surface of 100 square inches , for example , releases fiber filaments into the emulsified slurry that have a surface area that may be as much as 1 , 000 , 000 times the original 100 square inches , or 10 , 000 , 000 square inches . the wax from the surface of the waxed paper , is melted during the emulsification phase and forms a very thin micro - molecular film on the fiber filaments . in addition to the minute fiber filaments there are numerous microorganisms from the water and other ingredients of the recycling process . the microorganisms would in the usual paper making process cause decommission of the process ingredients . however , in the process of this invention these microorganisms becomes coated with a very thin layer of wax which prevents them from causing decommission of other ingredients found in the process . this hydrous cellular pulp is 95 % water , 4 . 67 % fiber and 0 . 32 % wax . the hydrous cellular pulp is then filtered through a 2 micrometer ( 0 . 000002 meters ) filter and the resulting filtrate is then used as the water base in products such as toothpaste , shampoo , soap , detergent , lotions and cream products . this filtrate is also used as an ingredient of a liquid preservative of this invention . the liquid preservative of this invention can be sprayed on sheets of newly produced wet lap pulp after it has been spread into sheets and or baled . this filtrate is 99 % water , 0 . 68 fiber and 0 . 32 % wax . the filtrate is free of microorganisms such as bacteria and fungi , possesses an unlimited shelf life , and may be produced either by recycling waste waxed paper , new waxed paper or by processing virgin vegetable constituents in the presence of wax during the emulsification phase of the defibering process . a protective barrier is also believed to form around the molecular structure of the water . the filtrate , which is 99 % water , and contains minute portions of fiber coated with a thin micro - molecular layer of wax derived from this process is non toxic and has an unlimited shelf life and thus can be utilized as the water base for products and provide the product with an unlimited shelf life . in accordance with this invention , an example of the starting waxed paper that can be used is the type used in bakeries and deli - contestants to wrap food products . waxed paper of this type is coated with a food grade paraffin wax , designated as a dry wax . waste waxed paper can be used in the preferred embodiment and is obtained directly from the paper producing facilities . for example , trimmings from a trimming machine or wax paper that did not meet required test standards may be used . such waxed paper is free of printing and thus is clean . the waxed paper is added to a pulper . a pulper is basically a vat for receiving a material that can be agitated by mechanical means and includes means to control the temperature . the process of pulping is essentially one of separating cells from intercellular material . it should be understood that any equipment such as a conventional high speed pulper may be used . the temperature of the wax - containing fiber slurry is raised to a temperature above the melting point of the wax and beating is continued until the wax and fiber are released into the aqueous solution . the resulting water - fiber slurry can then be subjected to a washing process to remove any impurities . newly manufactured wax paper does not need this washing process . the process of the present invention encompasses the use of 100 % waxed paper stock having a wax content of up to 30 % by weight . however , non - waxed waste paper , in modest proportions can be used without affecting the outcome . non waxed fiber products can be used as a starting product and a paraffin wax in the correct ratio to fiber added . the use of waxed paper as a starting point has the advantage that it contains the proper ratio of fiber to wax and it is available at economical rates . a water soluble non - ionic emulsifier is added to the pulper during the pulping phase of the paper making or recycling process . the water soluble non - ionic emulsifier being from the group consisting of : polyethylene glycol ethers of hydrophobic alcohols ; alkylphenoxy polyethoxyethanols ; fatty acid amides and mixtures thereof . the water soluble non - ionic emulsifier must also meet specific emulsion stability standards . the preferred water soluble non - ionic emulsifiers include : ethoxylated aliphatic alcohols wherein the alcohol is a hydrophobic secondary alcohol having from 11 to 15 carbon atoms and wherein the average molar ratio of ethylene oxide to hydrophobic alcohol is in a range of 5 : 1 to 15 : 1 ; ethoxylated alkyl phenols in which the ratio of moles of ethylene oxide per mole or ethylene oxide per mole of alkyl phenol is in the range of 7 - 8 inclusive ; ethoxylated alkyl phenols in which the alkyl substituent is linear ; and the fatty acid amide diethanol amine condensates derived from a member selected from the group consisting of myristic acid , lauric acid , palmitic acid , stearic acid and mixtures thereof . after the process for producing the hydrous cellulose pulp has been completed , it is filtered through a very fine filter , for example a 2 micrometer ( 0 . 000002 meters ) filter to remove the larger portions of hydrous cellulose pulp , leaving a filtrate that is free of microorganism and includes only minute fiber portions that are coated with a very thin layer of wax . although a 2 micrometer filter is used in the preferred embodiment it should be understood that a very fine filter is required but it need not be precisely 2 micrometers . the filtrate has a very low viscosity and can be readily sprayed through conventional nozzles . potassium sorbate , in powder form , is then mixed with the filtrate , at a ratio in the range of 0 . 1 %- 5 % by weight , and citric acid is added until the ph is 6 . 5 or below . the term ph indicates the hydrogen ion concentration of a solution , which is a measure of the solution &# 39 ; s acidity . the ph of pure water is 7 . 0 . if acid is added to pure water , an excess of h3o + ions is formed and the acid solution has a ph ranging from 6 for a weak acid to 1 for a strong acid . inversely , a basic solution has a low concentration of h 3 o + ions and an excess of oh - ions , and the ph ranges from 8 for a weak base to 14 for a strong base . thus , the resulting preservative is a weak acid . the mixture is blended to suspend the potassium sorbate evenly throughout the filtrate . the preservative is then sprayed on the layered or baled wet lap pulp . the wet lap pulp can then be stored and or shipped in , for example plastic bags , to processing facilities where it can undergo further processing . the wet lap pulp can be maintained in its moistened state and it will not decompose or decay . the preservative can be sprayed on the wet lap pulp and even though some preservative will escape into the atmosphere this does not pose a health hazard to the workers applying the spray or the area where the spraying is done . wax from the original waste waxed paper is present on minute portions of fiber that are dispersed in the preservative . the preservative coasts the fibers contained in the wet lap pulp and prevents the wet lap pulp from decaying . the food grade preservative potassium sorbate functions as a non - toxic ingredient that is carried by the slightly acid water base that alone has an unlimited shelf life . this unique combination of ingredients results in a preservative that can be easily sprayed on an organic product that is to be stored or preserved for use in the non - paper industry . although wax is present on the minute fibers filaments , in a very thin coating , this wax does not hinder the use of the wet lap pulp in any manner . while the invention has heretofore been described in detail with particular reference to specific products , it is to be understood that variation , modifications and the use of equivalents can be effected without departing from the scope of this invention . it is , therefore , intended that such changes and modifications be covered by the following claims .

a method for improving products such as toothpaste , shampoo , soap , detergent and lotions or creams and such improved products . the products are improved by adding a hydrous cellulose pulp that has an unlimited shelf life to the product . the hydrous cellulose pulp is resistant to decomposition and can be produced either by recycling waxed paper or through a process that begins with virgin vegetable constituents and wax . during the defibering process an emulsifier is added to the slurry and its temperature is elevated to 150 °- 190 ° fahrenheit .

the needle holder shown in fig1 and 2 contains a base body 2 , which for example may be formed of an appropriately soft , chemical inert material such as polyethylene . this base body has a flange 4 and serves as a closure in the end of preparation holder 6 which presents closure 10 which may be punctured by hollow needle 8 . the closure 10 may be formed in the usual manner out of rubber or rubber like material which is inert with respect to the preparation in preparation holder 6 . the hollow needle is sharpened in the customary manner on the end 12 adjacent closure 10 . if the syringe is an injection syringe or a syringe for the removal of body fluids the other end of the needle 14 is also sharpened in a known manner . the preparation holder 6 has a flange 16 and the two flanges 4 and 16 are connected with each other with the imposition of closure 10 with the help of a cuff 18 which may be formed out of metal and serves to securely couple the flanges together . in the base body 2 is located a central passage 20 which is provided with threads 22 . in the disclosed exemplary embodiment threads 22 extend from the lower end as shown in the figures to a position short of the upper end of the passage 20 as shown in the figures . the closure 10 can also only in passage 20 be provided , then can a separate seal between the base body 2 and the flange 16 be provided or these parts embodied in a piece as is appropriate in a syringe formed completely out of plastic . a hub part 24 has an outer thread 26 suitable for thread 22 and is by means of the threaded connection formed out of the threads 22 and 26 threaded in the base body 2 and is so moved to the work position shown in fig2 in which the end 12 of hollow needle 8 has punctured closure 10 of preparation holder 6 . in fig1 the hub body 24 is shown in a beginning twist position in which the end of the hollow needle 8 is spaced a distance from the closure 10 . the hub part 24 and the therein formed hub 11 are surrounded by a protective sleeve 28 which has an open end and a closed end and with its open end is unthreadable off the base body with the help of a second screw connection . in the embodiment shown it is assumed that the pitch of the threads of both screw connections 22 - 26 and 30 are similar . the direction of the threads of both screw connection is however opposite . between the hub part 24 and the protective sleeve 28 is an axial gear tooth system provided which a relative axial movement permits and which within its zone of contact produces a rotating drive connection between the protective sleeve and the hub part 24 . this axial zone corresponds at least to the region between the initial position of the hub part 24 shown in fig1 in the base body 2 and the work position shown in fig2 . the work position is characterized in that the needle has punctured the closure 10 whereby it is meaningless how far the needle enters the preparation holder . for a stronger seating of the needle can it advantageously be that the work position is defined through a mating . with the disclosed embodiment is the seating through a shoulder 34 on the hub body 24 effected which abuts with the under surface 36 of the base body 2 . it will be apparent by a comparison of fig1 and 2 that as a result of the opposite thread direction of screw connections 22 - 26 and 30 with the untwisting of protective sleeve 28 from the base body 2 , the fixed hub part 24 which is by the axial gear tooth system drivingly connected with the protective sleeve 28 is threaded into the working position . the required opposing dependency of the axial position of the hub 24 and the protective sleeve 28 with regard to the base body 2 must naturally be considered in the assembly . as may be seen from fig2 it is possible to so dimension the second screw connection that with the untwisting of the protective sleeve 28 , the connection steps out of engagement approximately with the attainment of the work position of the hub part 24 shown in fig2 . with the disclosed embodiment the second screw connection , what is more , so dimensioned that the screw connection with the untwisting of protective sleeve 28 arrives out of engagement just short of attainment of the working position of hub part 24 . it is thereby precluded that hub part 24 through seating 34 , 36 achieves the end position as a result of manufacturing errors or errors in the assembly of hub part 24 , so that hub part 24 thus cannot be further driven before protective sleeve 28 is entirely unthreaded from the base body 2 . it will be appreciated , on the other hand , that with the dislcosed embodiment , the axial gear tooth system is so dimensioned that the rotating driving connection between the protective sleeve and the hub part is at first lost after fully unthreading and a further axial parting movement of the protective sleeve . it is thus apparent that also after the loosening of the second connection 30 the hub part 24 is fully threaded in the work position shown in fig2 . in the use of the disclosed needle holder it is merely necessary to detach the protective sleeve 28 . the syringe is thus made ready since the needle 8 is already located in the correct working position . it will be appreciated that through the twisting of the hub part 24 with the base body 2 a stronger seating of the needle 8 is provided so that no additional outside help means is necessary and the entire arrangement is , without further , a workable single service syringe . for this purpose the protective sleeve 28 in known ways in the region of its free end 38 is smaller formed than the preparation holder 6 formed plunger and the preparation holder is provided in known ways ( not here disclosed ) with a plungerforming sliding plug in its other end . fig3 shows an embodiment in which a base body 302 is provided with a wide flange 305 . this flange affords the advantage that the free rim of the protective sleeve 328 mounts in the tight screwed position , not on the metal cuff 318 but instead on the surface of flange 304 which is better suited for the sealing purpose . in this way can one in the tightly twisted condition obtain a seal 340 between the protective sleeve 328 and the base body 302 . fig4 shows an embodiment in which the central passage 420 in the base body 402 narrows at the flange side end to a fitted seat for a corresponding tapered end piece 444 of the hub part 424 . in this way a better sealing and a stronger seating of the needle can be obtained . fig5 illustrates an embodiment by which the base body 502 is attachable on a preparation holder 506 . the contacting end of the preparation holder is closed in known ways with a closure 510 which is puncturable by the needle . the closure 510 is clamped between a flange 516 and a cuff 518 . the attached base body 502 has a clearance 546 which corresponds to the dimensions of the accommodating end of the preparation holder 506 in which elastic points 548 are provided and which by the insertion of the preparation holder in the base body 502 engage behind the flange 516 and cuff 518 . in the clearance 546 the base body seals with closing foil 550 puncturable by the needle ( not shown in fig5 ). with sterile storage of the needle holder such a seal is not ordinarily necessary . in general it will be appreciated to use the needle holder corresponding to the embodiment of fig1 and 2 for a stronger connection with the preparation holder . fig6 illustrates in schematic part representation an embodiment of a second threaded connection 630 which as a result of the elastic deformation of the protective sleeve 628 and the use of a saw tooth thread profile of the protective sleeve 628 is slipped on without rotation axial of the base body 602 . as a result of the saw tooth form of the thread profile an axial pulling off of protective sleeve 528 is not possible . also common , non saw tooth thread profiles can naturally be employed that the protective sleeve as a result of its elastic deformation allows axial pushing on whereby one has to employ , in each case , a correspondingly high axial force . in many cases therefore it will not be necessary to employ saw tooth thread profile ; that is to say it is not ordinarily expected that the user of the needle holder will attempt to pull the protective sleeve off instead of twisting it . with the embodiment shown in fig6 a good seal between the protective sleeve 628 and the base body is contemplated similar to the embodiment of fig3 . with the pushing on of the protective sleeve 628 without threading there is available only a proportionately small contact pressure and here a separate seal 640 is provided in the form of a soft plastic material ring . additionally the edge of the protective sleeve can taper or be provided with a circular rib about the inside of a proportionately large axial clearance a good seal to form . fig7 illustrates an embodiment in which an elastically flexible friction coupling is provided between the hub part 724 and the protective sleeve 728 in an axial direction . there exists in the disclosed embodiment a ring 752 of elastic flexible material mounted in a groove 754 of the hub part 724 and which has a light interference so that the ring is tightly seated in the protective sleeve 728 . this friction coupling keeps the needle holder under axial bias on the base body with the initial assembly of the needle holder when the hub part 724 is inserted in the protective sleeve and the protective sleeve is threaded on the base body ( not disclosed in fig7 ). this insures that with the later resulting unthreading of the protective sleeve the first screw connection immediately makes engagement between the hub part and the base body and thereby provides that the hub part is screwed in the work position . it is appreciated that the friction coupling may be otherwise formed as , in particular , out of many rings . fig8 illustrates a embodiment in which the lower end of the needle is not sharpened but is provided with a stub terminating projection 856 of the hub part 824 . this embodiment is suitable for vials , for example eyedrop vials . in the embodiment shown in fig8 an indication 858 is provided in the protective sleeve which points out to the user that he should loosen the protective sleeve by means of a rotating movement . other embodiments of the invention are possible without departing from its scope .

a needle holder includes a base body which receives the puncturable closure of a medical preparation holder . a hub part , containing the needle , is mounted in the base body through a first threaded connection for movement to a work position in which the needle punctures the closure . a protective sleeve for the needle is mounted on the base body through a second threaded connection , oppositely threaded with respect to the first connection . the sleeve and the hub part are coupled by an axial gear tooth arrangement which permits axial movement of the hub part upon rotation of the protective sleeve on the base body . the base body may exhibit a variety of forms , the second threaded connection may include a saw tooth profile which permits the protective sleeve to be slid on a base body without rotation , and a friction coupling may be provided between the hub part and the protective sleeve .

referring to fig1 there is shown a combine indicated generally by the numeral 10 in a side elevational view with the critical portion of the instant invention illustrated partially in phantom lines and partially in solid lines with the masking portion of the side section of the combine 10 broken away . the concave clearance control mechanism and indicator is shown generally by the numeral 11 . as can be seen , the combine 10 has a mobile frame mounted to a pair of primary driving wheels 12 and a pair of smaller steerable wheels 13 in the rear . it is powered by an engine 15 which is usually diesel fuel consuming . the engine is mounted to the upper portion of the combine 10 in a suitable fashion and , by means of drive belts or sprocket chains , is drivably connected to the operational components of the combine . the combine 10 generally has a header 16 and an infeed housing 18 mounted at its front , as seen in fig1 . the combine 10 has a main frame or housing indicated generally by the numeral 19 that internally supports threshing and separating means ( not shown ), as well as the operator &# 39 ; s cab 20 and the grain tank 21 . the operator &# 39 ; s cab 20 extends forwardly over the front of the main frame 19 and is atop the infeed housing 18 . the cab 20 has a ladder ( not shown ) that provides access for the operator to the cab and extends outwardly and downwardly therefrom . housings 22 and 24 enclose the engine and the discharge beater and discharge grate assembly ( the latter two not being shown ), respectively . also best seen in fig1 the grain tank 21 has a pivotal unloading auger tube 25 within which is contained a rotatable auger ( not shown ). tube 25 is suitably joined to the grain tank 21 and serves to unload grain to a receiving vehicle . the grain is transferred from threshing and separating means via cleaning means to the grain tank 21 during the harvesting operation . the structure thus far has been described generally since it is old and well known in the art . the structure and interrelationships between the various operating components of the combine are described in greater detail in u . s . pat . no . 3 , 626 , 472 issued dec . 7 , 1971 , and u . s . pat . no . 3 , 742 , 686 issued july 3 , 1973 , both to rowland - hill , hereinafter specifically incorporated by reference in their entirety insofar as they are consistent with the instant disclosure . the threshing and separating means or rotor are surrounded on at least their bottom portions by concaves . the concaves are adjustably suspended by mechanisms making it possible to maintain the concaves in a selected relationship with respect to the rotors . this adjusting mechanism is generally a supporting frame in the shape of an h and is described in greater detail in u . s . pat . no . 3 , 949 , 761 to mortier et al , issued apr . 13 , 1976 , hereinafter specifically incorporated by reference in its entirety , insofar as it is consistent with this disclosure . the supporting sub - frame assembly will not be discussed in any greater detail , relying upon the description provided in this aforementioned patent . the cab 20 is shown further in fig2 and 7 . an operator &# 39 ; s seat 25 is positioned rearwardly of a steering wheel and steering column 26 and control pedals 28 . a concave control mechanism , indicated generally by the numeral 29 , and a concave position indicator , indicated generally by the numeral 30 , are found within the cab 20 . the concave control mechanism 29 consists of a ratchet handle 31 connected to a rotatable connecting link 32 , best seen in fig2 . the connecting link 32 is rod - shaped and on the end opposing the ratchet handle 31 is threaded to form an acme screw 34 . the connecting link 32 is anchored at a thrust point 33 by passing through bracket 36 , which is anchored appropriately to the floor 38 of the cab 20 . the floor 38 is supported by cab beam 39 which is braced to the main frame 19 by bracing member 40 . link 32 is rotatable through bracket 36 , but is retained longitudinally in place by welded ring 41 and circular plate 42 , best seen in fig2 and 5 . plate 42 is retained by a pin 43 appropriately placed through link 32 . threaded portion 34 of link 32 passes through a threaded hole in bar 44 , best seen in fig2 and 5 . the extreme limit of movement of link 32 through bar 44 is established by stop nuts 45 . bar 44 , which essentially serves as a nut to the threaded portion of acme screw 34 of link 32 , pivots in its two mounting arms 46 , best seen in fig3 . as the ratchet handle 31 is rotated , the threaded portion of the acme screw end 34 screws through the threaded hole in bar 44 . this causes the bar 44 to move in an arc which requires that the thrust point bracket 36 allow for some vertical movement . this is accomplished through the use of an open slot 48 cut in the center of bracket 36 , best seen in fig3 . mounting arms 46 are fastened to sleeve 51 . collar 50 is mounted about sleeve 51 , which in turn fits over shaft 52 . this arrangement permits the sleeve 51 , inside collar 50 , to rotate with the mounting arms 46 and bar 44 . sleeve 51 , collar 50 and arms 46 are mounted about shaft 52 . collar 50 is rigidly fastened to thrust point bracket 36 by arms 49 . bracket 55 is fastened by a weldment 54 to shaft 52 and is mounted thereabout , as seen in fig3 . bracket 55 is appropriately fastened to adjustment link 56 . link 56 , shown in fig2 , 5 and 7 , connects to the concave supporting sub - assembly . interiorly of bracket 55 is another collar 58 which fastens about shaft 52 and is best seen in fig3 . a similar collar 59 is fastened about the opposing end of shaft 52 . bracing members 60 and 61 are fixedly fastened to cab beams 39 and collars 58 and 59 on opposing ends of shaft 52 to rigidly mount shaft 52 for rotational movement . sleeve 51 is fastened for rotational movement with shaft 52 by a pair of shear plates 62 and 64 , best seen in fig3 . shear plate 62 is appropriately fastened to sleeve 51 , such as by welding . similarly , shear plate 64 is appropriately fastened to shaft 52 . shear plates 62 and 64 are connected by shear bolt 65 , best seen in fig3 and 6 . shear bolt 65 has a retaining nut 66 and a pair of bushings 68 and 69 which insert within appropriate sized apertures within each plate . this arrangement permits the rotative motion initially transmitted by the turning of the ratchet handle 31 to be transferred through sleeve 51 , shear plate 62 and shear bolt 65 to shear plate 64 and the shaft 52 to which it is anchored . should the pressure upon the concaves be sufficient to exceed the predetermined strength level of the shear bolt 65 , the bolt will fail . the failure of bolt 65 thus stops the transfer of rotative motion between shaft 52 and the sleeve 51 , allowing the concaves to drop to a fully down position . the concave position indicator 30 comprises a connecting link 70 with 90 degree bends on each end . on its lower end , link 70 is suitably joined to a mounting bracket 71 , which is in turn fixedly fastened , such as by welding , to shaft 52 . on its opposing end link 70 projects through a 90 degree bend into a slot 72 that is within console 74 within the cab 20 . an appropriately sized ring 75 with a cotter pin retains the elbow portion 76 of connecting link 70 outside the console 74 , fig4 preventing the elbow portion from receding within the console . a shelf 78 is mounted beneath slot 72 and has a series of calibrations 79 marked thereon to indicate the relative positions of the concaves with respect to the rotors . in operation the combine 10 is driven across a field of crop material to be harvested . the header 16 cuts and gathers the crop material , from which it is fed into the infeed housing 18 . the infeed housing 18 directs the crop material into the rotors where the crop material is threshed and separated . the concaves underlie the rotors and are adjusted by means of the adjusting mechanism and the h - shaped supporting frame . the operator can adjust the clearance by means of turning the ratchet handle 31 , which in turn rotates the connecting link 32 . link 32 then is screwed at its threaded end portion 34 through bar 44 . rotational movement of the threaded portion 34 causes the mounting arms 46 to rotate . this rotation in turn causes sleeve 51 to rotate in a desired direction . this rotational movement is transferred via shear plate 62 , shear bolt 65 and shear plate 64 to shaft 52 . shaft 52 transfers the rotational movement via brackets 55 and adjustment link 56 to the concave supporting frame assembly . the relative position of the concaves with respect to the rotors are indicated by the concave position indicator 30 . the rotation of the shaft 52 causes the connecting link 70 , via mounting bracket 71 , to move within the slot 72 in the console 74 . the operator is thus able to gauge the clearance between the concaves and the rotors by looking at the calibrations 79 on shelf 78 . should a foreign object , such as a rock or a piece of metal , be fed into the threshing and separating rotors and be forced against the concaves with sufficient force to cause the shear bolt 65 to fail , shaft 52 will be disconnected from sleeve 51 and the connecting link 32 , thereby permitting the concaves to fall to the fully down position . in falling to this fully down position the shaft 52 of necessity must rotate , which in turn causes the connecting link 70 with its elbow portion 76 to move in the appropriate direction within the slot 72 . this movement can easily be detected by the operator by looking at the calibrations 79 to determine whether the concaves are set at the proper position for the particular crop material and conditions . in this manner , the operator can know almost immediately whether a foreign object has caused the shear bolt to fail and determine whether or not the concaves are properly set . while the preferred structure in which the principles of the present invention have been incorporated is shown and described above , it is to be understood that the invention is not to be limited to the particular details thus presented , but , in fact , widely different means may be employed in the practice of the broader aspects of this invention . the scope of the appended claims is intended to encompass all obvious changes in the details , materials and arrangements of parts which will occur to one of ordinary skill in the art upon a reading of this disclosure .

in a harvesting and threshing machine having concaves cooperative with rotatable threshing and separating apparatus there is provided a shearbolt safety mechanism coupled to a concave clearance indicator so that when a foreign object enters the threshing and separating apparatus and exerts a force above a predetermined level between the concaves and the threshing and separating apparatus , the shearbolt safety mechanism is effective to cause the concaves to drop to a fully lowered position and the concave clearance indicator to indicate the positioning of the concaves to the operator .

a first embodiment of the invention is a compound represented by formulae i - iv as described above , or a pharmaceutically acceptable salts , esters or prodrugs thereof , alone or in combination with a pharmaceutically acceptable carrier or excipient . another embodiment of the invention is a compound represented by formula v : or a pharmaceutically acceptable salt , ester or prodrug thereof , alone or in combination with a pharmaceutically acceptable carrier or excipient , where a , x and g are as defined in the previous embodiment . in one example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , and substituted — c 3 - c 12 cycloalkenyl , wherein each — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , and substituted — c 2 - c 8 alkynyl independently contains 0 , 1 , 2 , or 3 heteroatoms selected from o , s or n . a is selected from the group consisting of — c ( o )— r 1 , — c ( o )— o — r 1 and — c ( o )— nh — r 1 , where r 1 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g can be — nh — so 2 — nr 4 r 5 or — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl , and r 4 and r 5 are each independently selected from hydrogen , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still another example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 or — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g is — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still yet another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 , where r 1 is — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl or substituted — c 1 - c 8 alkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in still another example , a is —( c ═ o )— r 2 , wherein r 2 is — c 1 - c 8 alkyl substituted with ( 1 ) aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic or substituted heterocyclic and ( 2 ) — nhc ( o )— c 1 - c 12 - alkyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 3 - c 12 - cycloalkyl , — nhc ( o )- aryl , — nhc ( o )- heteroaryl , — nhc ( o )- heterocycloalkyl , — nhco 2 — c 1 - c 12 - alkyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 3 - c 12 - cycloalkyl , — nhco 2 - aryl , — nhco 2 - heteroaryl or — nhco 2 - heterocycloalkyl . in another example , x is aryl , heteroaryl , heterocyclic , — c 3 - c 12 cycloalkyl or — c 3 - c 12 cycloalkenyl and is substituted with - l ′- r ′, where l ′ is c 1 - c 6 alkylene , c 2 - c 6 alkenylene or c 2 - c 6 alkynylene , and r ′ is aryl , heteroaryl , heterocyclic , c 3 - c 12 cycloalkyl or c 3 - c 12 cycloalkenyl . a is — c ( o )— o — r 1 , where r 1 is aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl ; and g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl ( e . g ., cyclopropyl ) or substituted — c 3 - c 12 cycloalkyl . in another embodiment of the invention is a compound represented by formula vi or a pharmaceutically acceptable salt , ester or prodrug thereof , alone or in combination with a pharmaceutically acceptable carrier or excipient ; where a , g and x are as previously defined in the first embodiment . in one example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , and substituted — c 3 - c 12 cycloalkenyl , wherein each — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , and substituted — c 2 - c 8 alkynyl independently contains 0 , 1 , 2 , or 3 heteroatoms selected from o , s or n . a is selected from the group consisting of — c ( o )— r 1 , — c ( o )— o — r 1 and — c ( o )— nh — r 1 , where r 1 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g can be — nh — so 2 — nr 4 r 5 or — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl , and r 4 and r 5 are each independently selected from hydrogen , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still another example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 or — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g is — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still yet another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 , where r 1 is — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl or substituted — c 1 - c 8 alkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in still another example , a is —( c ═ o )— r 2 , wherein r 2 is — c 1 - c 8 alkyl substituted with ( 1 ) aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic or substituted heterocyclic and ( 2 ) — nhc ( o )— c 1 - c 12 - alkyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 3 - c 12 - cycloalkyl , — nhc ( o )- aryl , — nhc ( o )- heteroaryl , — nhc ( o )- heterocycloalkyl , — nhco 2 — c 1 - c 12 - alkyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 3 - c 12 - cycloalkyl , — nhco 2 - aryl , — nhco 2 - heteroaryl or — nhco 2 - heterocycloalkyl . in another example , x is aryl , heteroaryl , heterocyclic , — c 3 - c 12 cycloalkyl or — c 3 - c 12 cycloalkenyl and is substituted with - l ′- r ′, where l ′ is c 1 - c 6 alkylene , c 2 - c 6 alkenylene or c 2 - c 6 alkynylene , and r ′ is aryl , heteroaryl , heterocyclic , c 3 - c 12 cycloalkyl or c 3 - c 12 cycloalkenyl . a is — c ( o )— o — r 1 , where r 1 is aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl ; and g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl ( e . g ., cyclopropyl ) or substituted — c 3 - c 12 cycloalkyl . in another embodiment of the invention is a compound represented by formula vii or a pharmaceutically acceptable salt , ester or prodrug thereof , alone or in combination with a pharmaceutically acceptable carrier or excipient ; where a , g and x are as previously defined in the first embodiment . in one example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , and substituted — c 3 - c 12 cycloalkenyl , wherein each — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , and substituted — c 2 - c 8 alkynyl independently contains 0 , 1 , 2 , or 3 heteroatoms selected from o , s or n . a is selected from the group consisting of — c ( o )— r 1 , — c ( o )— o — r 1 and — c ( o )— nh — r 1 , where r 1 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g can be — nh — so 2 — nr 4 r 5 or — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl , and r 4 and r 5 are each independently selected from hydrogen , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still another example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 or — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g is — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still yet another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 , where r 1 is — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl or substituted — c 1 - c 8 alkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in still another example , a is —( c ═ o )— r 2 , wherein r 2 is — c 1 - c 8 alkyl substituted with ( 1 ) aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic or substituted heterocyclic and ( 2 ) — nhc ( o )— c 1 - c 12 - alkyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 3 - c 12 - cycloalkyl , — nhc ( o )- aryl , — nhc ( o )- heteroaryl , — nhc ( o )- heterocycloalkyl , — nhco 2 — c 1 - c 12 - alkyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 3 - c 12 - cycloalkyl , — nhco 2 - aryl , — nhco 2 - heteroaryl or — nhco 2 - heterocycloalkyl . in another example , x is aryl , heteroaryl , heterocyclic , — c 3 - c 12 cycloalkyl or — c 3 - c 12 cycloalkenyl and is substituted with - l ′- r ′, where l ′ is c 1 - c 6 alkylene , c 2 - c 6 alkenylene or c 2 - c 6 alkynylene , and r ′ is aryl , heteroaryl , heterocyclic , c 3 - c 12 cycloalkyl or c 3 - c 12 cycloalkenyl . a is — c ( o )— o — r 1 , where r 1 is aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl ; and g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl ( e . g ., cyclopropyl ) or substituted — c 3 - c 12 cycloalkyl . yet , in another embodiment of the invention is a compound represented by formula viii or a pharmaceutically acceptable salt , ester or prodrug thereof , alone or in combination with a pharmaceutically acceptable carrier or excipient ; where a , g and x are as previously defined in the first embodiment . in one example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , and substituted — c 3 - c 12 cycloalkenyl , wherein each — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , and substituted — c 2 - c 8 alkynyl independently contains 0 , 1 , 2 , or 3 heteroatoms selected from o , s or n . a is selected from the group consisting of — c ( o )— r 1 , — c ( o )— o — r 1 and — c ( o )— nh — r 1 , where r 1 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g can be — nh — so 2 — nr 4 r 5 or — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl , and r 4 and r 5 are each independently selected from hydrogen , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still another example , x is independently selected from the group consisting of hydrogen , aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 or — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . g is — nhso 2 — r 3 , where r 3 is selected from aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl . in still yet another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— o — r 1 , where r 1 is — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in another example , x is independently selected from the group consisting of aryl , substituted aryl , heteroaryl , and substituted heteroaryl . a is — c ( o )— nh — r 1 , where r 1 is — c 1 - c 8 alkyl or substituted — c 1 - c 8 alkyl . g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl or substituted — c 3 - c 12 cycloalkyl . in still another example , a is —( c ═ o )— r 2 , wherein r 2 is — c 1 - c 8 alkyl substituted with ( 1 ) aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic or substituted heterocyclic and ( 2 ) — nhc ( o )— c 1 - c 12 - alkyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 3 - c 12 - cycloalkyl , — nhc ( o )- aryl , — nhc ( o )- heteroaryl , — nhc ( o )- heterocycloalkyl , — nhco 2 — c 1 - c 12 - alkyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 3 - c 12 - cycloalkyl , — nhco 2 - aryl , — nhco 2 - heteroaryl or — nhco 2 - heterocycloalkyl . in another example , x is aryl , heteroaryl , heterocyclic , — c 3 - c 12 cycloalkyl or — c 3 - c 12 cycloalkenyl and is substituted with - l ′- r ′, where l ′ is c 1 - c 6 alkylene , c 2 - c 6 alkenylene or c 2 - c 6 alkynylene , and r ′ is aryl , heteroaryl , heterocyclic , c 3 - c 12 cycloalkyl or c 3 - c 12 cycloalkenyl . a is — c ( o )— o — r 1 , where r 1 is aryl , substituted aryl , heteroaryl , substituted heteroaryl , heterocyclic , substituted heterocyclic , — c 1 - c 8 alkyl , — c 2 - c 8 alkenyl , — c 2 - c 8 alkynyl , substituted — c 1 - c 8 alkyl , substituted — c 2 - c 8 alkenyl , substituted — c 2 - c 8 alkynyl , — c 3 - c 12 cycloalkyl , — c 3 - c 12 cycloalkenyl , substituted — c 3 - c 12 cycloalkyl , or substituted — c 3 - c 12 cycloalkenyl ; and g is — nhso 2 — r 3 , where r 3 is selected from — c 3 - c 12 cycloalkyl ( e . g ., cyclopropyl ) or substituted — c 3 - c 12 cycloalkyl . representative compounds of the invention include , but are not limited to , the following compounds ( table 1 ) according to formula ix : according to an alternate embodiment , the pharmaceutical compositions of the present invention may further contain other anti - hcv agents . examples of anti - hcv agents include , but are not limited to , interferon ( e . g ., alpha - interferon , beta - interferon , consensus interferon , pegylated interferon , or albumin or other conjugated interferon ), ribavirin , and amantadine . for further details see s . tan , a . pause , y . shi , n . sonenberg , hepatitis c therapeutics : current status and emerging strategies , nature rev . drug discov ., 1 , 867 - 881 ( 2002 ); wo 00 / 59929 ( 2000 ); wo 99 / 07733 ( 1999 ); wo 00 / 09543 ( 2000 ); wo 99 / 50230 ( 1999 ); u . s . pat . no . 5 , 861 , 297 ( 1999 ); and us2002 / 0037998 ( 2002 ) which are herein incorporated by reference in their entirety . according to an additional embodiment , the pharmaceutical compositions of the present invention may further contain other hcv protease inhibitors . according to yet another embodiment , the pharmaceutical compositions of the present invention may further comprise inhibitor ( s ) of other targets in the hcv life cycle , including , but not limited to , helicase , polymerase , metalloprotease , and internal ribosome entry site ( ires ). according to another embodiment , the pharmaceutical compositions of the present invention may further comprise another anti - viral , anti - bacterial , anti - fungal or anti - cancer agent , or an immune modulator , or another thearapeutic agent . according to still another embodiment , the present invention includes methods of treating hepatitis c infections in a subject in need of such treatment by administering to said subject an anti - hcv virally effective amount of a compound of the present invention or a pharmaceutically acceptable salt , ester , or prodrug thereof . according to a further embodiment , the present invention includes methods of treating hepatitis c infections in a subject in need of such treatment by administering to said subject an anti - hcv virally effective amount or an inhibitory amount of a pharmaceutical composition of the present invention . an additional embodiment of the present invention includes methods of treating biological samples by contacting the biological samples with the compounds of the present invention . yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein . listed below are definitions of various terms used to describe this invention . these definitions apply to the terms as they are used throughout this specification and claims , unless otherwise limited in specific instances , either individually or as part of a larger group . the term “ c 1 - c 6 alkyl ,” or “ c 1 - c 8 alkyl ,” as used herein , refer to saturated , straight - or branched - chain hydrocarbon radicals containing between one and six , or one and eight carbon atoms , respectively . examples of c 1 - c 6 alkyl radicals include , but are not limited to , methyl , ethyl , propyl , isopropyl , n - butyl , tert - butyl , neopentyl , n - hexyl radicals ; and examples of c 1 - c 8 alkyl radicals include , but are not limited to , methyl , ethyl , propyl , isopropyl , n - butyl , tert - butyl , neopentyl , n - hexyl , heptyl , octyl radicals . the term “ c 2 - c 6 alkenyl ,” or “ c 2 - c 8 alkenyl ,” as used herein , denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon - carbon double bond and contains from two to six , or two to eight carbon atoms , respectively . alkenyl groups include , but are not limited to , for example , ethenyl , propenyl , butenyl , 1 - methyl - 2 - buten - 1 - yl , heptenyl , octenyl and the like . the term “ c 2 - c 6 alkynyl ,” or “ c 2 - c 8 alkynyl ,” as used herein , denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon - carbon triple bond and contains from two to six , or two to eight carbon atoms , respectively . representative alkynyl groups include , but are not limited to , for example , ethynyl , 1 - propynyl , 1 - butynyl , heptynyl , octynyl and the like . the term “ c 3 - c 8 - cycloalkyl ”, or “ c 3 - c 12 - cycloalkyl ,” as used herein , denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom where the saturated carbocyclic ring compound has from 3 ot 8 , or from 3 to 12 , ring atoms , respectively . examples of c 3 - c 8 - cycloalkyl include , but not limited to , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cyclopentyl and cyclooctyl ; and examples of c 3 - c 12 - cycloalkyl include , but not limited to , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , bicyclo [ 2 . 2 . 1 ] heptyl , and bicyclo [ 2 . 2 . 2 ] octyl . the term “ c 3 - c 8 - cycloalkenyl ”, or “ c 3 - c 12 - cycloalkenyl ” as used herein , denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon - carbon double bond by the removal of a single hydrogen atom where the carbocyclic ring compound has from 3 ot 8 , or from 3 to 12 , ring atoms , respectively . examples of c 3 - c 8 - cycloalkenyl include , but not limited to , cyclopropenyl , cyclobutenyl , cyclopentenyl , cyclohexenyl , cycloheptenyl , cyclooctenyl , and the like ; and examples of c 3 - c 12 - cycloalkenyl include , but not limited to , cyclopropenyl , cyclobutenyl , cyclopentenyl , cyclohexenyl , cycloheptenyl , cyclooctenyl , and the like . the term “ aryl ,” as used herein , refers to a mono - or bicyclic carbocyclic ring system having one or two aromatic rings including , but not limited to , phenyl , naphthyl , tetrahydronaphthyl , indanyl , idenyl and the like . the term “ arylalkyl ,” as used herein , refers to a c 1 - c 3 alkyl or c 1 - c 6 alkyl residue attached to an aryl ring . examples include , but are not limited to , benzyl , phenethyl and the like . the term “ heteroaryl ,” as used herein , refers to a mono -, bi -, or tri - cyclic aromatic radical or ring having from five to ten ring atoms of which at least one ring atom is selected from s , o and n ; wherein any n or s contained within the ring may be optionally oxidized . heteroaryl includes , but is not limited to , pyridinyl , pyrazinyl , pyrimidinyl , pyrrolyl , pyrazolyl , imidazolyl , thiazolyl , oxazolyl , isooxazolyl , thiadiazolyl , oxadiazolyl , thiophenyl , furanyl , quinolinyl , isoquinolinyl , benzimidazolyl , benzooxazolyl , quinoxalinyl , and the like . the term “ heteroarylalkyl ,” as used herein , refers to a c 1 - c 3 alkyl or c 1 - c 6 alkyl residue residue attached to a heteroaryl ring . examples include , but are not limited to , pyridinylmethyl , pyrimidinylethyl and the like . the terms “ heterocyclic ” and “ heterocycloalkyl ,” can be used interchangeably and referred to a non - aromatic 3 -, 4 -, 5 -, 6 - or 7 - membered ring or a bi - or tri - cyclic group fused system , where ( i ) each ring contains between one and three heteroatoms independently selected from oxygen , sulfur and nitrogen , ( ii ) each 5 - membered ring has 0 to 1 double bonds and each 6 - membered ring has 0 to 2 double bonds , ( iii ) the nitrogen and sulfur heteroatoms may optionally be oxidized , ( iv ) the nitrogen heteroatom may optionally be quaternized , and ( iv ) any of the above rings may be fused to a benzene ring . representative heterocycloalkyl groups include , but are not limited to , [ 1 , 3 ] dioxolane , pyrrolidinyl , pyrazolinyl , pyrazolidinyl , imidazolinyl , imidazolidinyl , piperidinyl , piperazinyl , oxazolidinyl , isoxazolidinyl , morpholinyl , thiazolidinyl , isothiazolidinyl , and tetrahydrofuryl . the term “ substituted ” as used herein , refers to independent replacement of one , two , or three or more of the hydrogen atoms thereon with substituents including , but not limited to , — f , — cl , — br , — i , — oh , protected hydroxy , — no 2 , — cn , — nh 2 , protected amino , — nh — c 1 - c 12 - alkyl , — nh — c 2 - c 12 - alkenyl , — nh — c 2 - c 12 - alkenyl , — nh — c 3 - c 12 - cycloalkyl , — nh - aryl , — nh - heteroaryl , — nh - heterocycloalkyl , - dialkylamino , - diarylamino , - diheteroarylamino , — o — c 1 - c 12 - alkyl , — o — c 2 - c 12 - alkenyl , — o — c 2 - c 12 - alkenyl , — o — c 3 - c 12 - cycloalkyl , — o - aryl , — o - heteroaryl , — o - heterocycloalkyl , — c ( o )— c 1 - c 12 - alkyl , — c ( o )— c 2 - c 12 - alkenyl , — c ( o )— c 2 - c 12 - alkenyl , — c ( o )— c 3 - c 12 - cycloalkyl , — c ( o )- aryl , — c ( o )- heteroaryl , — c ( o )- heterocycloalkyl , — conh 2 , — conh — c 1 - c 12 - alkyl , — conh — c 2 - c 12 - alkenyl , — conh — c 2 - c 12 - alkenyl , — conh — c 3 - c 12 - cycloalkyl , — conh - aryl , — conh - heteroaryl , — conh - heterocycloalkyl , — oco 2 — c 1 - c 12 - alkyl , — oco 2 — c 2 - c 12 - alkenyl , — oco 2 — c 2 - c 12 - alkenyl , — oco 2 — c 3 - c 12 - cycloalkyl , — oco 2 - aryl , — oco 2 - heteroaryl , — oco 2 - heterocycloalkyl , — oconh 2 , — oconh — c 1 - c 12 - alkyl , — oconh — c 2 - c 12 - alkenyl , — oconh — c 2 - c 12 - alkenyl , — oconh — c 3 - c 12 - cycloalkyl , — oconh - aryl , — oconh - heteroaryl , — oconh - heterocycloalkyl , — nhc ( o )— c 1 - c 12 - alkyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 2 - c 12 - alkenyl , — nhc ( o )— c 3 - c 12 - cycloalkyl , — nhc ( o )- aryl , — nhc ( o )- heteroaryl , — nhc ( o )- heterocycloalkyl , — nhco 2 — c 1 - c 12 - alkyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 2 - c 12 - alkenyl , — nhco 2 — c 3 - c 12 - cycloalkyl , — nhco 2 - aryl , — nhco 2 - heteroaryl , — nhco 2 - heterocycloalkyl , — nhc ( o ) nh 2 , — nhc ( o ) nh — c 1 - c 12 - alkyl , — nhc ( o ) nh — c 2 - c 12 - alkenyl , — nhc ( o ) nh — c 2 - c 12 - alkenyl , — nhc ( o ) nh - c 3 - c 12 - cycloalkyl , — nhc ( o ) nh - aryl , — nhc ( o ) nh - heteroaryl , — nhc ( o ) nh - heterocycloalkyl , nhc ( s ) nh 2 , — nhc ( s ) nh — c 1 - c 12 - alkyl , — nhc ( s ) nh — c 2 - c 12 - alkenyl , — nhc ( s ) nh — c 2 - c 12 - alkenyl , — nhc ( s ) nh — c 3 - c 12 - cycloalkyl , — nhc ( s ) nh - aryl , — nhc ( s ) nh - heteroaryl , — nhc ( s ) nh - heterocycloalkyl , — nhc ( nh ) nh 2 , — nhc ( nh ) nh — c 1 - c 12 - alkyl , — nhc ( nh ) nh — c 2 - c 12 - alkenyl , — nhc ( nh ) nh — c 2 - c 12 - alkenyl , — nhc ( nh ) nh — c 3 - c 12 - cycloalkyl , — nhc ( nh ) nh - aryl , — nhc ( nh ) nh - heteroaryl , — nhc ( nh ) nh - heterocycloalkyl , — nhc ( nh )— c 1 - c 12 - alkyl , — nhc ( nh )— c 2 - c 12 - alkenyl , — nhc ( nh )— c 2 - c 12 - alkenyl , — nhc ( nh )— c 3 - c 12 - cycloalkyl , — nhc ( nh )- aryl , — nhc ( nh )- heteroaryl , — nhc ( nh )- heterocycloalkyl , — c ( nh ) nh — c 1 - c 12 - alkyl , — c ( nh ) nh — c 2 - c 12 - alkenyl , — c ( nh ) nh — c 2 - c 12 - alkenyl , — c ( nh ) nh — c 3 - c 12 - cycloalkyl , — c ( nh ) nh - aryl , — c ( nh ) nh - heteroaryl , — c ( nh ) nh - heterocycloalkyl , — s ( o )— c 1 - c 12 - alkyl , — s ( o )— c 2 - c 12 - alkenyl , — s ( o )— c 2 - c 12 - alkenyl , — s ( o )— c 3 - c 12 - cycloalkyl , — s ( o )- aryl , — s ( o )- heteroaryl , — s ( o )- heterocycloalkyl — so 2 nh 2 , — so 2 nh — c 1 - c 12 - alkyl , — so 2 nh — c 2 - c 12 - alkenyl , — so 2 nh — c 2 - c 12 - alkenyl , — so 2 nh — c 3 - c 12 - cycloalkyl , — so 2 nh - aryl , — so 2 nh - heteroaryl , — so 2 nh - heterocycloalkyl , — nhso 2 — c 1 - c 12 - alkyl , — nhso 2 — c 2 - c 12 - alkenyl , — nhso 2 — c 2 - c 12 - alkenyl , — nhso 2 — c 3 - c 12 - cycloalkyl , — nhso 2 - aryl , — nhso 2 - heteroaryl , — nhso 2 - heterocycloalkyl , — ch 2 nh 2 , — ch 2 so 2 ch 3 , - aryl , - arylalkyl , - heteroaryl , - heteroarylalkyl , - heterocycloalkyl , — c 3 - c 12 - cycloalkyl , polyalkoxyalkyl , polyalkoxy , - methoxymethoxy , - methoxyethoxy , — sh , — s — c 1 - c 12 - alkyl , — s — c 2 - c 12 - alkenyl , — s — c 2 - c 12 - alkenyl , — s — c 3 - c 12 - cycloalkyl , — s - aryl , — s - heteroaryl , — s - heterocycloalkyl , methylthiomethyl , or - l ′- r ′, wherein l ′ is c 1 - c 6 alkylene , c 2 - c 6 alkenylene or c 2 - c 6 alkynylene , and r ′ is aryl , heteroaryl , heterocyclic , c 3 - c 12 cycloalkyl or c 3 - c 12 cycloalkenyl . it is understood that the aryls , heteroaryls , alkyls , and the like can be further substituted . in some cases , each substituent in a substituted moiety is additionally optionally substituted with one or more groups , each group being independently selected from — f , — cl , — br , — i , — oh , — no 2 , — cn , or — nh 2 . in accordance with the invention , any of the aryls , substituted aryls , heteroaryls and substituted heteroaryls described herein , can be any aromatic group . aromatic groups can be substituted or unsubstituted . it is understood that any alkyl , alkenyl , alkynyl , cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group , an alicyclic group or a heterocyclic group . an “ aliphatic group ” is non - aromatic moiety that may contain any combination of carbon atoms , hydrogen atoms , halogen atoms , oxygen , nitrogen or other atoms , and optionally contain one or more units of unsaturation , e . g ., double and / or triple bonds . an aliphatic group may be straight chained , branched or cyclic and preferably contains between about 1 and about 24 carbon atoms , more typically between about 1 and about 12 carbon atoms . in addition to aliphatic hydrocarbon groups , aliphatic groups include , for example , polyalkoxyalkyls , such as polyalkylene glycols , polyamines , and polyimines , for example . such aliphatic groups may be further substituted . it is understood that aliphatic groups may be used in place of the alkyl , alkenyl , alkynyl , alkylene , alkenylene , and alkynylene groups described herein . the term “ alicyclic ,” as used herein , denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom . examples include , but not limited to , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , bicyclo [ 2 . 2 . 1 ] heptyl , and bicyclo [ 2 . 2 . 2 ] octyl . such alicyclic groups may be further substituted . it will be apparent that in various embodiments of the invention , the substituted or unsubstituted alkyl , alkenyl , alkynyl , cycloalkyl , cycloalkenyl , cycloalkynyl , arylalkyl , heteroarylalkyl , and heterocycloalkyl are intended to be monovalent or divalent . thus , alkylene , alkenylene , and alkynylene , cycloaklylene , cycloalkenylene , cycloalkynylene , arylalkylene , hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions , and are applicable to provide the formulas herein with proper valency . the term “ hydroxy activating group ”, as used herein , refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or elimination reactions . examples of hydroxy activating group include , but not limited to , mesylate , tosylate , triflate , p - nitrobenzoate , phosphonate and the like . the term “ activated hydroxy ”, as used herein , refers to a hydroxy group activated with a hydroxy activating group , as defined above , including mesylate , tosylate , triflate , p - nitrobenzoate , phosphonate groups , for example . the term “ protected hydroxy ,” as used herein , refers to a hydroxy group protected with a hydroxy protecting group , as defined above , including benzoyl , acetyl , trimethylsilyl , triethylsilyl , methoxymethyl groups . the terms “ halo ” and “ halogen ,” as used herein , refer to an atom selected from fluorine , chlorine , bromine and iodine . the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers , diastereomers , and other stereoisomeric forms that may be defined , in terms of absolute stereochemistry , as ( r )— or ( s )—, or as ( d )- or ( l )- for amino acids . the present invention is meant to include all such possible isomers , as well as their racemic and optically pure forms . optical isomers may be prepared from their respective optically active precursors by the procedures described above , or by resolving the racemic mixtures . the resolution can be carried out in the presence of a resolving agent , by chromatography or by repeated crystallization or by some combination of these techniques , which are known to those skilled in the art . further details regarding resolutions can be found in jacques , et al ., enantiomers , racemates , and resolutions ( john wiley & amp ; sons , 1981 ). when the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry , and unless specified otherwise , it is intended that the compounds include both e and z geometric isomers . likewise , all tautomeric forms are also intended to be included . the configuration of any carbon - carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states ; thus a carbon - carbon double bond depicted arbitrarily herein as trans may be cis , trans , or a mixture of the two in any proportion . the term “ subject ” as used herein refers to a mammal . a subject therefore refers to , for example , dogs , cats , horses , cows , pigs , guinea pigs , and the like . preferably the subject is a human . when the subject is a human , the subject may be referred to herein as a patient . as used herein , the term “ pharmaceutically acceptable salt ” refers to those salts of the compounds formed by the process of the present invention which are , within the scope of sound medical judgment , suitable for use in contact with the tissues of humans and lower animals without undue toxicity , irritation , allergic response and the like , and are commensurate with a reasonable benefit / risk ratio . pharmaceutically acceptable salts are well known in the art . the term “ hydroxy protecting group ,” as used herein , refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures . after said synthetic procedure ( s ) the hydroxy protecting group as described herein may be selectively removed . hydroxy protecting groups as known in the are described generally in t . h . greene and p . g ., s . m . wuts , protective groups in organic synthesis , 3rd edition , john wiley & amp ; sons , new york ( 1999 ). examples of hydroxy protecting groups include benzyloxycarbonyl , 4 - nitrobenzyloxycarbonyl , 4 - bromobenzyloxycarbonyl , 4 - methoxybenzyloxycarbonyl , methoxycarbonyl , tert - butoxycarbonyl , isopropoxycarbonyl , diphenylmethoxycarbonyl , 2 , 2 , 2 - trichloroethoxycarbonyl , 2 -( trimethylsilyl ) ethoxycarbonyl , 2 - furfuryloxycarbonyl , allyloxycarbonyl , acetyl , formyl , chloroacetyl , trifluoroacetyl , methoxyacetyl , phenoxyacetyl , benzoyl , methyl , t - butyl , 2 , 2 , 2 - trichloroethyl , 2 - trimethylsilyl ethyl , 1 , 1 - dimethyl - 2 - propenyl , 3 - methyl - 3 - butenyl , allyl , benzyl , para - methoxybenzyldiphenylmethyl , triphenylmethyl ( trityl ), tetrahydrofuryl , methoxymethyl , methylthiomethyl , benzyloxymethyl , 2 , 2 , 2 - triehloroethoxymethyl , 2 -( trimethylsilyl ) ethoxymethyl , methanesulfonyl , para - toluenesulfonyl , trimethylsilyl , triethylsilyl , triisopropylsilyl , and the like . preferred hydroxy protecting groups for the present invention are acetyl ( ac or — c ( o ) ch 3 ), benzoyl ( bz or — c ( o ) c 6 h 5 ), and trimethylsilyl ( tms or — si ( ch 3 ) 3 ). berge , et al . describes pharmaceutically acceptable salts in detail in j . pharmaceutical sciences , 66 : 1 - 19 ( 1977 ). the salts can be prepared in situ during the final isolation and purification of the compounds of the invention , or separately by reacting the free base function with a suitable organic acid . examples of pharmaceutically acceptable salts include , but are not limited to , nontoxic acid addition salts e . g ., salts of an amino group formed with inorganic acids such as hydrochloric acid , hydrobromic acid , phosphoric acid , sulfuric acid and perchloric acid or with organic acids such as acetic acid , maleic acid , tartaric acid , citric acid , succinic acid or malonic acid or by using other methods used in the art such as ion exchange . other pharmaceutically acceptable salts include , but are not limited to , adipate , alginate , ascorbate , aspartate , benzenesulfonate , benzoate , bisulfate , borate , butyrate , camphorate , camphorsulfonate , citrate , cyclopentanepropionate , digluconate , dodecylsulfate , ethanesulfonate , formate , fumarate , glucoheptonate , glycerophosphate , gluconate , hemisulfate , heptanoate , hexanoate , hydroiodide , 2 - hydroxy - ethanesulfonate , lactobionate , lactate , laurate , lauryl sulfate , malate , maleate , malonate , methanesulfonate , 2 - naphthalenesulfonate , nicotinate , nitrate , oleate , oxalate , palmitate , pamoate , pectinate , persulfate , 3 - phenylpropionate , phosphate , picrate , pivalate , propionate , stearate , succinate , sulfate , tartrate , thiocyanate , p - toluenesulfonate , undecanoate , valerate salts , and the like . representative alkali or alkaline earth metal salts include sodium , lithium , potassium , calcium , magnesium , and the like . further pharmaceutically acceptable salts include , when appropriate , nontoxic ammonium , quaternary ammonium , and amine cations formed using counterions such as halide , hydroxide , carboxylate , sulfate , phosphate , nitrate , alkyl having from 1 to 6 carbon atoms , sulfonate and aryl sulfonate . the term “ amino protecting group ,” as used herein , refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures . after said synthetic procedure ( s ) the amino protecting group as described herein may be selectively removed . amino protecting groups as known in the are described generally in t . h . greene and p . g . m . wuts , protective groups in organic synthesis , 3rd edition , john wiley & amp ; sons , new york ( 1999 ). examples of amino protecting groups include , but are not limited to , t - butoxycarbonyl , 9 - fluorenylmethoxycarbonyl , benzyloxycarbonyl , and the like . as used herein , the term “ pharmaceutically acceptable ester ” refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof . suitable ester groups include , for example , those derived from pharmaceutically acceptable aliphatic carboxylic acids , particularly alkanoic , alkenoic , cycloalkanoic and alkanedioic acids , in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms . examples of particular esters include , but are not limited to , formates , acetates , propionates , butyrates , acrylates and ethylsuccinates . the term “ pharmaceutically acceptable prodrugs ” as used herein refers to those prodrugs of the compounds formed by the process of the present invention which are , within the scope of sound medical judgment , suitable for use in contact with the tissues of humans and lower animals with undue toxicity , irritation , allergic response , and the like , commensurate with a reasonable benefit / risk ratio , and effective for their intended use , as well as the zwitterionic forms , where possible , of the compounds of the present invention . “ prodrug ”, as used herein means a compound , which is convertible in vivo by metabolic means ( e . g . by hydrolysis ) to afford any compound delineated by the formulae of the instant invention . various forms of prodrugs are known in the art , for example , as discussed in bundgaard , ( ed . ), design of prodrugs , elsevier ( 1985 ); widder , et al . ( ed . ), methods in enzymology , vol . 4 , academic press ( 1985 ); krogsgaard - larsen , et al ., ( ed ). “ design and application of prodrugs , textbook of drug design and development , chapter 5 , 113 - 191 ( 1991 ); bundgaard , et al ., journal of drug deliver reviews , 8 : 1 - 38 ( 1992 ); bundgaard , j . of pharmaceutical sciences , 77 : 285 et seq . ( 1988 ); higuchi and stella ( eds .) prodrugs as novel drug delivery systems , american chemical society ( 1975 ); and bernard testa & amp ; joachim mayer , “ hydrolysis in drug and prodrug metabolism : chemistry , biochemistry and enzymology ,” john wiley and sons , ltd . ( 2002 ). the term “ acyl ” includes residues derived from acids , including but not limited to carboxylic acids , carbamic acids , carbonic acids , sulfonic acids , and phosphorous acids . examples include aliphatic carbonyls , aromatic carbonyls , aliphatic sulfonyls , aromatic sulfinyls , aliphatic sulfinyls , aromatic phosphates and aliphatic phosphates . examples of aliphatic carbonyls include , but are not limited to , acetyl , propionyl , 2 - fluoroacetyl , butyryl , 2 - hydroxy acetyl , and the like . the term “ aprotic solvent ,” as used herein , refers to a solvent that is relatively inert to proton activity , i . e ., not acting as a proton - donor . examples include , but are not limited to , hydrocarbons , such as hexane and toluene , for example , halogenated hydrocarbons , such as , for example , methylene chloride , ethylene chloride , chloroform , and the like , heterocyclic compounds , such as , for example , tetrahydrofuran and n - methylpyrrolidinone , and ethers such as diethyl ether , bis - methoxymethyl ether . such solvents are well known to those skilled in the art , and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions , depending upon such factors as the solubility of reagents , reactivity of reagents and preferred temperature ranges , for example . further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs , for example : organic solvents physical properties and methods of purification , 4th ed ., edited by john a . riddick et al ., vol . ii , in the techniques of chemistry series , john wiley & amp ; sons , ny , 1986 . the terms “ protogenic organic solvent ” or “ protic solvent ” as used herein , refer to a solvent that tends to provide protons , such as an alcohol , for example , methanol , ethanol , propanol , isopropanol , butanol , t - butanol , and the like . such solvents are well known to those skilled in the art , and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions , depending upon such factors as the solubility of reagents , reactivity of reagents and preferred temperature ranges , for example . further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs , for example : organic solvents physical properties and methods of purification , 4th ed ., edited by john a . riddick et al ., vol . ii , in the techniques of chemistry series , john wiley & amp ; sons , ny , 1986 . combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds . the term “ stable ”, as used herein , refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein ( e . g ., therapeutic or prophylactic administration to a subject ). the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography , high pressure liquid chromatography , or recrystallization . as can be appreciated by the skilled artisan , further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art . additionally , the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds . in addition , the solvents , temperatures , reaction durations , etc . delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention . synthetic chemistry transformations and protecting group methodologies ( protection and deprotection ) useful in synthesizing the compounds described herein are known in the art and include , for example , those such as described in r . larock , comprehensive organic transformations , vch publishers ( 1989 ); t . w . greene and p . g . m . wuts , protective groups in organic synthesis , 2d . ed ., john wiley and sons ( 1991 ); l . fieser and m . fieser , fieser and fieser &# 39 ; s reagents for organic synthesis , john wiley and sons ( 1994 ); and l . paquette , ed ., encyclopedia of reagents for organic synthesis , john wiley and sons ( 1995 ). the compounds of this invention may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties . such modifications are known in the art and include those which increase biological penetration into a given biological system ( e . g ., blood , lymphatic system , central nervous system ), increase oral availability , increase solubility to allow administration by injection , alter metabolism and alter rate of excretion . the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers . as used herein , the term “ pharmaceutically acceptable carrier ” means a non - toxic , inert solid , semi - solid or liquid filler , diluent , encapsulating material or formulation auxiliary of any type . some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose , glucose and sucrose ; starches such as corn starch and potato starch ; cellulose and its derivatives such as sodium carboxymethyl cellulose , ethyl cellulose and cellulose acetate ; powdered tragacanth ; malt ; gelatin ; talc ; excipients such as cocoa butter and suppository waxes ; oils such as peanut oil , cottonseed oil ; safflower oil ; sesame oil ; olive oil ; corn oil and soybean oil ; glycols ; such a propylene glycol ; esters such as ethyl oleate and ethyl laurate ; agar ; buffering agents such as magnesium hydroxide and aluminum hydroxide ; alginic acid ; pyrogen - free water ; isotonic saline ; ringer &# 39 ; s solution ; ethyl alcohol , and phosphate buffer solutions , as well as other non - toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate , as well as coloring agents , releasing agents , coating agents , sweetening , flavoring and perfuming agents , preservatives and antioxidants can also be present in the composition , according to the judgment of the formulator . the pharmaceutical compositions of this invention can be administered to humans and other animals orally , rectally , parenterally , intracisternally , intravaginally , intraperitoneally , topically ( as by powders , ointments , or drops ), buccally , or as an oral or nasal spray . the pharmaceutical compositions of this invention may be administered orally , parenterally , by inhalation spray , topically , rectally , nasally , buccally , vaginally or via an implanted reservoir , preferably by oral administration or administration by injection . the pharmaceutical compositions of this invention may contain any conventional non - toxic pharmaceutically - acceptable carriers , adjuvants or vehicles . in some cases , the ph of the formulation may be adjusted with pharmaceutically acceptable acids , bases or buffers to enhance the stability of the formulated compound or its delivery form . the term parenteral as used herein includes subcutaneous , intracutaneous , intravenous , intramuscular , intra - articular , intraarterial , intrasynovial , intrasternal , intrathecal , intralesional and intracranial injection or infusion techniques . liquid dosage forms for oral administration include pharmaceutically acceptable emulsions , microemulsions , solutions , suspensions , syrups and elixirs . in addition to the active compounds , the liquid dosage forms may contain inert diluents commonly used in the art such as , for example , water or other solvents , solubilizing agents and emulsifiers such as ethyl alcohol , isopropyl alcohol , ethyl carbonate , ethyl acetate , benzyl alcohol , benzyl benzoate , propylene glycol , 1 , 3 - butylene glycol , dimethylformamide , oils ( in particular , cottonseed , groundnut , corn , germ , olive , castor , and sesame oils ), glycerol , tetrahydrofurfuryl alcohol , polyethylene glycols and fatty acid esters of sorbitan , and mixtures thereof . besides inert diluents , the oral compositions can also include adjuvants such as wetting agents , emulsifying and suspending agents , sweetening , flavoring , and perfuming agents . injectable preparations , for example , sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents . the sterile injectable preparation may also be a sterile injectable solution , suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent , for example , as a solution in 1 , 3 - butanediol . among the acceptable vehicles and solvents that may be employed are water , ringer &# 39 ; s solution , u . s . p . and isotonic sodium chloride solution . in addition , sterile , fixed oils are conventionally employed as a solvent or suspending medium . for this purpose any bland fixed oil can be employed including synthetic mono - or diglycerides . in addition , fatty acids such as oleic acid are used in the preparation of injectables . the injectable formulations can be sterilized , for example , by filtration through a bacterial - retaining filter , or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use . in order to prolong the effect of a drug , it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection . this may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility . the rate of absorption of the drug then depends upon its rate of dissolution , which , in turn , may depend upon crystal size and crystalline form . alternatively , delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle . injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide - polyglycolide . depending upon the ratio of drug to polymer and the nature of the particular polymer employed , the rate of drug release can be controlled . examples of other biodegradable polymers include poly ( orthoesters ) and poly ( anhydrides ). depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues . compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non - irritating excipients or carriers such as cocoa butter , polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound . solid dosage forms for oral administration include capsules , tablets , pills , powders , and granules . in such solid dosage forms , the active compound is mixed with at least one inert , pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or : a ) fillers or extenders such as starches , lactose , sucrose , glucose , mannitol , and silicic acid , b ) binders such as , for example , carboxymethylcellulose , alginates , gelatin , polyvinylpyrrolidinone , sucrose , and acacia , c ) humectants such as glycerol , d ) disintegrating agents such as agar - agar , calcium carbonate , potato or tapioca starch , alginic acid , certain silicates , and sodium carbonate , e ) solution retarding agents such as paraffin , f ) absorption accelerators such as quaternary ammonium compounds , g ) wetting agents such as , for example , cetyl alcohol and glycerol monostearate , h ) absorbents such as kaolin and bentonite clay , and i ) lubricants such as talc , calcium stearate , magnesium stearate , solid polyethylene glycols , sodium lauryl sulfate , and mixtures thereof . in the case of capsules , tablets and pills , the dosage form may also comprise buffering agents . solid compositions of a similar type may also be employed as fillers in soft and hard - filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like . the active compounds can also be in micro - encapsulated form with one or more excipients as noted above . the solid dosage forms of tablets , dragees , capsules , pills , and granules can be prepared with coatings and shells such as enteric coatings , release controlling coatings and other coatings well known in the pharmaceutical formulating art . in such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose , lactose or starch . such dosage forms may also comprise , as is normal practice , additional substances other than inert diluents , e . g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose . in the case of capsules , tablets and pills , the dosage forms may also comprise buffering agents . they may optionally contain opacifying agents and can also be of a composition that they release the active ingredient ( s ) only , or preferentially , in a certain part of the intestinal tract , optionally , in a delayed manner . examples of embedding compositions which can be used include polymeric substances and waxes . dosage forms for topical or transdermal administration of a compound of this invention include ointments , pastes , creams , lotions , gels , powders , solutions , sprays , inhalants or patches . the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required . ophthalmic formulation , ear drops , eye ointments , powders and solutions are also contemplated as being within the scope of this invention . the ointments , pastes , creams and gels may contain , in addition to an active compound of this invention , excipients such as animal and vegetable fats , oils , waxes , paraffins , starch , tragacanth , cellulose derivatives , polyethylene glycols , silicones , bentonites , silicic acid , talc and zinc oxide , or mixtures thereof . powders and sprays can contain , in addition to the compounds of this invention , excipients such as lactose , talc , silicic acid , aluminum hydroxide , calcium silicates and polyamide powder , or mixtures of these substances . sprays can additionally contain customary propellants such as chlorofluorohydrocarbons . transdermal patches have the added advantage of providing controlled delivery of a compound to the body . such dosage forms can be made by dissolving or dispensing the compound in the proper medium . absorption enhancers can also be used to increase the flux of the compound across the skin . the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel . an inhibitory amount or dose of the compounds of the present invention may range from about 0 . 1 mg / kg to about 500 mg / kg , alternatively from about 1 to about 50 mg / kg . inhibitory amounts or doses will also vary depending on route of administration , as well as the possibility of co - usage with other agents . according to the methods of treatment of the present invention , viral infections are treated or prevented in a subject such as a human or lower mammal by administering to the subject an anti - hepatitis c virally effective amount or an inhibitory amount of a compound of the present invention , in such amounts and for such time as is necessary to achieve the desired result . an additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result . the term “ anti - hepatitis c virally effective amount ” of a compound of the invention , as used herein , mean a sufficient amount of the compound so as to decrease the viral load in a biological sample or in a subject . as well understood in the medical arts , an anti - hepatitis c virally effective amount of a compound of this invention will be at a reasonable benefit / risk ratio applicable to any medical treatment . the term “ inhibitory amount ” of a compound of the present invention means a sufficient amount to decrease the hepatitis c viral load in a biological sample or a subject . it is understood that when said inhibitory amount of a compound of the present invention is administered to a subject it will be at a reasonable benefit / risk ratio applicable to any medical treatment as determined by a physician . the term “ biological sample ( s ),” as used herein , means a substance of biological origin intended for administration to a subject . examples of biological samples include , but are not limited to , blood and components thereof such as plasma , platelets , subpopulations of blood cells and the like ; organs such as kidney , liver , heart , lung , and the like ; sperm and ova ; bone marrow and components thereof , or stem cells . thus , another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention . upon improvement of a subject &# 39 ; s condition , a maintenance dose of a compound , composition or combination of this invention may be administered , if necessary . subsequently , the dosage or frequency of administration , or both , may be reduced , as a function of the symptoms , to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level , treatment should cease . the subject may , however , require intermittent treatment on a long - term basis upon any recurrence of disease symptoms . it will be understood , however , that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment . the specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder ; the activity of the specific compound employed ; the specific composition employed ; the age , body weight , general health , sex and diet of the patient ; the time of administration , route of administration , and rate of excretion of the specific compound employed ; the duration of the treatment ; drugs used in combination or coincidental with the specific compound employed ; and like factors well known in the medical arts . the total daily inhibitory dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts , for example , from 0 . 01 to 50 mg / kg body weight or more usually from 0 . 1 to 25 mg / kg body weight . single dose compositions may contain such amounts or submultiples thereof to make up the daily dose . in general , treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound ( s ) of this invention per day in single or multiple doses . unless otherwise defined , all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art . all publications , patents , published patent applications , and other references mentioned herein are hereby incorporated by reference in their entirety . abbreviations which have been used in the descriptions of the schemes and the examples that follow are : acn for acetonitrile ; ac for acetyl ; boc for tert - butoxycarbonyl ; bz for benzoyl ; bn for benzyl ; cdi for carbonyldiimidazole ; dba for dibenzylidene acetone ; cdi for 1 , 1 ′- carbonyldiimidizole ; dbu for 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 - ene ; dcm for dichloromethane ; diad for diisopropylazodicarboxylate ; dmap for dimethylaminopyridine ; dmf for dimethyl formamide ; dmso for dimethyl sulfoxide ; dppb for diphenylphosphino butane ; etoac for ethyl acetate ; hatu for 2 -( 7 - aza - 1h - benzotriazole - 1 - yl )- 1 , 1 , 3 , 3 - tetramethyluronium hexafluorophosphate ; iproh for isopropanol ; nahmds for sodium bis ( trimethylsilyl ) amide ; nmo for n - methylmorpholine n - oxide ; meoh for methanol ; ph for phenyl ; popd for dihydrogen dichlorobis ( di - tert - butylphosphino ) palladium ( ii ); tbahs for tetrabutyl ammonium hydrogen sulfate ; tea for triethylamine ; thf for tetrahydrofuran ; tpp for triphenylphosphine ; tris for tris ( hydroxymethyl ) aminomethane ; bme for 2 - mercaptoethanol ; bop for benzotriazol - 1 - yloxy - tris ( dimethylamino ) phosphonium hexafluorophosphate ; cod for cyclooctadiene ; dast for diethylaminosulfur trifluoride ; dabcyl for 6 -( n - 4 ′- carboxy - 4 -( dimethylamino ) azobenzene )- aminohexyl - 1 - o -( 2 - cyanoethyl )-( n , n - diisopropyl )- phosphoramidite ; dcm for dichloromethane ; diad for diisopropyl azodicarboxylate ; dibal - h for diisobutylaluminum hydride ; diea for diisopropyl ethylamine ; dmap for n , n - dimethylaminopyridine ; dme for ethylene glycol dimethyl ether ; dmem for dulbecco &# 39 ; s modified eagles media ; dmf for n , n - dimethyl formamide ; dmso for dimethylsulfoxide ; duphos for the compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared . scheme 1 describes the synthesis of intermediate ig . the cyclic peptide precursor ig was synthesized from boc - l - 2 - amino - 8 - nonenoic acid ia and cis - l - hydroxyproline methyl ester ib via steps a - d set forth generally in scheme 1 . for further details of the synthetic methods employed to produce the cyclic peptide precursor ig , see u . s . pat . no . 6 , 608 , 027 , which is herein incorporated by reference in its entirety . other amino acid derivatives containing a terminal alkene may be used in place of ia in order to create varied macrocyclic structures ( for further details see wo / 0059929 ). ring closure methathesis with a ruthenium - based catalyst gave the desired key intermediate ig ( for further details on ring closing metathesis see recent reviews : grubbs et al ., acc . chem . res ., 1995 , 28 , 446 ; shrock et al ., tetrahedron 1999 , 55 , 8141 ; furstner , a . angew . chem . int . ed . 2000 , 39 , 3012 ; tmka et al ., acc . chem . res . 2001 , 34 , 18 ; and hoveyda et al ., chem . eur . j . 2001 , 7 , 945 ). scheme 2 illustrates the general synthetic method of tetrazole analogs . 5 - substituted tetrazoles ( 2 - 2 ) were synthesized from nitrile compounds ( 2 - 1 ) with azide , but not limited to sodium azide . intermediate ( 2 - 4 ) and ( 2 - 5 ) can be made through sn2 replacement of activated hydroxyl group by converting hydroxy intermediate ig to a suitable leaving group such as , but not limited to oms , ots , otf , bromide , or iodide . subsequent hydrolysis of the ester gives compounds of formula ( 2 - 6 ) or ( 2 - 7 ). intermediate ( 3 - 1 ) was synthesized under the conditions with macrocyclic mesylate ( 2 - 3 ) and 5 - substitued tetrazoles as described in scheme 2 . intermediate ( 3 - 1 ) may then undergo suzuki coupling reactions , sonogashira reactions , or stille couplings at the position occupied by the halide or otf . for further details concerning the suzuki coupling reaction see : a . suzuki , pure appl . chem . 1991 , 63 , 419 - 422 and a . r . martin , y . yang , acta chem . scand . 1993 , 47 , 221 - 230 . for further details of the sonogashira reaction see : sonogashira , comprehensive organic synthesis , volume 3 , chapters 2 , 4 and sonogashira , synthesis 1977 , 777 . for further details of the stille coupling reaction see : j . k . stille , angew . chem . int . ed . 1986 , 25 , 508 - 524 , m . pereyre et al ., tin in organic synthesis ( butterworths , boston , 1987 ) pp 185 - 207 passim , and a review of synthetic applications in t . n . mitchell , synthesis 1992 , 803 - 815 . the buchwald reaction allows for the substitution of amines , both primary and secondary , as well as 1h - nitrogen heterocycles at the aryl bromide . for further details of the buchwald reaction see j . f . hartwig , angew . chem . int . ed . 1998 , 37 , 2046 - 2067 . scheme 4 illustrates the modification of the n - terminal and c - teminal of the macrocycle . deprotection of the boc moiety with an acid , such as , but not limited to hydrochloric acid yields compounds of formula ( 4 - 2 ). the amino moiety of formula ( 4 - 2 ) can be alkylated or acylated with appropriate alkyl halide or acyl groups to give compounds of formula ( 4 - 3 ). compounds of formula ( 4 - 3 ) can be hydrolyzed with base such as lithium hydroxide to free up the acid moiety of formula ( 4 - 4 ). subsequent activation of the acid moiety followed by treatment with appropriate acyl or sulfonyl groups to provide compounds of formula ( 4 - 5 ). the sulfonamides ( 5 - 2 ) were prepared from the corresponding acids ( 5 - 1 ) by subjecting the acid to a coupling reagent ( i . e . cdi , hatu , dcc , edc and the like ) at rt or at elevated temperature , with the subsequent addition of the corresponding sulfonamide r 3 — s ( o ) 2 — nh 2 in the presence of base wherein r 3 is as previously defined . carbon - linkage tetrazoles ( 6 - 6 ) were prepared from commercially available starting material ( 6 - 1 ) by the procedures illustrated in scheme 6 . compounds ( 6 - 6 ) could be converted easily to the corresponding acids and sulfonamides using the methods demonstrated in scheme 4 and scheme 5 . tetrazoles ( 6 - 6 ) could be prepared from an alternative way as showed scheme 7 . the synthesis started from the common intermediate ( 6 - 2 ), instead of the installation of aromatic groups on tetrazole ring , compound ( 6 - 2 ) was coupled with p1 followed by p3 to give ( 7 - 3 ), which was able to form a macrocyclic compound ( 7 - 4 ) under metathesis conditions . compound ( 7 - 4 ) was served as a common intermediate for further modification on the tetrazole ring to furnish ( 6 - 6 ). the compounds and processes of the present invention will be better understood in connection with the following examples , which are intended as an illustration only and not to limit the scope of the invention . various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including , without limitation , those relating to the chemical structures , substituents , derivatives , formulations and / or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims . u . s . patent application publication no . 20050153877 also describes compounds where g = oh , the entire content of which is herein incorporated by reference . 1a . to a solution of boc - l - 2 - amino - 8 - nonenoic acid 1a ( 1 . 36 g , 5 mol ) and the commercially available cis - l - hydroxyproline methyl ester 1b ( 1 . 09 g , 6 mmol ) in 15 ml dmf , was added diea ( 4 ml , 4eq .) and hatu ( 4 g , 2eq ). the coupling was carried out at 0 ° c . over a period of 1 hour . the reaction mixture was diluted with 100 ml etoac , and followed by washing with 5 % citric acid 2 × 20 ml , water 2 × 20 ml , 1m nahco 3 4 × 20 ml and brine 2 × 10 ml , respectively . the organic phase was dried over anhydrous na 2 so 4 and then was evaporated , affording the dipeptide 1c ( 1 . 91 g , 95 . 8 %) that was identified by hplc ( retention time = 8 . 9 min , 30 - 70 %, 90 % b ), and ms ( found 421 . 37 , m + na + ). 1b . the dipeptide 1c ( 1 . 91 g ) was dissolved in 15 ml of dioxane and 15 ml of 1 n lioh aqueous solution and the hydrolysis reaction was carried out at rt for 4 hours . the reaction mixture was acidified by 5 % citric acid and extracted with 100 ml etoac , and followed by washing with water 2 × 20 ml , and brine 2 × 20 ml , respectively . the organic phase was dried over anhydrous na 2 so 4 and then removed in vacuum , yielding the free carboxylic acid compound 1d ( 1 . 79 g , 97 %), which was used for next step synthesis without need for further purification . 1c . to a solution of the free acid obtained above ( 1 . 77 , 4 . 64 mmol ) in 5 ml dmf , d - β - vinyl cyclopropane amino acid ethyl ester 1e ( 0 . 95 g , 5 mmol ), diea ( 4 ml , 4eq .) and hatu ( 4 g , 2eq ) were added . the coupling was carried out at 0 ° c . over a period of 5 hours . the reaction mixture was diluted with 80 ml etoac , and followed by washing with 5 % citric acid 2 × 20 ml , water 2 × 20 ml , 1m nahco 3 4 × 20 ml and brine 2 × 10 ml , respectively . the organic phase was dried over anhydrous na 2 so 4 and then evaporated . the residue was purified by silica gel flash chromatography using different ratios of hexanes : etoac as elution phase ( 5 : 1 → 3 : 1 → 1 : 1 → 1 : 2 → 1 : 5 ). the linear tripeptide 1f was isolated as an oil after removal of the elution solvents ( 1 . 59 g , 65 . 4 %), identified by hplc ( retention time = 11 . 43 min ) and ms ( found 544 . 84 , m + na + ). 1d . ring closing metathesis ( rcm ). a solution of the linear tripeptide 1f ( 1 . 51 g , 2 . 89 mmol ) in 200 ml dry dcm was deoxygenated by bubbling n 2 . hoveyda &# 39 ; s 1 st generation catalyst ( 5 mol % eq .) was then added as solid . the reaction was refluxed under n 2 atmosphere 12 hours . the solvent was evaporated and the residue was purified by silica gel flash chromatography using different ratios of hexanes : etoac as elution phase ( 9 : 1 → 5 : 1 → 3 : 1 → 1 : 1 → 1 : 2 → 1 : 5 ). the cyclic peptide precursor 1 was isolated as a white powder after removal of the elution solvents ( 1 . 24 g , 87 %), identified by hplc ( retention time = 7 . 84 min , 30 - 70 %, 90 % b ), and ms ( found 516 . 28 , m + na + ). for further details of the synthetic methods employed to produce the cyclic peptide precursor 1 , see u . s . pat . no . 6 , 608 , 027 , which is herein incorporated by reference in its entirety . 2a . to a solution of the macrocyclic peptide precursor 1 ( 500 mg , 1 . 01 mmol ) and diea ( 0 . 4 ml , 2 mmol ) in 2 . 0 ml dcm , mesylate chloride ( 0 . 1 ml ) was added slowly at 0 ° c . where the reaction was kept for 3 hours . 30 ml etoac was then added and followed by washing with 5 % citric acid 2 × 10 ml , water 2 × 10 ml , 1m nahco 3 2 × 10 ml and brine 2 × 10 ml , respectively . the organic phase was dried over anhydrous na 2 so 4 and evaporated , yielding the title compound mesylate that was used for next step synthesis without need for further purification . structurally diverse tetrazoles iiia - iiiq , for use in preparing tetrazolyl macrocycles of the invention were synthesized from commercially available nitrile compounds as described below : to a sealed tube containing 5 ml xylene , was added 3 - cl - 4 - hydroxy - benzoacetonitile ( 0 . 31 g , 5 mol ), nan 3 ( 0 . 65 g , 10 mmol ) and the triethylamine hydrochloride ( 0 . 52 g , 3 mmol ). the mixture was stirred vigorously at 140 ° c . over a period of 20 - 30 hours . the reaction mixture was then cooled and poured to a mixture of etoac ( 30 ml ) and aqueous citric acid solution ( 20 ml ). after washing with water 2 × 10 ml and brine 2 × 10 ml , the organic phase was dried over anhydrous na 2 so 4 and was evaporated to a yellowish solid . after re - crystallization with etoac - hexanes , the tetrazole compound 3a was obtained in good yield ( 0 . 4 g , 86 %%), high purity (& gt ; 90 %, by hplc ), and identified by nmr and ms ( found 197 . 35 and 199 . 38 , m + h + ). the title compound was prepared via the replacement of the mesylate from example 2 and tetrazole 3g . the replacement method is performed by dissolving 0 . 041 mmol of the macrocyclic peptide precursor mesylate 2 and 0 . 123 mmol of tetrazole 3g in 3 ml of dmf and adding 0 . 246 mmol of sodium carbonate ( 60 mg ). the resulting reaction mixture is stirred at 60 ° c . for 4 - 10 hours and subsequently cooled and extracted with ethyl acetate . the organic extract was washed with water ( 2 × 30 ml ), and the organic solution is concentrated in vacuo to be used in crude form for hydrolysis of the ethyl ester . the title compound was prepared by dissolving the title compound of example 4 ( 20 mg ) in 2 ml of dioxane and 1 ml of 1 n lioh aqueous solution . the resulting reaction mixture was stirred at rt for 4 - 8 hours . the reaction mixture was acidified with 5 % citric acid , extracted with 10 ml etoac , and washed with water 2 × 20 ml . the solvent was evaporated and the residue was purified by hplc on a ymc aq12s11 - 0520wt column with a 30 - 80 % ( 100 % acetonitrile ) gradient over a 20 min period . after lyophilization , title compound was obtained as a white amorphous solid . example 5 to example 14 were made with different 5 - substituted tetrazoles following the similar procedures described in example 4 . to a solution of the compound ( 33 mg ) of example 4 in dmf was added cdi ( 12 mg ). the reaction mixture was stirred at 40 ° c . for 1 h and then added cyclopropylsulfonamide ( 12 mg ) and dbu ( 15 μl ). the reaction mixture was stirred overnight at 40 ° c . the reaction mixture was extracted with etoac . the organic extracts were washed with 1m nahco 3 , brine , dried over na 2 so 4 , filtered and concentrated . the residue was purified by silica gel chromatograph to give desired product ( 22 mg ). 13c ( cd3od ): δ177 . 5 , 173 . 7 , 169 . 4 , 165 . 0 , 161 . 1 , 155 . 9 , 135 . 4 , 128 . 2 , 125 . 1 , 119 . 7 , 114 . 6 , 79 . 0 , 63 . 5 , 63 . 4 , 60 . 1 , 53 . 6 , 52 . 3 , 43 . 8 , 33 . 6 , 32 . 0 , 30 . 7 , 30 . 3 , 27 . 3 , 27 . 0 , 26 . 3 , 22 . 2 , 21 . 5 , 13 . 9 , 5 . 6 , 5 . 4 . example 16 to example 35 were made with different sulfonamides following the similar procedures described in example 15 . the solution of the compound from example 16 in 5 ml 4nhcl / dioxne was stirred at rt for 1 h . the reaction mixture was concentrated in vacuum . the residue was evaporated twice with dcm . the desired product was carried out directly to the next step . to the solution of the compound from step 36a in 2 ml dcm was added diea ( 143 μl )) and cyclopentylchloroformate ( 0 . 246 mmol )). the reaction mixture was stirred at rt for 1 h . the reaction mixture was extracted with etoac . the organic layer was washed with 1m nahco 3 , water , brine , dried over na 2 so 4 , filtered and concentrated . the residue was purified by hplc to give 42 mg of desired product . 13c ( cd3od ): δ177 . 5 , 173 . 4 , 169 . 4 , 165 . 1 , 161 . 8 , 156 . 6 , 135 . 4 , 128 . 2 , 125 . 1 , 119 . 9 , 114 . 1 , 77 . 5 , 63 . 3 , 60 . 2 , 54 . 7 , 53 . 4 , 52 . 5 , 43 . 9 , 43 . 8 , 33 . 7 , 32 . 3 , 32 . 2 , 32 . 0 , 30 . 7 , 30 . 3 , 27 . 3 , 27 . 0 , 26 . 3 , 23 . 2 , 22 . 2 , 21 . 5 , 5 . 6 , 5 . 4 . example 37 to example 94 ( formula ix ) are made following the procedures described in examples 15 or 36 . step 95a . to a seal tube containing 95a ( 2 . 54 g , 10 mmol ) and toluene ( 30 ml ) were charged with nan 3 ( 1 . 95 g , 30 mmol ) and et 3 n . hcl . ( 4 . 13 g , 30 mmol ). the reaction mixture was stirred at 110 ° c . for 20 h . a solution of saturated nahco 3 ( 10 ml ) was added to the reaction mixture followed by meoh ( 3 ml ). the resulting mixture was stirred at room temperature for 30 minutes . 10 % citric acid was added slowly to adjust the ph to 6 . the mixture was extracted with etoac 3 times . the combined organic phases were dried over anhydrous na 2 so 4 and then evaporated . the residue was purified by silica gel flash chromatography using etoac as elution phase to yield compound 95b as oil ( 2 . 8 g ). step 95b . a solution of 95b ( 350 mg , 1eq ) in ch 2 cl 2 ( 12 ml ) was treated with ( 4 - methoxyphenyl ) boronic acid ( 232 mg , 2eq ), pyridine ( 198 μl , 2eq ), cu ( oac ) 2 ( 244 mg , 1 . 5eq ), molecule sieve 4a ( 0 . 95 g ). the reaction mixture was stirred at room temperature under air for 24 h , and then filtered through celite . the resulting solution was concentrated and purified by silica gel flash chromatography ( hexane : etoac = 2 : 3 ) to yield compound 95c as oil ( 85 mg ). step 95c - f . the title compound was prepared following the similar procedures described in example 1 ( step 1a - d ). the title compound was prepared from compound 95 following the similar procedures described in example 15 . step 97a . to a solution of 95b in thf ( 3 ml ) was added bnbr ( 48 μl , 0 . 40 mmol ) followed by k 2 co 3 ( 138 mg , 1 . 0 mmol ). the reaction mixture was stirred at 65 ° c . for 16 h . the solvents were removed . the residue was purified by silica gel flash chromatography ( meoh : ch 2 cl 2 = 1 : 10 ) to give 97a ( 108 mg ). step 97b - e . the title compound was prepared following the similar procedures described in example 95 ( step 95c - f ). the title compound was prepared from compound 97 following the similar procedures described in example 15 . the title compound was prepared following the similar procedures described in example 97 . the title compound was prepared from compound 99 following the similar procedures described in example 15 . the title compound was prepared from compound 96 following the similar procedures described in example 36 . the title compound was prepared from compound 96 and cyclobutylchloroformate following the similar procedures described in example 36 . with hatu as coupling reagent following the similar procedures described in example 36 . the title compound was prepared from compound 103 following the similar procedures described in example 36 . with hatu as coupling reagent following the similar procedures described in example 36 . example 106 to example 121 ( formula ix ) were made following the procedures described in examples 4 , 15 or 36 . 13c ( cd3od ): δ177 . 5 , 177 . 4 , 173 . 6 , 169 . 3 , 162 . 9 , 156 . 6 , 135 . 8 , 135 . 4 , 130 . 9 , 129 . 9 , 125 . 1 , 125 . 0 , 77 . 4 , 63 . 8 , 60 . 1 , 60 . 0 , 53 . 7 , 52 . 6 , 43 . 9 , 33 . 5 , 32 . 3 , 32 . 0 , 30 . 7 , 30 . 3 , 27 . 3 , 27 . 0 , 26 . 3 , 23 . 2 , 23 . 1 , 22 . 2 , 21 . 4 , 5 . 6 , 5 . 4 . 13c ( cd3od ): δ177 . 4 , 173 . 5 , 169 . 4 , 163 . 4 , 156 . 6 , 135 . 3 , 125 . 1 , 123 . 6 , 123 . 5 , 118 . 1 , 118 . 0 , 115 . 9 , 115 . 7 , 77 . 4 , 63 . 6 , 60 . 0 , 53 . 5 , 52 . 5 , 43 . 8 , 33 . 7 , 32 . 3 , 32 . 2 , 32 . 0 , 30 . 7 , 30 . 3 , 27 . 3 , 27 . 0 , 26 . 3 , 23 . 1 , 23 . 1 , 22 . 2 , 21 . 5 , 5 . 6 , 5 . 4 . 13c ( cd3od ): δ177 . 4 , 173 . 6 , 169 . 4 , 164 . 7 , 164 . 3 , 163 . 3 , 162 . 7 , 162 . 6 , 156 . 6 , 135 . 3 , 131 . 0 , 125 . 1 , 109 . 7 , 109 . 6 , 109 . 5 , 105 . 5 , 105 . 3 , 105 . 1 , 77 . 4 , 63 . 7 , 60 . 0 , 53 . 5 , 52 . 5 , 43 . 8 , 33 . 7 , 32 . 3 , 32 . 2 , 32 . 0 , 30 . 7 , 30 . 4 , 27 . 3 , 27 . 0 , 26 . 3 , 23 . 1 , 22 . 2 , 21 . 5 , 5 . 6 , 5 . 4 . 13c ( cd3od ): δ176 . 8 , 173 . 1 , 168 . 3 , 165 . 7 , 155 . 9 , 136 . 5 , 134 . 1 , 131 . 3 , 130 . 6 , 128 . 8 , 128 . 7 , 127 . 6 , 126 . 5 , 125 . 9 , 125 . 3 , 124 . 7 , 124 . 0 , 78 . 2 , 67 . 3 , 62 . 7 , 59 . 9 , 53 . 2 , 52 . 5 , 44 . 6 , 33 . 9 , 32 . 9 , 32 . 8 , 32 . 4 , 31 . 3 , 30 . 0 , 27 . 4 , 27 . 2 , 26 . 1 , 23 . 6 , 22 . 6 , 21 . 0 , 6 . 9 , 6 . 3 . 13c ( cd3od ): δ177 . 6 , 177 . 5 , 173 . 6 , 169 . 4 , 165 . 2 , 156 . 6 , 135 . 4 , 134 . 5 , 133 . 4 , 128 . 6 , 128 . 4 , 127 . 7 , 127 . 2 , 126 . 7 , 126 . 4 , 125 . 1 , 124 . 8 , 123 . 7 , 77 . 4 , 63 . 5 , 60 . 2 , 60 . 1 , 53 . 6 , 52 . 5 , 43 . 8 , 33 . 7 , 32 . 2 , 32 . 0 , 30 . 7 , 30 . 3 , 27 . 3 , 27 . 0 , 26 . 3 , 23 . 0 , 22 . 9 , 22 . 3 , 21 . 5 , 5 . 6 , 5 . 4 . 13c ( cd3od ): δ177 . 5 , 173 . 4 , 169 . 3 , 165 . 1 , 161 . 1 , 156 . 6 , 135 . 4 , 128 . 2 , 125 . 1 , 119 . 8 , 114 . 7 , 77 . 5 , 63 . 5 , 63 . 3 , 60 . 1 , 60 . 0 , 53 . 4 , 52 . 5 , 43 . 9 , 43 . 8 , 33 . 7 , 32 . 3 , 32 . 2 , 32 . 0 , 30 . 7 , 30 . 3 , 27 . 3 , 27 . 0 , 26 . 3 , 23 . 2 , 22 . 3 , 21 . 3 , 13 . 9 , 5 . 6 , 5 . 4 . the compounds of the present invention exhibit potent inhibitory properties against the hcv ns3 protease . the following examples describe assays in which the compounds of the present invention can be tested for anti - hcv effects . hcv protease activity and inhibition is assayed using an internally quenched fluorogenic substrate . a dabcyl and an edans group are attached to opposite ends of a short peptide . quenching of the edans fluorescence by the dabcyl group is relieved upon proteolytic cleavage . fluorescence is measured with a molecular devices fluoromax ( or equivalent ) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm . the assay is run in corning white half - area 96 - well plates ( vwr 29444 - 312 [ corning 3693 ]) with full - length ns3 hcv protease 1b tethered with ns4a cofactor ( final enzyme concentration 1 to 15 nm ). the assay buffer is complemented with 10 μm ns4a cofactor pep 4a ( anaspec 25336 or in - house , mw 1424 . 8 ). ret s1 ( ac - asp - glu - asp ( edans )- glu - glu - abu -[ coo ] ala - ser - lys -( dabcyl )- nh 2 , anaspec 22991 , mw 1548 . 6 ) is used as the fluorogenic peptide substrate . the assay buffer contains 50 mm hepes at ph 7 . 5 , 30 mm nacl and 10 mm bme . the enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors . the peptide inhibitors hcv inh 1 ( anaspec 25345 , mw 796 . 8 ) ac - asp - glu - met - glu - glu - cys - oh , [− 20 ° c ] and hcv inh 2 ( anaspec 25346 , mw 913 . 1 ) ac - asp - glu - dif - cha - cys - oh , are used as reference compounds . ic50 values are calculated using xlfit in activitybase ( idbs ) using equation 205 : y = a +(( b − a )/( 1 +(( c / x )̂ d ))) quantification of hcv replicon rna ( hcv cell based assay ) is accomplished using the huh 11 - 7 cell line ( lohmann , et al science 285 : 110 - 113 , 1999 ). cells are seeded at 4 × 10 3 cells / well in 96 well plates and fed media containing dmem ( high glucose ), 10 % fetal calf serum , penicillin - streptomycin and non - essential amino acids . cells are incubated in a 7 . 5 % co 2 incubator at 37 ° c . at the end of the incubation period , total rna is extracted and purified from cells using ambion rnaqueous 96 kit ( catalog no . am 1812 ). to amplify the hcv rna so that sufficient material can be detected by an hcv specific probe ( below ), primers specific for hcv ( below ) mediate both the reverse transcription of the hcv rna and the amplification of the cdna by polymerase chain reaction ( pcr ) using the taqman one - step rt - pcr master mix kit ( applied biosystems catalog no . 4309169 ). the nucleotide sequences of the rt - pcr primers , which are located in the ns5b region of the hcv genome , are the following : detection of the rt - pcr product is accomplished using the applied biosystems ( abi ) prism 7500 sequence detection system ( sds ) that detects the fluorescence that is emitted when the probe , which is labeled with a fluorescence reporter dye and a quencher dye , is degraded during the pcr reaction . the increase in the amount of fluorescence is measured during each cycle of pcr and reflects the increasing amount of rt - pcr product . specifically , quantification is based on the threshold cycle , where the amplification plot crosses a defined fluorescence threshold . comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples ( abi user bulletin # 2 dec . 11 , 1997 ). the data is analyzed using the abi sds program version 1 . 7 . the relative template concentration can be converted to rna copy numbers by employing a standard curve of hcv rna standards with known copy number ( abi user bulletin # 2 dec . 11 , 1997 ). the rt reaction is performed at 48 ° c . for 30 minutes followed by pcr . thermal cycler parameters used for the pcr reaction on the abi prism 7500 sequence detection system are : one cycle at 95 ° c ., 10 minutes followed by 40 cycles each of which include one incubation at 95 ° c . for 15 seconds and a second incubation for 60 ° c . for 1 minute . to normalize the data to an internal control molecule within the cellular rna , rt - pcr is performed on the cellular messenger rna glyceraldehyde - 3 - phosphate dehydrogenase ( gapdh ). the gapdh copy number is very stable in the cell lines used . gapdh rt - pcr is performed on the same rna sample from which the hcv copy number is determined . the gapdh primers and probesare contained in the abi pre - developed taqman assay kit ( catalog no . 4310884e ). the ratio of hcv / gapdh rna is used to calculate the activity of compounds evaluated for inhibition of hcv rna replication . activity of compounds as inhibitors of hcv replication ( cell based assay ) in replicon containing huh - 7 cell lines . the effect of a specific anti - viral compound on hcv replicon rna levels in huh - 11 - 7cells is determined by comparing the amount of hcv rna normalized to gapdh ( e . g . the ratio of hcv / gapdh ) in the cells exposed to compound versus cells exposed to the dmso vehicle ( negative control ). specifically , cells are seeded at 4 × 10 3 cells / well in a 96 well plate and are incubated either with : 1 ) media containing 1 % dmso ( 0 % inhibition control ), or 2 ) media / 1 % dmso containing a fixed concentration of compound . 96 well plates as described above are then incubated at 37 ° c . for 4 days ( ec50 determination ). s = the ratio of hcv rna copy number / gapdh rna copy number in the sample ; c1 = the ratio of hcv rna copy number / gapdh rna copy number in the 0 % inhibition control ( media / 1 % dmso ). the dose - response curve of the inhibitor is generated by adding compound in serial , three - fold dilutions over three logs to wells starting with the highest concentration of a specific compound at 1 . 5 um and ending with the lowest concentration of 0 . 23 nm . further dilution series ( 500 nm to 0 . 08 nm for example ) is performed if the ec50 value is not positioned well on the curve . ec50 is determined with the idbs activity base program “ xl fit ” using a 4 - paramater , non - linear regression fit ( model # 205 in version 4 . 2 . 1 , build 16 ). in the above assays , representative compounds of the present invention are found to have hcv replication inhibitory activity and hcv ns3 protease inhibitory activity . these compounds were also effective in inhibiting hcv ns3 proteases of different hcv genotypes including genotypes 1 , 2 , 3 and 4 . representative compounds were tested in the above assays ( example 122 and example 123 ). exemplary compounds disclosed herein were found to have activities in the ranges of & lt ;= 0 . 2 nm - 100 nm in the ns3 / ns4a protease enzyme assay and & lt ;= 0 . 2 nm - 1000 nm in the cell - based replicon assay . for example , compounds of examples 36 , 101 and 117 showed ic50 of 0 . 1 nm , 0 . 4 nm and 0 . 2 nm in the ns3 / ns4a protease enzyme assay respectively , and all showed ec50 of 0 . 8 nm in the cell - based replicon assay . pharmacokinetic analysis of representing compounds showed high liver drug levels . for example , a single oral dose of 20 mg / kg in rat , compound of examples 36 showed a bioavailability of 76 %, with cmax and auc of 16 . 1 μg / ml and 52 . 9 μg . hr / ml , respectively . these compounds were also tested and found no significant inhibitions of cytochrome p450 enzymes .

the present invention relates to compounds of formula i , ii , iii or iv , or pharmaceutically acceptable salts , esters , or prodrugs thereof : which inhibit serine protease activity , particularly the activity of hepatitis c virus ns3 - ns4a protease . consequently , the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents . the present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from hcv infection . the invention also relates to methods of treating an hcv infection in a subject by administering a pharmaceutical composition comprising a compound of the present invention .

the present invention provides compositions and methods for inducing chitinase enzyme production in the soil of lawns , home gardens and turf , to destroy or lessen the effects of soil pathogens on the growing plants , and thereby avoiding the use of synthetic pesticidal chemicals . the term “ pathogen ” in this context refers to those insect and microbial species which are deemed harmful to growing plants and includes , but is not limited to , beetles , grubs , nematodes , other insects inimical to normal plant growth and fungal species injurious to plants . the term “ plants ” includes all stages of the growing vegetation , from seed to a fully mature plant . synthetic pesticidal chemicals refers to those chemical compounds , including herbicides , insecticides , nematocides , larvacides and related materials that are used to treat lawns , home gardens and shrubs to reduce or eliminate unwanted insect and fungal soil organisms . the induced generation of chitinase in the soil is brought about by the addition thereto of chitin , the presence of which stimulates microorganisms that are present and / or intentionally added , so as to elaborate chitinase enzyme . the chitin can be provided either as a component of naturally occurring materials , such as from seafood wastes , or in some purified form . the addition of chitin to the soil is either by distribution over the surface of a developed lawn , garden or turf , or by direct inclusion into the soils of new growth areas . when distributed over the soil of a developed area , the level of use generally varies from about 100 grams / meter 2 to about 500 grams / meter 2 of the “ as is ” material . the form of the chitin can be either powder , prill , granule or flake , or mixtures thereof . the application can be as either the dry product , as an aqueous slurry or via dispersion of the product . the aqueous dispersion can also include a dispersing and / or thickening or suspending agent , in order to promote uniformity . appropriate dispersing , thickening or suspending agents can be readily determined by those skilled in the art of selecting appropriate materials for uniform delivery of particulated material . in a preferred embodiment a combination of several physical forms of chitin will allow rapid initial stimulation of microbially - induced chitinase , these forms ranging from finely divided chitin , to coarser forms , with lower surface - to - volume ratios , which result in a protracted delivery of chitin to soil environment . more rapid inducement of chitinase activity occurs when the chitin is incorporated into the soil than when broadcast onto its surface . this results from the low aqueous solubility of chitin . incorporation into soil allows for a more ready access to it by soil microorganisms than would be the case by its slow leaching from soil and growing surfaces . in a preferred embodiment , the soil is partially digested by fermentation or chemical means , which deacetylates and / or cleaves the chain of the carbohydrate chitin and increases its aqueous solubility through the production of smaller polymeric units and / or increased availability of polar hydroxyl groups on the glucosyl moieties . deacetylation , to the degree that it occurs , leaves a primary amino group on the glucosyl unit , which group can serve as a potential source of ammonia , a preferred form of nitrogen for fertilization . in general , fermentation of chitin can be brought about by adding chitin to a well aerated aqueous slurry in the presence of a small amount of soil from the area to be treated , along with continuous agitation . the reduction of polymer chain length ( depolymerization ) can be accomplished through the action of aqueous acidic or alkaline agents . specific details of these operations are well know to those skilled in the art . preferred degrees of fermentation are in the range of about 10 % to about 90 %. preferred degrees of deacetylation are those which reduce the level of nitrogen in the chitin from about 6 . 9 % to the range of approximately 1 % to approximately 4 %. in a preferred embodiment of the present invention , the chitin soil amendment can be supplemented with specific bacteria . the bacteria can be , for example : ( a ) lytobacter kobii , wherein the chitanase and glucanase elaborations of which have been shown to be capable of controlling summer patch disease of kentucky bluegrass ; or ( b ) directly obtained from the particular lawn , garden or turf to be treated and externally optimized to create chitinase or ( c ) common bacterial strains which experience has shown can be stimulated to produce chitinase in the presence of chitin . the bacteria do not include those which have been genetically modified to produce chitinase , through insertion of a specific gene which codes for its production . the chitin and bacterial mix can range in composition from about 1000 : 1 of chitin ( as is , dry basis ) to bacteria ( dry basis , and with 103 cfu / gm population ) to about 100 : 1 by weight . in a further , preferred embodiment of the invention , the chitin soil amendment can be supplemented with specific nutrients which enhance the proliferation of chitinase - producing bacteria . these nutrients may be included in chitin amendments either with , or without , the addition of specific bacteria , which are naturally predisposed to chitinase production . such nutrients include , but are not limited to , phosphorus and bio - available trace nutrients . in yet another preferred embodiment of the present invention , a sample of soil from the potential treatment site is subjected to an aerobic fermentation process in which chitin and appropriate inorganic nutrients are used to stimulate the growth of those native bacteria which can most effectively utilize chitin as a carbon source through stimulation of their chitin - degrading enzyme systems . specific details of such fermentation can be determined by those qualified and adept , by training , to design such aerobic fermentations , but , in general , the following range of compositions , temperatures and conditions will apply ; 200 - 30 ° c . ; amount of chitin added is a function of dissolved oxygen to reduce ammonia generation ; buffers or absorptive polymers optionally added to adjust the ph of the mix , and / or free nitrogen . subcultures of those enzyme - producing optimized bacteria will be selected for use in future situations where the temperature and soil conditions will favor their inclusion in a chitin / bacterial amendment , without the need for pre - optimization of native bacteria that readily utilize chitin through elaboration of chitanase and related glucanases . in a further , preferred embodiment of the present invention , dried shrimp shells are utilized for the production of an economically - viable non - genetically - modified organism - based chitinase lawn and garden care fermentation broth . a food - grade ( commercially available ) protease enzyme is used for a hydrolysis of proteins as a way for achieving the elimination of undesirable odors , via a protein hydrolysis lag - time reduction during chitinase fermentation . additionally , the use of food - grade protease enzyme for the hydrolysis of proteins in the dried shrimp shells achieves an allergen decrease and , particularly , decreases protein fractions of approximately 40 kd , which have been revealed to be the most potent allergen group in crustaceans . the present invention is further illustrated by the following examples . unless otherwise noted , all parts and percentages in the examples , as well as in this specification and the claims are by weight . this example demonstrates the ability of microbially - induced enzymatically - digested chitin to stimulate the growth of a turf grass , as cf . undigested chitin - treated , and control plots . a two - square meter plot of fescue grass , maintained by the farmingdale horticulture department of the state university of new york , was subdivided into four one - square meter plots . treatment occurred in late summer ( early september ) when the turf grass is dormant . the ambient daytime temperature during treatment was in the mid - to high - 80 &# 39 ; s (° f .) during the day , dropping to the 60 &# 39 ; s to low 70 &# 39 ; s overnight . one plot was maintained as the control . two others , diagonally across from each other , received quantities of finely - ground chitin ( obtained from aldrich chemicals ) equivalent to 0 . 5 % and 1 . 0 %, by weight , with respect to dry weight of soil , calculated to a depth of four inches . the comminuted chitin was sprinkled over the surface of the respective plots , and both were watered to facilitate permeation of the powder into the underlying loam . a similar degree of watering was applied to the control plot , as well as the fourth plot , after the following application . a previously - prepared biogard ® fermentation mix was applied to the fourth plot , as follows : the fermentation mixture was prepared with 10 % chitin in spring water and 1 gm of soil , in a covered 2 - liter erlenmeyer flask [ total contents of chitin and soil , per two - liters , was 200 gms and 1 gm of soil , respectively . the mixture was continuously agitated for one month , at ambient temperatures , on a labline orbit shaker at 60 cycles / minute . this mixture serves as a microbial library , for stimulating the growth of naturally - occurring chitinase producing microorganisms in the soil . one liter of the two - liter quantity was uniformly distributed over the one - square meter , fourth plot , followed by watering , as described above . the flask was reconstituted to full volume , by adding appropriate amounts of chitin , water and soil . after two weeks , another one - liter portion of the biogard ferment was again applied to the fourth plot . as appropriate , the two - meter square subdivided plot was watered bi - weekly to minimize drying , to a degree dependent on natural precipitation . only two 1 - liter applications of the biogard were made , at the two - week interval . results : it could be readily discerned , as the fall growth of the turf resumed ( by mid - october ), that the plot that had received the biogard treatment , was significantly greener than the other , adjoining plots . this greening , which was subsequently observed over an x - week / month period , is attributed to a combination of two factors , the relative contribution of each not being determinable however . the factors are the additional nitrogen available from enzymatic cleavage of the glucosamine side chain on the chitin structure , to fertilize the growth of the turf . the other factor is the destruction of growth - inhibiting pathogens in the soil ( e . g ., fungi ) through action of chitinase enzymes elaborated by the organisms which were stimulated to grow by the presence of chitin in the biogard ferment . the pathogen destruction is brought about by penetration of structural elements ( e . g . hyphae ) of soil fungi , and the permeability of the resulting structures to the bi - directional flow of critical elements from and into their cells . this example demonstrates the induced generation of antifungal microflora in soil by addition of chitin to an aqueous soil dispersion , such induction being noted through a comparison of the microfloral distribution in the initial soil with that of the incubated soil / chitin broth . specifically , 1 . 0 gram ( dry weight ) portions of the soil sediment of the biogard broth prepared for example 1 , and a comparable fresh soil sample were individually shaken with 5 ml of tap water for a few seconds , then centrifuged to obtain the mother liquors . these were serially diluted to 10 - 4 , plated on noble agar containing 1 % finely - comminuted chitin , and incubated at ambient temperature for 4 days . a visual comparison was then made of the microbial populations in the biogard soil residue and the control soil . results : in comparison with the microflora distribution on the control plates , the microflora derived from the biogard chitin - digest soil showed a much greater preponderance of actinomycetes spp . this was most evident at the macroscopic levels by very strong geosmine smell in both the fermentation and the soil samples treated with chitin . control soil did not smell of geosmine at all and the biogard sample was made from the control soil and chitin . geosmine is the compound which accounts for the strong earthy smell found right after it rains . it is also characteristic of mushroom prone soil and is referred to as the odor associated “ la terre des champignons ” in france and is an olifactive clue to the possible presence of mushrooms in areas where the later are harvested . geosmine is released when actinomycete spores germinate . it is a compound which is specific to this class of microorganism and is unmistakable in its smell . actinomycetes are indigenous soil microbes that form long complex filaments in networks and produce fruiting bodies or asexual spores similar in microscopic appearance to structures found in fungi . like fungi , actinomycetes assist in soil clumping and cohesion . they also have a profound effect on soil micro - environments by releasing antimicrobial compounds and adding biomass which plays a significant role in soil structure properties . they are also key in the mineralization process and can degrade a wide variety of chemicals including some pesticides and hydrocarbons . in addition , insects and arthropods containing lesions brought on by chitinase can be opportunistically infected by actinomycete spores . the control sample flora were a rich variety of diverse fungal and bacterial colonies . this demonstrates that the addition of chitin to moist soil stimulates the growth of those organisms which can readily metabolize this substrate , through the elaboration of the chitinase enzymes necessary for its utilization as a food source . such organisms , e . g . the actinomycetes spp . noted here , are recognized antifungal species , by virtue of the chitinase activity associated with fungal destruction . this example demonstrates the insecticidal properties of an chitinase - elaborated microbial broth , derived from an aqueous soil dispersion containing comminuted chitin . specifically , the biogard ferment utilized in examples 1 and 2 , was sprayed as fine droplets onto 30 ants ( teramorium caespitum ) placed in a covered 100 × 15 mm petri dish . a control batch of 30 ants were similarly sprayed with a fine tap water spray . the ants were randomly selected from an “ ant - farm ” purchased through the mail from a toys - r - us ® store , and appeared stressed from shipping . the ants were allowed to remain in the covered dish for 24 hours , under ambient conditions , and were not fed during this period . results : after the one - day period , 12 of the 30 control ants had died , while all 30 of the test ants had died . this demonstrates that the soil / chitin - digest contained insecticidal materials , undoubtedly chitinase enzyme produced by the soil bacteria in the incubated soil - chitin digest . the chitnase attacks and partially digest the outer cuticle of the ants body , making it porous and susceptible to environmental pathogens , including soil bacteria . this example demonstrates that an aqueous soil digest , containing suspended chitin , will generate materials that can inhibit the germination of undesired , airborne seeds of a competitive species , which might fall on an established turf or lawn . specifically duplicate sets of 50 fescue seeds ( genus festuca ) were placed on 30 grams of moist soil ( 20 grams dry weight at 50 % water - holding capacity ) at the bottom of two - liter erlenmeyer flasks . to the test flask was added 0 . 2 gms , dry - weight basis , of the residue from a biogard digest equivalent to that described in the preceding examples . this residue , which represents 1 % of the 20 - gm of dry weight soil , was distributed uniformly over the soil bed . for the subsequent one - week period , both soils were maintained at a constant water - holding capacity , by periodic weighings and aqueous supplementation as needed . results : there was an 100 %- germination inhibition of the seeds in the biogard digest - treated test flask , whereas there was obvious germination of the seeds in the control flask . this example demonstrates that while a soil - chitin digest can stimulate ( i . e ., fertilize ) the growth of an established lawn , it can concomitantly inhibit the germination of potentially - competitive seeds which may have randomly deposited onto the soil bed . the inhibition probably results from the cidal action of digest - containing chitinase on the fungal species associated with the seeds , the involvement of which is a recognized and necessary component of seed germination . while only several embodiments of the present invention have been shown and described , it will be obvious to those skilled in the art that many modifications may be made to the present invention without departing from the spirit and scope thereof .

a method for controlling the growth of destructive insects and microorganisms in ground soil , includes the step of adding chitin to ground soil for inducing bacteria in the ground soil to synthesize chitinase for controlling the spread of destructive insects and microorganisms therein . the chitin may be added to the ground soil by distributing it on the upper surface of the soil or , preferably , by incorporating into the soil . in a preferred embodiment , the step of deacetylating the carbohydrate chains of the chitin for is carried out before adding to the ground soil for increasing the aqueous solubility of the chitin by producing smaller polymeric units or by increasing the availability of polar hydroxyl groups on glucosyl moieties thereof . various bacterial cultures may also be added to the chitin prior to its distribution on , or incorporation in , the ground soil . a method for using dried shrimp shells for the production of an economically - viable non - genetically - modified organism - based chitinase lawn and garden fermentation broth , for eventual addition to ground soil for controlling the growth of destructive insects and microorganisms in ground soil , is also provided .

referring first to fig1 there is shown an apparatus which comprises a receptacle in the form of a sac 1 made of caoutchouc or another suitable acid - resistant material . the dimensions of the receptacle 1 are selected in such a way ( or the receptacle can be collapsed to such an extent ) that it can be readily introduced into a body cavity , for example , through the urethra and through the urinary bladder into one of the ureters and , if necessary , all the way to or into the pelvis of a kidney . once introduced sufficiently close to a confined calculus ( such as a renal calculus ), the receptacle is expanded ( if necessary ) to receive and confine the calculus . a wall 2 of the receptacle 1 carries a deformable sealing element or closure 5 which can be inflated and / or otherwise manipulated to seal an inlet 3 of the receptacle as soon as the latter properly receives and confines a calculus . thus , the internal space of the receptacle 1 is then sealed from the kidney , from the respective ureter and from all surrounding tissue . the means for actuating the closure 5 to cause the latter to assume the closing or sealing position of fig2 includes a conduit 4 which extends from the proximal end of the receptacle 1 to the exterior of the body of a patient and is connected with or is connectable to a small pump 10 , e . g ., a syringe , which can be actuated by hand or otherwise to seal the inlet 3 of the receptacle 1 by inflating and / or otherwise influencing the closure 5 . the inlet 3 is sealed to such an extent that it prevents any flow , or any appreciable flow , of fluids from and / or into the internal space of the receptacle 1 by way of the inlet 3 . this is important when the nature of a solvent which is used to dissolve a confined calculus is such that it could cause much damage to the tissue around the fully inserted receptacle 1 and / or to the adjacent organ . the means for circulating an acid solvent or another suitable solvent through the receptacle 1 ( while the latter contains a calculus and while its inlet 3 is sealed by the closure 5 ) comprises two solvent - resistant conduits 6 , 7 , which are connected to the proximal end of the receptacle and extend from the animal body , e . g ., from the body of a human patient . the means for admitting solvent via conduit 6 comprises a first pump 8 ( e . g ., a syringe ) which can constitute a source of solvent , and the means for evacuating solvent and dissolved calculus from the internal space of the receptacle 1 through the conduit 7 comprises a second pump 9 ( e . g ., a syringe ). the pumps 8 and 9 are located outside of the body cavity . the conduits 4 , 6 and 7 can be designed and coupled to each other in such a way that they constitute ( or form part of ) the means for introducing the receptacle 1 into a selected portion of a body cavity , e . g ., into the pelvis of a kidney or into one of the ureters . it is clear that the pump or syringe 8 and / or 9 can be replaced with other suitable means for respectively introducing a solvent into and for evacuating solvent and dissolved calculus from the sealed receptacle 1 . for example , and as shown in fig6 the pump 8 can be replaced with a first infusor vessel 108 which is disposed at a first level to admit a solvent into the conduit 6 by gravity flow , and the pump 9 can be replaced by a second vessel 109 located at a second level below the first level and serving to receive spent solvent and dissolved calculus through the conduit 7 . when the apparatus of fig1 is in actual use , i . e ., when a calculus is already confined in the internal space of the receptacle 1 and the inlet 3 of this receptacle is properly sealed by the closure 5 , the pump 8 is actuated first to admit a selected quantity of solvent through the conduit 6 . the next step involves actuation of the pump 9 in a sense to draw a mixture of spent solvent and the already dissolved portion of the calculus through the conduit 7 . these procedures are thereupon repeated as often as necessary in order to complete the dissolution and evacuation of the entire calculus . the next step can involve replacement of the pump 8 or 9 with a pump which contains a supply of flushing liquid and replacement of the pump 9 or 8 with a pump which can receive spent flushing liquid . when the flushing of the interior of the receptacle 1 is completed , the receptacle is collapsed ( e . g ., deflated simultaneously with deactivation of the closure 5 ) and the receptacle , its closure and the conduits 4 , 6 and 7 are then ready for withdrawal from the body of a patient . it is clear that the circulating means with two conduits 6 and 7 constitutes but one of a variety of circulating means which can be utilized for the practice of the present invention . for example , the conduit 6 or 7 can be omitted and the apparatus then employs two pumps ( e . g ., the pumps 8 , 9 ) or two vessels ( e . g ., 108 , 109 ) one of which is attached to the proximal end of the conduit 6 or 7 to admit a supply of solvent and the other of which thereupon replaces the one pump or vessel to receive spent solvent and dissolved calculus . such alternating admission of solvent into and evacuation of a mixture of solvent and dissolved calculus is repeated as often as necessary , i . e ., until the evacuation of the fully dissolved calculus is completed . it is further clear that the receptacle 1 need not be flushed prior to extraction from the body of a patient . for example , if the inlet 3 can remain sealed and the receptacle can be adequately collapsed or contracted for convenient withdrawal from a body , the flushing operation can be carried out upon extraction of the receptacle , e . g ., through the urethra . fig2 shows the receptacle 1 ( which resembles a relatively short hose or tube ) in expanded condition . the closure 5 is shown in operative or actuated condition , i . e ., it seals the inlet 3 from the surrounding area . the receptacle 1 and / or the closure 3 has twin walls to define a path for admission of a fluid from the pump 10 and through the conduit 4 in order to expand the receptacle and / or to move the closure 5 to the sealing position . lifting of the plunger of the pump 10 will result in a collapse of the receptacle 1 and / or in retraction or collapse of the closure 5 to an inoperative position so that the inlet 3 is exposed and the receptacle is ready for extraction from the body of a patient or for reception of a calculus . fig3 shows a portion of another apparatus which employs a thin - walled receptacle 1 adapted to be twisted into a practically solid elongated flexible member ready to be introduced into a body cavity . the properly introduced twisted member 1 can be expanded to receive a calculus in response to admission of a fluid through at least one of the conduits 4 , 6 , 7 . for example , the twisted receptacle 1 of fig3 can be introduced all the way into one of the ureters or all the way into the pelvis of a kidney . by way of example only , when expanded the receptacle 1 of fig3 can have a diameter of 0 . 8 to 1 . 5 cm . fig4 illustrates a portion of a further apparatus wherein the means for inducing expansion or collapse of an elongated tubular receptacle 1 includes a further pump 11 ( e . g ., a syringe ) connected to the proximal end of the receptacle by a further flexible conduit 12 . the receptacle 1 of fig4 has a twin wall 15 which defines an annular compartment serving to receive a supply of gaseous or liquid fluid in order to expand the receptacle subsequent to introduction into close proximity of a calculus . the structure of fig4 can be used to calibrate the receptacle 1 , i . e ., to select the diameter of the expanded receptacle for dissolution of a particular calculus . the closure or sealing element 5 is or can be designed in such a way that it automatically seals the inlet 3 in response to expansion of the receptacle 1 . alternatively , and as actually shown in fig4 the sealing element 5 can be actuated by a fluid which is to be admitted through the conduit 4 . fig5 shows a further receptacle 1 which can be expanded in response to admission of a fluid medium through the conduit 12 and into a helical conduit 16 which surrounds the wall of the receptacle . such receptacle need not have a twin wall . furthermore , the helical conduit 16 can be replaced by or used jointly with conduits extending in substantial parallelism with the axis of the tubular receptacle 1 to ensure that the receptacle expands in response to admission of a suitable fluid through the conduit 12 . fig3 a shows a portion of a cable 14 which replaces the conduits 4 , 6 and 7 or 4 , 6 and 12 or 4 , 7 and 12 . furthermore , this cable can be replaced with a cable defining four passages , i . e ., with a cable which can be used in lieu of conduits 4 , 6 , 7 and 12 . an advantage of the cable 14 or an equivalent cable is that it contributes to convenience of introduction of the receptacle 1 into an animal body . for example , the diameter of the cable 14 can be in the range of 2 mm which is not much more than the diameter of the conduit 4 , 6 , 7 or 12 . an important advantage of the improved method and apparatus is that the removal of a calculus is nearly painless . thus , the path to a calculus must be expanded just sufficiently to permit introduction of the collapsed receptacle 1 into close proximity to the calculus which is to be removed ( dissolved ). the receptacle 1 is thereupon expanded to an extent which is necessary to permit introduction of the calculus through the unsealed inlet 3 , and the sealing element or closure 5 is thereupon actuated to seal the inlet . the apparatus is then ready to start with dissolution of the calculus in the internal space of the receptacle 1 . withdrawal or extraction of the apparatus is equally painless since the receptacle 1 can be collapsed to a fraction of its maximum diameter to be thereupon withdrawn from the cavity . another important advantage of the improved apparatus is that the solvent cannot come in contact with the tissue and / or with one or more organs . this enhances the safety of the calculus removing operation while permitting the use of a highly effective solvent which can complete the dissolution of a confined calculus within a short interval of time . all that is necessary is to make the receptacle 1 , its closure 5 and the conduits 6 and 7 of a material which can stand the action of the solvent and of a mixture of solvent with dissolved calculus . a further important advantage of the improved apparatus is that the introduction of the preferably collapsible receptacle 1 into and its extraction from a body cavity can be completed within a short interval of time . the same applies for introduction of a calculus into the internal space of the properly inserted and positioned receptacle 1 . such manipulation of the receptacle and of a calculus at the inlet 3 can be monitored by an ultrasonic or x - ray apparatus . the person in charge manipulates the introducing means ( such as the cable 14 or the conduits 4 , 6 , 7 or 4 , 6 , 7 and 12 ) to ensure that the partly or fully expanded receptacle 1 slides over and around the calculus so that the latter can be sealingly confined in the internal space of the receptacle as soon as the closure 5 is actuated to assume its closed or sealing position . the improved apparatus is susceptible of numerous additional modifications without departing from the spirit of the invention . for example , the closure or sealing element 5 can constitute an inflatable and deflatable balloon which can be inflated by way of the conduit 4 or by resorting to a separate hollow flexible catheter , not shown . for example , the medium which is used to inflate the closure 5 can be atmospheric air . each of the conduits 4 , 6 , 7 and 12 can constitute a hollow catheter . it is advisable to employ a solvent which ensures complete dissolution of a calculus . this eliminates the danger of clogging the conduit 7 with particles of a calculus which would prevent rapid and predictable evacuation of solvent and calculus from the internal space of the receptacle 1 . a further important advantage of the improved apparatus is that it is not necessary to raise the pressure in the receptacle 1 to a relatively high level . in fact , the only rise of pressure which is necessary is that which ensures adequate expansion of an expandible or collapsible receptacle and / or adequate sealing action of an inflatable closure 5 . the admission of solvent into and evacuation of solvent and of dissolved calculus from the receptacle 1 can take place during successive stages of treatment so that the pressure in the internal space of the receptacle ( i . e ., in the space which receives a calculus ) rises very little or not at all . the same holds true when the pumps 8 and 9 are replaced with the vessels 108 and 109 of fig6 . the vessel 108 can be placed above the body of the patient and the vessel 109 is then placed to a level sufficiently below the level of the vessel 108 to ensure that the solvent can flow through the receptacle 1 without any , or without any appreciable , rise of pressure in the space for the confined calculus . the means for flushing the receptacle 1 upon completed dissolution of a calculus therein can include a neutral liquid or a suitable buffering solution . such flushing renders it possible to open the inlet 3 of the receptacle 1 prior to extraction of the apparatus from the body of a patient . the solvent can be an acid or an alkaline solution . the exact composition of the solvent will be selected in dependency on the composition of the calculus and / or upon the size of the calculus . the utilization of an expandible and contractible ( e . g ., twistable ) receptacle 1 constitutes an optional but highly desirable feature of the improved apparatus . such collapsible receptacle can be utilized with advantage for removal of renal calculi . thus , the receptacle will be collapsed to permit rapid and convenient passage through the urethra , through the urinary bladder and thereupon through an ureter , and the receptacle is thereupon expanded ( either entirely or in part ) prior to or after introduction into the pelvis of a kidney to permit convenient introduction of a calculus through the exposed inlet 3 . twisting of a receptacle 1 in a manner as shown in fig3 is particularly simple and advantageous when the wall or walls of the receptacle are very thin so that the latter can be collapsed into a slender elongated member having a surprisingly small diameter . untwisting of the receptacle can be effected by resorting to an expanding operation , e . g ., with the pump 11 and conduit 12 of fig4 . in other words , it is possible to combine mechanical and pneumatic or hydraulic collapsing actions to ensure the deformation of the receptacle into a member adapted to be rapidly and painlessly introduced into a body cavity close to a calculus which is to be removed by dissolving it in a suitable liquid . without further analysis , the foregoing will so fully reveal the gist of the present invention that others can , by applying current knowledge , readily adapt it for various applications without omitting features that , from the standpoint of prior art , fairly constitute essential characteristics of the generic and specific aspects of my contribution to the art and , therefore , such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the appended claims .

apparatus for removing kidney stones or other calculi from the cavities of animal bodies by litholysis has an expandible and collapsible receptacle of acid - resistant material and a mechanism for introducing the receptacle into a cavity so that an inlet of the receptacle admits the calculus to be removed . a closure is thereupon actuated from the outside of the animal body to seal the inlet prior to circulation of an acid solvent through the thus sealed receptacle . the acid dissolves the calculus , and the dissolved calculus is evacuated from the receptacle with the solvent . the receptacle is thereupon flushed and collapsed to facilitate its extraction from the cavity . the circulating system can employ a solvent - admitting first conduit , a solvent evacuating second conduit , and discrete pumps one of which admits fresh solvent into the first conduit and the other of which draws solvent and dissolved calculus from the second conduit . a single conduit can be used for alternating admission of fresh solvent into and evacuation of solvent and dissolved calculus from the receptacle . it is also possible to employ a solvent - containing bottle which is connected to the first conduit and is located at a first level , and a second bottle which is located at a second level below the first level and is connected with the second conduit to receive solvent and dissolved calculus .

detailed in fig1 - 5 is food presentation module 10 of the present invention . as depicted , module 10 includes a frame 12 having a generally planar upper surface 14 from which multiple wells 18 ( see fig6 ) depend . although module 10 is shown as having four such wells 18 a - d , more or fewer wells 18 may be incorporated instead . adjacent wells 18 typically are spaced distance d1 along length l of module 10 , with d1 preferably being approximately three inches and l preferably being approximately fifty - eight and one - half inches . again , however , values of d1 and l different from these preferred values may be selected . ( indeed , although the value of d1 preferably is uniform between adjacent wells 18 of a module 10 , it need not necessary be uniform and instead may vary along length l .) fig6 illustrates , in cross - section , certain aspects of well 18 . well 18 may comprise generally vertically - extending interior walls 22 connected by bottom or floor 26 . four such walls 22 typically are present in well 18 , with three ( 22 a - c ) of the four shown in fig6 . well 18 additionally may comprise four exterior walls 30 , again with three ( 30 a - c ) of these walls being shown in fig6 . each exterior wall 30 preferably is spaced a distance d2 from its corresponding interior wall 22 so as to form an insulative air gap a therebetween . a preferred value for d2 is two inches , although it may differ from the preferred value as desired . upper surface 36 may interconnect the various interior and exterior walls 22 and 30 , respectively . additionally , well 18 preferably — although not necessarily — is formed of stainless steel . because each well 18 lacks a lid or door , bulk food placed therein is ( intentionally ) exposed to the ambient environment for easy access by consumers . positioned within air gap a may be one or tubes coils or pipes 40 . such pipes 40 advantageously contact external sides 44 of interior walls 22 for more efficient transfer of thermal energy between the pipes 40 and well 18 . three pipes 40 a - c are depicted in fig6 spaced along height h of well 18 , although greater or fewer such pipes 40 may be employed instead . likewise , although pipes 40 a - c preferably are made of copper and approximately one - half inch in diameter , other materials and sizes may be utilized instead . also detailed in fig6 is the non - flat nature of floor 26 . floor 26 may comprise multiple areas 46 a - d , with areas 46 a and 46 d being generally flat . between areas 46 a and 46 d , in area 46 b floor 26 rises to its highest level ( at hl ) before sloping in area 46 c down to the level of area 46 d . one or more drains preferably is located in area 46 d of floor 26 so as to allow fluid to exit well 18 . attached to interior surface 48 of floor 26 may be thermal blanket 52 . blanket 52 beneficially is made of silicone rubber so as to provide good heat transfer therethrough . other heat conducting materials may be used instead , however . a vulcanization process is preferred for attaching blanket 52 to floor 26 , although other processes or connection mechanisms may be employed . captured between blanket 52 and floor 26 is at least one heating mechanism , preferably an electrical - resistance type element . blanket 52 disperses heat from the element into well 18 relatively efficiently and uniformly , reducing likelihood of substantial heat leakage into adjacent wells 18 . similarly , air gaps a help reduce thermal leakage ( from either or both of blanket 52 and pipes 40 ) from a well 18 into adjacent wells . heating and cooling of any well 18 may occur regardless of the thermal status of any other well 18 within module 10 . electronic system controls 56 exist for each well 18 of a module 10 . fig2 illustrates an exemplary interface plate for four controls 56 a - d , with one control present for each of wells 18 a - d . hence , if a particular well ( e . g . well 18 a ) of module 10 is to be heated , its associated control 56 a may be used to connect the heating element in floor 26 of well 18 a to a source of electricity . such source typically will be an electrical outlet of the building housing module 10 , although it conceivably could be a battery or other source located within module 10 itself . conversely , if the particular well 18 a is to be cooled , control 56 a may be employed to operate condensing unit 60 in a manner causing refrigerant to flow through pipes 40 contacting interior walls 22 of the well 18 a . normally only one condensing unit 60 is needed for a module 10 ; in such case , it need merely be configured so that valving precludes refrigerant flow through pipes 40 not intended to be actively cooling at any given time . controls 56 a - d may , if desired , display or otherwise provide real - time temperature information about their corresponding wells 18 a - d . also if desired , they additionally may prevent concurrent heating and cooling of a well 18 so as to avoid inadvertent waste of energy . in at least one version of module 10 , well 18 has dimensions of approximately 12 ″× 20 ″× 6 ″ and is designed to receive a foodstuff - containing pan . consistent with various standards such nos . 4 and 7 of the nsf , each well 18 readily may maintain the foodstuff at 150 ° f . ( for product needing to be heated ) or at 41 ° f . ( for product needing to be refrigerated ). indeed , tests indicate that , with one well 18 maintaining foodstuff at 150 ° f ., an adjacent well 18 may maintain cold food at 10 ° f . or less . module 10 thus provides a versatile , multi - purpose device capable of simultaneously presenting hot food , cold food , and combinations thereof in bulk for ready access by consumers , who select portions of the food for placement on their individual plates . further , module 10 may in some cases be employed for purposes other than food presentation . indeed , module 10 may be useful in presenting other materials that need heating or cooling . preferably , module 10 has its positioned fixed and is generally immobile in use , although it may include castors or wheels enabling its movement between uses . the foregoing is provided for purposes of illustrating , explaining , and describing embodiments of the present invention . modifications and adaptations to these embodiments will be apparent to those skilled in the art and may be made without departing from the scope or spirit of the invention .

thermally convertible food presentation modules are described . a single module may be used for both heating and refrigeration of foodstuffs as desired at any given time . any well of a module may be switched between heating and cooling of food regardless of the status of any other well of the module .

referring initially to fig1 a laser system 10 is shown for conducting a laser procedure on the eye 12 of a patient 14 . as shown , the eye 12 of the patient 14 is aligned to receive a plurality of pulsed laser beams from the laser system 10 . as detailed further below , a plurality of pulsed laser beams that are preferably centered substantially along axis 16 are simultaneously focused by the laser system 10 to focal points within the eye 12 of the patient 14 to photoalter stromal tissue . in accordance with the present invention , the photoalteration can be performed to create a flap suitable for a lasik type procedure , to effect a refractive change in the cornea , to create a passageway or drainage channel in the eye 12 , or to effect any other type of surgical procedure , in whole or in part , known in the pertinent art that requires either the incision or removal of ocular tissue . [ 0022 ] fig2 shows the anatomical structure of the human eye 12 including the cornea 18 , the pupil 20 , the iris 22 , and the sclera 24 . in fig3 it can be seen that the cornea 18 includes five anatomically definable layers of tissue . going in a direction from anterior to posterior in fig3 the tissue layers of the cornea 18 are : the epithelium 26 , bowman &# 39 ; s membrane 28 , the stroma 30 , decemet &# 39 ; s membrane 32 and the endothelium 34 . of these , the stroma 30 is the thickest layer and contains the stromal tissue that is of general importance for the present invention . specifically , the removal or destruction of stromal tissue is recognized as an effective way to reshape the cornea 18 and thereby effect a refractive change to the cornea 18 . additionally , creation of a flap suitable for use in a typical lasik procedure requires the incision of stromal tissue . referring now to fig4 an embodiment of a laser system 10 is shown . as shown , the laser system 10 includes a laser source 36 for producing a pulsed laser beam 38 . for purposes of the present invention , a pulsed laser beam 38 preferably has physical characteristics similar to those of the pulsed laser beams generated by a pulsed laser source as generally disclosed and claimed in u . s . pat . no . 4 , 764 , 930 , which issued to josef f . bille et al . for an invention entitled “ multiwavelength laser source .” furthermore , the present invention contemplates the use of a pulsed laser beam 38 having a pulse frequency of approximately 4 khz with pulse durations as long as a few nanoseconds or as short as only a few femtoseconds . preferably , the pulsed laser beam 38 has pulses with durations between approximately ten femtoseconds and five picoseconds ( 10 fsec — 5 psec ), and a wavelength longer than approximately nine hundred nanometers ( 900 nm ). also , the pulsed laser beam 38 preferably has a fluence of less than one hundred joules per square centimeter (& lt ; 100 j / cm 2 ). with these characteristics , the pulsed laser beam can be focused to a focal point having a diameter of approximately ten micrometers ( 10 μm ) that has an average pulse energy of approximately sixty microjoules ( 60 μj ). referring now with cross reference to fig4 and 5 , it can be seen that the laser beam 38 produced by the laser source 36 is directed into a lenslet array 40 having seven lenslets 42 a - g . it is to be appreciated that the seven lenslets 42 a - g partition the laser beam 38 into seven spaced apart beams , three of which ( i . e . beams 44 a - c ) are shown in fig4 . as shown in fig5 the lenslet array 40 is preferably constructed having six lenslets 42 a - f arranged about a circle surrounding a center lenslet 42 g . preferably , the lenslets 42 a - f have a diameter 41 of approximately two millimeters ( 2 mm ), and are close packed , as shown , within a circle having a diameter 43 of approximately six millimeters ( 6 mm ). from the lenslet array 40 , the beams 44 a - c are first directed into a negative field lens 46 to diverge the beams 44 a - c , thereby creating diverging beams 48 a - c . from the field lens 46 , the diverging beams 48 a - c are directed to a collimating lens 50 to place the seven beams onto parallel beam paths . next , the collimated beams 52 a - c are directed through relay lens 54 and relay lens 56 for magnification . as shown , the relay lenses 54 , 56 are arranged as a telescope to magnify the collimated beams 52 a - c . preferably , the relay lenses 54 , 56 are configured to magnify the collimated beams 52 a - c at a magnification of approximately 8 : 1 . referring still to fig4 it can be seen that after passing through the relay lenses 54 , 56 , the magnified beams 58 a - c are directed to a focusing lens 59 ( i . e . a cutting lens ) to focus each of the magnified beams 58 a - c to a separate focal point 60 a - c . with cross - reference now to fig4 and 6 , it can be seen that a cluster 61 of seven focal points 60 a - g is established . like the lenslet array 40 ( shown in fig5 ), the cluster 61 of focal points 60 a - g is preferably arranged with six focal points ( 60 a and 60 c - g ) distributed uniformly around a circle with the seventh focal point 60 b positioned at the center of the circle . preferably , focal points 60 a - g having a diameter 62 of approximately ten micrometers ( 10 μm ) are formed by the laser system 10 and have an average energy of approximately five microjoules ( 5 μj ), rendering each focal point suitable for photoalteration of stromal tissue . further , in the preferred embodiment of the present invention , the six focal points ( 60 a and 60 c - g ) are arranged in a circle having a diameter 64 of approximately one hundred micrometers ( 100 μm ), ensuring that each focal point 60 a - g is spaced from the remaining focal points 60 a - g by a distance 66 of at least approximately twenty micrometers ( 20 μm ). this spacing assures adequate heat dissipation during photoalteration , thereby preventing heat damage to non - target tissue . referring now to fig4 it can be seen that a scanner 68 is preferably interposed between relay lens 54 and relay lens 56 . for the present invention , any scanner known in the pertinent art for controlling the movement of a plurality of laser beams can be used . cross referencing now to fig4 and 7 , it can be seen that the scanner 68 is provided to move the cluster 61 of focal points 60 through the cornea 18 ( such as in the direction of arrow 69 in fig7 ). preferably , the cluster 61 is scanned at a rate such that the cluster 61 is positioned at a location requiring photoalteration for approximately { fraction ( 1 / 4000 )} th of a second ( for a 4 khz laser source ). as such , approximately one pulse of energy will be focused at each focal point 60 , for each location that is photoaltered . for example , for the creation of a ten millimeter ( 10 mm ) flap 67 as shown in fig8 approximately 200 , 000 points in the stroma 30 require photoalteration . for a cluster 61 having seven focal points 60 , approximately 30 , 000 locations require photoalteration . thus , for this example , the scanner 68 is configured to scan the ten millimeter ( 10 mm ) area in approximately seven to eight seconds . alternatively , the cluster 61 of focal points 60 can be scanned within the stroma 30 to photoalter a volume of stromal tissue ( such as volume 72 shown in fig3 ) to effect a refractive change in the cornea 18 . [ 0027 ] fig9 shows another embodiment of a laser system 10 ′ in accordance with the present invention . for clarity , the prime (′) has been used to denote elements in fig9 that are similar or identical in nature to like - numbered elements in the embodiment shown in fig4 . as shown in fig9 a laser source 36 ′, as described above is used to direct a pulsed laser beam 38 ′ to an active mirror 70 . preferably , an active mirror 70 having approximately 40 , 000 active facets is used . as shown , the active mirror 70 is configured to reflect the pulsed laser beam 38 ′ into seven , spaced apart diverging beams , of which three ( 48 a ′- 48 c ′) are shown in fig9 . it is to be appreciated by those skilled in the art that one or more optical prisms ( not shown ) can be substituted in place of the active mirror 70 to partition the pulsed laser beam 38 ′ into diverging beams . referring still to fig9 from the active mirror 70 , the diverging beams 48 a ′- 48 c ′ are directed to a collimating lens 50 ′ to place the seven beams onto parallel beam paths . next , the collimated beams 52 a ′- 52 c ′ are directed through relay lens 54 ′ and relay lens 56 ′ for magnification . from the relay lenses 54 ′, 56 ′, the magnified beams 58 a ′- 58 c ′ are directed to a focusing lens 59 ′ to focus each of the magnified beams 58 a ′- 58 c ′ to a separate focal point 60 a ′- 60 c ′. scanner 68 ′ is provided to simultaneously move all the focal points 60 a ′- 60 c ′ during the procedure . while the particular laser beam delivery system with multiple focal points 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 .

an optical system for partitioning and focusing a laser beam into a plurality of focal points to simultaneously photoalter corneal tissue at a plurality of locations includes a laser source . in one embodiment , an active mirror is used to partition the master beam into diverging beams . in another embodiment , a lenslet array in combination with a field lens is used to partition the master beam into seven diverging beams . the resultant diverging beams are then collimated , magnified and focused into a plurality of focal points using a set of optical lenses . each focal point has an average pulse energy of approximately 5 μj rendering it suitable for subsurface photoalteration of corneal tissue . a scanning mechanism is provided to move the plurality of focal points , as a group , along a predetermined path through the cornea to quickly and safely photoalter a predetermined volume of subsurface corneal tissue .

a preferred embodiment of a centrifugal blood pump 10 of the present invention is shown in fig1 - 4 . blood pump 10 includes housing 12 which encloses impeller 14 and support shaft or spindle 16 . impeller 14 and spindle 16 rotate about axis of rotation 18 . housing 12 has separate parts for ease of assembly , including upper enclosure 12a and base 12b , which are connected and sealed together , such as by ultrasonic welding . upper enclosure 12a includes inlet wall 20 , circumferential wall 22 , inlet 24 , and outlet 26 . base 12b includes bottom wall 28 , cylindrical side wall 30 , mounting flange 32 , and pedestal 34 . pumping chamber 36 ( fig4 ) is defined as the volume enclosed by inlet wall 20 , circumferential wall 22 and bottom wall 28 . inlet 24 is a j - shaped tubular member which has one end 38 attached to inlet wall 20 and an opposite free end 40 . ridge 42 on an outer surface of inlet 24 facilitates attachment of inlet tubing ( not shown ) from a reservoir / oxygenator or from the patient to free end 40 of inlet 24 . outlet 26 is a tubular member which extends from circumferential wall 22 to free end 44 . ridge 46 , adjacent free end 44 , facilitates attachment to outlet 26 of outlet tubing ( not shown ) which leads to the patient . as shown in fig3 a , impeller 14 rotates about axis of rotation 18 with a direction of rotation indicated by arrow r . impeller 14 has full impeller blades 48 and short impeller blades 50 which are attached to platform section 52 of impeller 14 . platform section 52 is disk - shaped and includes top surface 54 , bottom surface 56 , outer cylindrical surface 58 and central circulation hole 60 . full blades 48 extend from hub 62 across central circulation hole 60 to platform section 52 , while short blades 50 extend only along top surface 54 of platform section 52 . as shown in fig3 b , bottom surface 56 of platform section 52 contains a plurality of radial grooves 63 . the purpose of grooves 63 is to counteract a tendency of impeller 14 to shift in the axial direction toward inlet 24 as impeller 14 rotates . fig4 shows impeller 14 attached to spindle 16 , so that impeller 14 and spindle 16 rotate together about axis of rotation 18 . inlet end 16a of spindle 16 extends into and rotates within journal bearing 64a . base end 16b of spindle 16 extends into and rotates within journal bearing 64b . the constraining mechanism of the present invention is provided by journal bearings 64a and 64b , which capture and support spindle 16 while permitting spindle 16 to rotate . journal bearings 64a , 64b are disposed coaxially with and circumferentially around axis of rotation 18 . journal bearing 64a is press fit into recess 66 in the interior side wall of inlet 24 . journal bearing 64b is press fit into recess 68 in pedestal 34 . the inner diameters of the recesses of journal bearings 64a and 64b are slightly greater than the outer diameters of the respective ends 16a , 16b of spindle 16 , so that a small lateral clearance is defined . the distance between the inner end surfaces of journal bearings 64a , 64b is slightly greater than the length of spindle 16 , defining a small axial clearance . platform section 52 of impeller 14 contains magnets 70 , which couple with magnets 72 carried by rotor 74 , to rotate impeller 14 and spindle 16 about axis of rotation 18 . electric motor drive shaft 76 is connected to rotor 74 and provides torque to rotate magnets 72 and rotor 74 about axis of rotation 18 . magnets 70 and 72 couple together so that impeller 14 rotates at the same speed as rotor 74 . the speed of drive shaft 76 , therefore , determines the speed of impeller 14 . impeller 14 is attached to spindle 16 such that bottom surface 56 of platform section 52 is a small distance above bottom wall 28 . impeller 14 fits within pumping chamber 36 to leave clearance between the top and sides of impeller 14 and upper enclosure member 12a . housing 12 is shown in fig4 adjacent thin mounting surface 78 . housing 12 includes mounting flange 32 , which may facilitate attachment of the housing 12 to the mounting surface 78 . housing 12 may be attached to the mounting surface 78 by an attachment mechanism ( not shown ) so as to provide correct positioning of the blood pump 10 with respect to the external source of rotation ( i . e ., rotor 74 and magnets 72 ). blood from the patient enters pumping chamber 36 through inlet 24 . as it enters pumping chamber 36 , inlet flow is in the axial direction at axis of rotation 18 . this orientation and location of inlet flow allows the blood to make a gentle directional transition without placing excess forces on the blood . the blood contacts rotating impeller blades 48 and 50 , and is propelled to and through outlet 26 and back to the patient . blood pump 10 of the present invention is magnetically driven by a source of rotation which is external to pumping chamber 36 . therefore , blood pump 10 of the present invention does not have a torque - providing shaft or other part extending through a wall of housing 12 . this eliminates the need for a seal and the possibility of seal wear and leakage . the possibility of dislocation or misalignment of impeller 14 is prevented by spindle 16 being constrained in the axial and the lateral directions by journal bearings 64a and 64b . bottom surface 56 of impeller 14 does not contact bottom wall 28 , preventing any friction between these surfaces . the clearance between the top and sides of impeller 14 and enclosure 12a likewise prevents any friction between these surfaces . the structure of the constraining mechanism reduces the amount of friction between the rotating spindle 16 and the housing 12 . the small lateral clearance between the ends 16a , 16b of spindle 16 and journal bearings 64a , 64b allows for slight lateral movement of spindle 16 and ensures minimal pressure between parts . this allows minimal friction and minimal heat buildup between ends 16a , 16b of spindle 16 and journal bearings 64a , 64b . the small axial clearance between ends 16a , 16b of the spindle 16 and the inner end surfaces of journal bearings 64a , 64b ensures minimal pressure between parts , again reducing friction and heat buildup . bearings 64a , 64b of the present invention are located in areas of high blood flow velocity . base journal bearing 64b is located by pedestal 34 in the center of central circulation hole 60 . inlet journal bearing 64a is located in inlet 24 , and is exposed to the inlet flow of blood into pumping chamber 36 . the location of bearings 64a , 64b ensures rapid dissipation of any frictional heat that is created . mounting flange 32 allows blood pump 10 to be quickly and easily removed , and a new pump can be quickly and easily attached . quick and easy removal and attachment of the pump is useful for the frequent replacement necessary to ensure sterility . quick replacement also aids in the event of a pump malfunction . because the source of rotation does not have to be replaced with replacement of the rest of the pump , the cost of replacement is lowered . an important feature of blood pump 10 is the elimination of the requirement for a shaft seal . it was described previously that early failure of the shaft seal is the primary reason for the relatively short operational life of currently available centrifugal blood pumps . elimination of the shaft seal requires that bearings be designed which can operate effectively in blood . by using spindle 16 with a minimum diameter consistent with the required shaft strength , surface velocity is minimized . minimization of surface velocity also minimizes friction , frictional heat and shear forces , all of which can cause blood damage and clot formation . while a small diameter for spindle 16 is beneficial in reducing blood damage , it also reduces the areas of spindle 16 which serve as axial thrust bearings , namely at both ends 16a and 16b of spindle 16 . since pump 10 is driven by magnetic coupling , there is an axial load in the direction of the magnetic coupling ( i . e ., toward rotor 74 ) when pump 10 is at rest or operating at low speeds . the use of a magnetic coupling requires a close proximity of impeller magnet 70 and drive magnet 72 . therefore , the preferred design is to have impeller blades 48 and 50 only on the side of impeller 14 which faces the pump inlet 24 . this causes an asymmetrical axial flow across the two faces of impeller 14 and results in an increasing axial force toward pump inlet 24 as flow increases ( the &# 34 ; lifting force &# 34 ;). the required area of the axial thrust bearing and hence , the minimum diameter of is spindle 16 determined by this maximum axial load . as shown in fig3 b , the lifting force is preferably counteracted by placing radial grooves 63 in the base side of impeller 14 to increase the axial flow across this surface . the use of grooves 63 , rather than blades , does not require increased space between the driven and drive magnets 70 and 72 ( which would require more or stronger magnets to maintain the same coupling strength ). by proper selection of the number and depth of grooves 63 , pump 10 can be designed such that the lifting force &# 34 ; floats &# 34 ; impeller 14 such that , within the operating rpm of pump 10 , the axial load on both bearings 64a and 64b and both spindle ends 16a and 16b is minimal . this reduces frictional heat , blood damage and bearing wear . in a preferred embodiment , a groove 63 extends radially between adjacent magnets 70 of opposite polarity . this is illustrated in fig3 b by the polarity symbols &# 34 ; n &# 34 ; and &# 34 ; s &# 34 ;. an alternative embodiment of the present invention is shown in fig5 and 6 . this embodiment has journal bearing 64a disposed in the center of straight inlet tube 26 &# 39 ;. journal bearing 64a is supported in cup 90 by struts 92 , which extend from cup 90 to the inner wall of inlet 26 &# 39 ;. this allows inlet 26 &# 39 ; to remain straight ( rather than j - shaped as in fig1 ) while still providing inlet flow in the axial direction at axis of rotation 18 . although the present invention has been described with reference to preferred embodiments , workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention . for instance , a stationary pin going through a central hole in hub 62 of impeller 14 may be substituted for spindle 16 , such that the top side and the bottom side of impeller 14 are constrained from movement in the axial and lateral directions by the stationary pin , while impeller 14 remains free to rotate around the pin . also , in some embodiments grooves 63 are not required and therefore are omitted .

a centrifugal pump for pumping biological fluids such as blood includes a housing which defines a pumping chamber . the pumping chamber encloses an impeller mounted on a spindle . the impeller carries coupling mechanisms which couple with an external source of rotation to rotate the impeller . the spindle allows the impeller to rotate freely , but both ends of the spindle are constrained in the axial and lateral directions . the housing includes an inlet and an outlet .

referring to fig1 and also to the remaining figure drawings is shown , a headpiece ornament , identified in general by the reference numeral 10 . the headpiece ornament 10 may include any circular 10 a , oval 10 b , or other geometric shape 10 c that forms a continuous loop or ring when attached to a headpiece . the stock that is used to form the headpiece ornament 10 can include a circular , oval , or polygonal cross - section , as desired . it can be any size ( i . e ., diameter ) so as to make the headpiece ornament either more or less noticeable . the headpiece ornament 10 can be formed out of any desired material and be any overall size . on small headpieces , a smaller version of the headpiece ornament 10 ( i . e ., smaller diameter stock and / or a smaller overall diameter of the ornament 10 ) may be preferred , whereas on larger headpiece sizes and styles , a larger version of the headpiece ornament 10 ( i . e ., larger diameter stock and / or a larger overall diameter of the ornament 10 ) is preferred . headpieces of all types are suitable for use with the headpiece ornament 10 a portion of the types of headpieces that are available are shown in remaining drawing fig2 - 11 and include various types of hats , caps , sun visors , berets , beanies , wool hats , even cloth hanker chiefs or other cloth materials such as turbans that are worn around a portion of a head . the headpiece ornament 10 is intended to be included with all of these various headpieces as well as with any other type of a headpiece not shown . the term “ headpiece ” as used herein is intended to include any type of a garment that is worn proximate ( i . e ., in contact with ) the head of a person . the headpiece ornament 10 is primarily intended to be installed at the factory during manufacture of the headpiece . if the headpiece ornament 10 is formed of a metal ( gold , silver , platinum , or other types of metals or alloys ), then it is inserted through a hole that is provided in any of the headpieces ( or it is inserted through naturally occurring openings , for example in between the threads of a wool hat ). after insertion through the hole , the disparate ends of the ornament 10 are brought into contact with each other and are soldered or welded together so as to form a continuous loop . this ensures that the headpiece ornament cannot become lost , fall from the headpiece , or be misplaced . it remains with the headpiece . as such , manufacturers of the headpiece will likely welcome the benefits that are provided by the headpiece ornament in that their product lines are intended to become more distinctive and appealing to consumers . it is important that when the headpiece ornament 10 is installed on the headpiece that a continuous loop be attained . ordinary jewelry ( not shown ) includes a clasp that can become opened and lost . this is not suitable for use with the headpiece ornament 10 . if the headpiece ornament 10 were to fall of the headpiece , the consumer would not likely purchase it or would purchase a less expensive version . conversely , if the headpiece ornament 10 can never become separated apart from the headpiece , consumers are more apt to make such purchases , especially purchases that include more expensive variations of the headpiece ornament 10 . however , virtually any other type of material , including plastics or composite materials can also be used to form the headpiece ornament 10 . if these are used , the ends are fused or glued together . it is also possible to market the headpiece ornament 10 for retrofitting to existing headpieces ( i . e ., for after market sales ). because proper installation is important , the manufacturer of the headpiece ornament 10 may offer consumers the option to bring their favorite headpiece in to the ornament 10 manufacturer ( or an authorized agent or representative of the ornament 10 manufacturer ) for installation of the headpiece ornament 10 on their favorite headpiece in whatever location that they prefer . this provides great versatility to the consumer . installation of the ornament 10 on the headpiece is similar regardless of who installs it . the headpiece manufacturer must decide on the size , style , type , quantity , and location of the ornament 10 on the headpiece . the headpiece ornament 10 manufacturer , agent , or representative would assist the consumer in selecting the size , style , and material used for the headpiece ornament 10 . then both the headpiece manufacturer or the headpiece ornament 10 manufacturer , agent , or representative would form the hole ( or holes if more than one of the headpiece ornaments 10 is to be simultaneously applied , as is described below in greater detail ) where desired in the headpiece or in the favorite headpiece and do so in as safe a way as possible while also ensuring that the hole is of the proper size . for example , a punch could be used to perforate the headpiece with an opening ( i . e ., hole ) size that is precisely suited for the size of the headpiece ornament 10 that is selected . a tight fit between the headpiece ornament 10 and the headpiece itself prevents movement of the headpiece ornament 10 with respect to the headpiece , which in turn decreases wear of both the ornament 10 and the headpiece proximate the opening . the manufacturer of the headpiece or the headpiece ornament 10 manufacturer , agent , or representative would pass a first end of the headpiece ornament 10 through the opening and urge the first end adjacent to a second end of the ornament 10 . the body of the ornament 10 is then adjusted as necessary to ensure that the proper planar shape is attained , for example a circle , oval , triangle , or other polygonal shape . more complex shapes can also be included as part of the ornament 10 , if desired . finally , the headpiece manufacturer or the headpiece ornament 10 manufacturer , agent , or representative would attach the first and second ends of the headpiece ornament 10 together after insertion through the hole and secure each end together using whatever is the preferred method . solder , silver solder , gold solder , welding , fusing , epoxy , glue , and other methods are all possible depending upon the material used to form both the headpiece ornament 10 and also taking into account limitations concerning the headpiece itself and the desired appearance of the finished article . clearly , many other changes will become apparent to those as a result of having benefited from the instant disclosure . for example , more than one of the headpiece ornaments 10 can be used on any given headpiece as mentioned hereinabove . when more than one headpiece ornament 10 is used on the same headpiece , the size and shape of each one can also vary . accordingly , a way to personalize and accent the headpiece is provided that allows individual expression . after having benefited from the instant invention , many of the headpieces tend to appear mundane , even boring , without benefit of the headpiece ornament 10 . referring in particular now to fig2 , is shown the headpiece ornament 10 on a rim 12 of a hat 14 , the hat 14 being a type of headpiece . referring in particular now to fig3 , is shown the headpiece ornament 10 on a beret 16 , the beret 16 being an alternative type of headpiece . referring in particular now to fig4 , is shown the headpiece ornament 10 on a bill 18 of a cap 20 , the cap 20 being an alternative type of headpiece . referring in particular now to fig5 , is shown the headpiece ornament 10 on a rolled brim 22 of a wool hat 24 the wool hat 24 being an alternative type of headpiece . referring in particular now to fig6 , is shown the headpiece ornament 10 on a turban 26 , the turban 26 being an alternative type of headpiece . referring in particular now to fig7 , is shown a smaller size of the headpiece ornament 10 on a cloth headpiece 28 , the cloth headpiece 28 being an alternative type of headpiece . referring in particular now to fig6 , is shown a larger size of the headpiece ornament 10 on the cloth headpiece 28 of fig7 . fig7 and fig8 show by way of comparison that different sizes of the headpiece ornament 10 can be used on any given type of headpiece . referring in particular now to fig9 , is shown the headpiece ornament 10 on a bill of a stylish cap 30 , the bill facing to the rear of the wearer and the stylish cap 30 being an alternative type of headpiece . referring in particular now to fig1 , is shown the headpiece ornament 10 on an edge of the stylish cap 30 of fig9 . referring in particular now to fig1 , is shown the headpiece ornament 10 on the body of the stylish cap 30 of fig9 . by way of comparison , fig1 - 11 show how varying the location of the headpiece ornament 10 on the same headpiece can create and entirely different appearance or “ look ” thereby personalizing the appearance to match the mood of the wearer . it is also noted that when the headpiece ornament 10 is inserted into a brim or edge of the headpiece , that only one hole is required in the headpiece to accept the ornament 10 . however , when the headpiece ornament 10 is inserted into the body of the headpiece ( see fig1 ), then two adjacent openings ( i . e ., holes ) must be provided in the body , one to accept the entry of one side of the ornament 10 and the other to allow for its exit on the same side of the headpiece . if desired , the two openings can be located on a protruding fold of the headpiece ( so that the ornament 10 is flush with the surface of the headpiece ) or the two openings can be spaced apart from each other any desired amount . if desired , any other type of an item can also be attached to the headpiece ornament including items that are part of its structure or suspended from it . for example , precious stones , such as a diamond or diamonds , can be included with the headpiece ornament 10 as desired . the invention has been shown , described , and illustrated in substantial detail with reference to the presently preferred embodiment . it will be understood by those skilled in this art that other and further changes and modifications may be made without departing from the spirit and scope of the invention which is defined by the claims appended hereto .

an accent device for use with a headpiece includes a headpiece with at least one opening in the headpiece through which one end of the accent is inserted . an opposite end of the accent device is brought into contact with the one end and attached thereto . the accent device includes a structure that is disposed on a plane and can include any circular , oval , or polygonal shape . any other item , including jewelry can also be attached to the accent device . a method for permanently attaching an accent piece to a headpiece is also described .

in describing a preferred embodiment of the invention illustrated in the drawings , specific terminology will be resorted to for the sake of clarity . however , the invention is not intended to be limited to the specific terms so selected , and it is to be understood that each specific term includes all technical equivalents that operate in similar manner to accomplish a similar purpose . turning to the drawings , fig1 shows the display cart 5 of the present invention . the cart 5 has three primary components : a housing or base member or section 10 , an intermediate display member or intermediate section 20 and an upper member or upper section 30 . the display cart 5 has wheels attached to the trunk 10 , so that the cart 5 can be easily moved and loaded into a vehicle , such as a cargo van or the like . the base 10 is slidably engaged with the intermediate display section 20 , so that the intermediate display section 20 telescopes in a vertical direction with respect to the base 10 . similarly , the intermediate display section 20 is slidably engaged with the upper section 30 , so that the upper section 30 telescopes in a vertical direction with respect to the intermediate display section 20 and the base section 10 . the cart 5 has two positions : an operating position ( fig1 ) and a storage position ( fig2 ). in the operating position , the intermediate display section 20 and the upper section 30 are fully extended upward in the vertical direction . in the operating position , the shelves 24 of the intermediate display section 20 can be extended , and product placed on the shelves 24 for display to passersby . the upper section 30 protects the product and attendant from the sun and rain . in addition , the raised position of the upper section 30 draws attention to the cart 5 , and enables any advertisements located on the canopy 36 of the upper section 30 to be visible from a greater distance . the cart 5 preferably has a height of about eight feet in the operating position . in the storage position ( fig2 ), the intermediate display section 20 and the upper section 30 are fully withdrawn . the intermediate display section 20 is substantially located within an interior chamber or cavity of the base 10 . the upper section 30 is lowered to encase the top portion of the combined base 10 and intermediate display section 20 . a stop member 21 ( fig1 ) is provided on at least one of the side walls 22 which comes into contact with the upper edge of the base section 10 to prevent the intermediate section 20 from being lowered too far into the base section 10 . however , it should be appreciated that the intermediate section 20 need not protrude from the top of the base section 10 , but instead can be fully enclosed within the base section 10 . in the storage position , the cart 5 is compact for easy movement and storage . in the storage position , the cart 5 is especially designed to fit within a standard size cargo van for movement between various locations . accordingly , when the cart 5 is in the storage position , it preferably has a width of about 34 inches , a length of about 75 inches , and a height of about 3 feet . the base 10 has a height of about 22 inches , and the intermediate section has a height of about 20 inches . the cart 5 maximizes display space by minimizing the space required for the side walls 22 of the intermediate section 20 . thus , the shelves 24 extend substantially the entire length of the cart 5 , approximately 72 inches long . the trunk 10 is a rectangular , hollow metal container having side walls 14 . sliding doors 12 are located on the front of the trunk 10 which allow the user to gain access to the interior cavity of the base 10 . when the cart 5 is in the operating position , the cart attendant can store additional product or sales material in the base 10 . the doors 12 have a lock so that the doors 12 can be locked in the storage and operating positions . as best shown in fig4 - 6 , a rectangular elongated support post 16 is attached along the side wall 14 of the trunk 10 . the support posts 16 form a channel which extends vertically to receive and slidably engage a respective external post 26 of the intermediate display section 20 . the support posts 16 are hollow , to receive a first chain 46 used to raise and lower the intermediate display section 20 . turning back to fig1 the intermediate display section 20 is defined by two side walls 22 and shelves 24 which extend between the two side walls 22 . one or more of the shelves 24 are slidably engaged with the side walls 22 in a horizontal direction . thus , the shelves 24 can slide outwardly beyond the width of the base 10 when the cart 5 is in the operating position . conversely , the shelves 24 also slide inwardly to be narrower than the width of the base 10 to position the cart 5 in the storage position . when the shelves 24 are fully extended , they form tapered tiered layers , such that each shelf 24 is slightly above and behind the shelf 24 just below it . if shelves 24 are provided which extend outwardly at both the front and back of the cart 5 , as shown in the embodiment of fig1 the shelves 24 form a general pyramid shape . the shelves 24 are tapered to permit product to be placed on each shelf 24 without being obstructed from viewing by the shelves 24 above it . the shelves 24 are slidably connected to the side walls 22 in any conventional manner . in the preferred embodiment shown , the shelves 24 have a bottom and upright sides . sliding tracks with rollers are secured to the outside of the shelf sides and the inside of the side walls 22 . in the preferred embodiment shown in fig1 there are eight ( 8 ) shelves 24 , four of which are located at the front half of the cart 5 , and four which are located at the back half of the cart 5 . however , shelves 24 need not be provided on the front and back of the cart 5 . instead , shelves 24 can be provided which extend from the back to the front of the cart 5 , but only pull outward at the front of the cart 5 . in addition , any suitable number , size and shape of the shelves 24 can be provided without departing from the spirit and scope of the invention . the shelves are about 12½ inches wide . the top shelf 24 is fixed , and the second and third highest shelves slide out about 12 inches , with the lower of the two shelves positioned about 2 inches forward of the higher of the two shelves . the lowest shelf 24 slides out about 14 inches . preferably , the products are displayed on display cases that are retained on the shelves 24 . an example of a display case is shown in co - pending application ser . no . ______ , which is incorporated herein by reference . the shelves 24 have a front bar which prevents the cases from inadvertently being pulled or otherwise falling off of the shelf 24 , while allowing the case to be removed by an attendant to open the case and retrieve product stored in the case . returning to fig4 - 6 , h - shaped frame members 25 are provided at the center of each of the side walls 22 of the intermediate display section 20 . the h - frame 25 is formed by an external post 26 and an internal post 27 . the external post 26 forms a vertically extending guide , and engages the respective post member 16 of the base 10 . the intermediate external posts 26 are hollow to receive a second and third chain 48 , 49 used to raise and lower the upper section 30 with respect to the intermediate display section 20 . the top corners of the side walls 22 are beveled so that the side walls 22 do not obstruct viewing of product located on the top shelves 24 . the side walls 22 are also beveled to reduce risk of injury , and to increase the attractiveness of the cart 5 . the upper section 30 has two downwardly extending telescoping members 32 . each telescoping member 32 is received in the internal post 27 of the intermediate display section 20 . the telescoping member 32 is formed of two telescoping leg sections 31 , 33 to further compact the height of the cart 5 in the stored position and achieve a maximum height of the cart 5 in the operating position . the telescoping member 32 is part of a canopy frame 34 that secures an awning or canopy 36 at the upper section 30 of the cart 5 . advertisements or sales information can be displayed on the canopy 36 to attract customers . the canopy 36 also provides protection to the product and cart attendant against inclement weather , such as rain , sun and snow . when the cart 5 is in the storage position , the canopy 36 extends down to encase at least the top portion of the intermediate display section 20 and base 10 . the canopy frame 34 and the canopy 36 are slightly larger than the base 10 to fit over the base 10 in the storage position . the canopy 36 is a strong material , such as a tarpaulin or rugged plastic , which prevents rain and snow from entering the encased cart 5 in the operating and storage positions . in addition , the canopy 34 secures the product against theft while the cart 5 is in the storage position . turning to fig3 a crank system 40 is provided to raise and lower the cart 5 between the operating and storage positions . the crank system 40 includes a gear box , cables 43 - 45 , chains 46 , 48 , 49 and gears which simultaneously raise and lower the intermediate display section 20 and the upper section 30 . accordingly , the intermediate display section 20 and upper section 30 both reach the storage position and the operating position at the same time , and it is not necessary to individually raise and lower each of the sections 20 , 30 . a handle 42 is provided at the exterior of the base 10 to enable the cart attendant to manually raise and lower the intermediate and upper sections 20 , 30 of the cart 5 . once the cart 5 is in the appropriate operating or storage position , the handle 42 can be removed , thereby locking the cart 5 in that position . the handle 42 can be stored in the internal cavity of the base 10 , or retained by the attendant . however , the handle 42 can be replaced by a motor which raises and lowers the intermediate and upper sections 20 , 30 . the gear box is connected to a first cable 43 , which in turn is connected to a second and third cable 44 , 45 . the second cable 44 extends to the far end of the cart 10 , where it connects to the first chain 46 . the third cable 45 is wrapped around a horizontally mounted pulley , and extends back to the near end of the cart 5 at which the gear box is mounted , and connects to another first chain 46 . the cables 43 , 44 , 45 maintain tension on the crank system 40 as the cart 5 is raised and lowered . the cables 43 - 45 also absorb energy , to prevent the gearbox from exerting too much force on the chains . as best shown in fig4 - 7 , the first chain 46 is positioned about a first pulley 52 located underneath each end of the cart 5 just beneath the support post 16 of the base 10 . the first pulley 52 directs the first chain 46 up through the hollow support post 16 . the support post 16 protects against passersby coming into contact with the chain 46 . the first chain 46 extends around a second pulley 54 , back down through an opening in the support post 16 , and is secured by a weld 55 or the like to the inside of the external post 26 of the h - frame 25 at the intermediate section 20 . the second pulley 54 is attached at the top of the support post 16 by a pin ( not shown ) affixed to the sides of the support post 16 . a second chain 48 is connected to the floor of the base 10 at weld 51 , and extends up through the hollow internal post 27 of the h - frame 25 of the intermediate section 20 . the second chain 48 wraps around a third pulley 56 and extends back down and attaches to the inside of the lower leg 31 of the telescoping member 32 by a weld 57 or the like . the third pulley 56 is attached to the internal post 27 of the h - frame 25 by a pin 61 . the pin 61 is attached to the sides of the internal post 27 and extends through openings 62 , 63 in the lower and upper telescoping legs 31 , 33 . a third chain 49 attaches to the inside of the upper leg 33 of the telescoping member 32 at a weld 58 . the third chain 49 extends around a pulley 59 which is attached to the lower leg 31 of the telescoping member 32 by a pin 62 that extends through an opening 62 in the upper leg 33 . the opposite end of the third chain 49 is attached to the bottom of the internal post 27 of the h - frame 25 at a weld 60 . respective slots 62 , 63 are located in the upper leg 33 and lower leg 31 which enable the legs 33 , 31 to move with respect to the pins retaining the pulleys . the slot 62 of the upper leg 33 extends completely through the bottom of the upper leg 33 so that the upper leg 33 can be raised past the pin of the pulley 56 . thus , the upper leg 33 has the slot 62 cut in its sides to form an inverted u - shape . the upper leg 33 remains sturdy since it is positioned within the lower leg 31 and since the top of the upper leg 33 connects the u - shape . accordingly , as the gear box is operated to raise the cart 5 to the operating position , the first cable 43 pulls the second pulley 44 , which pulls the first chain 46 . since the first chain 46 is attached to the external post 26 of the intermediate section 20 , the first chain 46 raises the intermediate section 20 . as the intermediate section 20 raises , it causes the second chain 48 ( which is attached to the floor of the base 10 ) to raise the lower leg 31 of the telescoping member 32 . since the third chain 49 is fixed to the bottom of the internal post 27 of the intermediate section 20 , the raising of the lower leg 31 causes the third chain 49 to raise the upper leg 33 of the telescoping member 32 . when lowering the cart 5 to the storage position , the crank system 40 operates in a reverse manner . the weight of the cart 5 assists in the cart 5 being lowered . a spring can also be provided to further assist in lowering the cart 5 . the sprint attaches to the bottom of the base 10 and the side walls 22 of the intermediate section 20 to maintain the tension on the cables and chain as the cart 5 is being lowered . likewise , springs can be connected to the telescoping member 32 to maintain tension on the third chain 49 as the cart 5 is being lowered . in operation , the cart 5 is initially in the storage position and delivered to a general location by van . the cart 5 is rolled out of the van to approximately the desired location . the wheels are then locked to prevent inadvertent movement due to bumping or pushing of the cart 5 . the handle 42 is inserted into a gearbox of the crank system 40 , and turned to simultaneously raise the intermediate and upper sections 20 , 30 to the operating position . once the cart 5 is in the operating position , the handle 42 can be removed to lock the cart 5 in that position . to return the cart 5 to the storage position , the handle 42 is inserted into the crank system 40 , and turned to simultaneously lower the intermediate and upper sections 20 , 30 to the storage position . once the cart 5 is in the storage position , the handle 42 can be removed to lock the cart 5 in that position . the wheels can then be unlocked and the cart 5 moved and loaded to the van . the cart 5 is preferably constructed of a strong , yet lightweight metal , so that the cart 5 is easy to move , yet durable . in addition , although the cart 5 has only been described as being moved when it is in the storage position , the cart 5 can also be moved in the operating position . thus , the vendor can move the cart 5 while in the operating position , so that the vendor can cover a greater area such as a beach strip , mall or the like . in addition , though the cart 5 is preferably rectangular , other suitable shapes may be used , such as a circle or oval . the foregoing description and drawings should be considered as illustrative only of the principles of the invention . the invention may be configured is not intended to be limited by the preferred embodiment . numerous applications of the invention will readily occur to those skilled in the art . therefore , it is not desired to limit the invention to the specific examples disclosed or the exact construction and operation shown and described . rather , all suitable modifications and equivalents may be resorted to , falling within the scope of the invention .

a display cart has three sections : a base , an intermediate display section and an upper section having a canopy . the cart can be placed in a storage position , wherein the intermediate display section and upper section are lowered . in the storage position , the intermediate display section is substantially contained within the base and the canopy of the upper section surrounds the top portion of the base . the intermediate display section and the product are thereby concealed within the base , and protected by the canopy of the upper section . the cart can be locked in the storage position to secure the product when the cart attendant is absent . the cart can also be placed in an operating position , wherein the intermediate display section and the upper section are fully extended . the intermediate display section includes shelves that slide outward to display the product in a tapered manner so that all the products can be easily viewed without interference from other product . the upper section raises the canopy high to be viewed from greater distances to attract customers .

with reference firstly to the drawings an electric fence standard generally indicated by arrow 1 , and in accordance with the present invention , is arranged to support a fence wire 2 above a ground surface 3 such that the standard is rotatable about the wire . the standard can comprise an insulated hub generally indicated by arrow 15 through which the wire 2 passes , a plurality of electrically conductive legs 5 extending radially outwardly from the hub , and a contactor generally indicated by arrow 6 which is adapted to make contact with all legs of the fence standard except those in contact with the ground surface 3 , at a given time . thus the invention automatically electrically connects and disconnects successively the various legs 5 from the fence wire 2 as the standard is rotated to prevent the legs in ground contact from short - circuiting the fence . with reference to fig2 and 3 , a fence standard 1 in accordance with a further embodiment of the present invention for supporting the electric fence wire 2 , may comprise a hub generally indicated by arrow 15 , arranged to receive and support the electric fence wire 2 , said hub 15 mounting a plurality of radially spaced and extending legs 5 , which in use support the standard 1 from a ground surface 3 . the hub 15 is arranged to accommodate a contactor generally indicated by arrow 16 , said contactor being arranged to ensure that an electric current is distributed to the legs 5 of the standard not in contact with the ground surface whilst no electric current reaches those legs 5 of the standard which are in contact with the ground surface . the contactor is an apertured disc accommodated within a chamber 17 of the hub 15 such that an inner portion 18 thereof makes contact with an electrified wire supporting member 19 passing through the hub 15 whilst radially spaced apertures 20 of the disc are arranged to surround inner inturned ends 21 of the legs 5 mounted by the hub 15 . the hub 15 and the contactor 16 are each provided with radially extending slots 22 and 23 respectively , such that a fence wire 2 can be conveniently introduced into the hub 15 . the hub of the standard can comprise an axial sleeve 24 and intermediate mounting portion 25 defining the chamber 17 for accommodating the contactor 16 , and a plurality of radially spaced apertures 26 for receiving the ends 21 of the legs 5 . an outer flange 27 fixed to or intergrally formed with the intermediate portion is provided , said outer flange including a plurality of support means 28 such as u - shaped resilient clips , whose ends engage with rectangular apertures 27a , for supporting inner ends 21 of said legs 5 . whilst the legs 5 have their inner ends 21 engaging in the aperture 26 in the intermediate portion 25 of the hub , the outer ends 29 ( see fig1 ) which may also be inturned are arranged to ensure that the weight of the standard is more evenly spread on the ground surface then would be the case if the ends 29 of the legs 5 were plain . in the embodiment illustrated and by way of example , six legs are provided and correspondingly the hub provides six apertures 26 , six sets of mounting means 28 in which the inner ends of legs 5 may be a snap fit , and six apertures 20 for surrounding the ends 21 of the legs 5 are provided in the contactor 16 , the arrangement being such that on assembly of the legs 5 to the hub 15 , the ends 21 of the legs project through the apertures 20 in the contactor 16 . preferably , the apertures 20 in the contactor 16 are provided with a number of straight edges , that is , the apertures may be hexagonal as shown such that when the standard is rotated to a new position , there is a reduced likelihood of the contactor sticking . further , the contactor is free to float in its chamber 17 such that in the position illustrated by fig1 where two of the legs 5 are in contact with the ground below , there is a clear and regular air space 17a between the ends 21 of the legs in contact with the ground , and the inner edges of the apertures 20 in the contactor . thus there is no electrical contact between the contactor 16 and the legs 5 in contact with the ground . after an electric fence wire 2 has been introduced to the hub and contact plate 10 , via slits 22 and 23 respectively , ringlet clamps ( not shown ) may be mounted on the wire support member to prevent dislocation of the wire from the standard . preferably the hub 15 for a support means in accordance with the present invention is moulded in a plastics material whilst the contact plate may be fabricated in an aluminium alloy , and similarly the legs 5 may be fabricated from an electrically conductive material , such as aluminium . so that the contactor 16 has minimal frictional contact surface 17b of the chamber 17 the surfaces may be provided with a plurality of equally radially spaced ribs 30 , and to prevent lateral movement of the contactor 17 a series of tabs 31 can be provided which overlie and locate the outer edges 16a of the contactor 16 . in alignment with the apertures 27a and the support means 28 supporting the ends 21 of the legs 5 , the flange 27 may be provided with a series of outwardly extending u - shaped supports or guides 35 intergrally formed with the flange 27 ; and to strengthen the hub 15 a plurality of radially extending support braces 36 ( see fig3 ) can be provided .

this invention relates to wheel - like electric fence standards where an electrified fence wire passes through an insulated hub member from which radiates a number of legs to form a wheel - like configuration and is characterized in that a contactor within the hub automatically connects and disconnects successively the legs from the fence wire to prevent the legs in contact with the ground from short - circuiting the fence .

referring now to fig1 , it schematically illustrates a pregnant patient 10 having a uterus 11 and a fetus 12 disposed within the uterus 11 . the uterus 11 is enclosed by the abdominal wall 18 of the patient and includes an amniotic cavity 14 which is defined by the uterine wall 15 . the uterine wall 15 is primarily comprised of the uterine muscle or myometrium 16 . as is well known , the fetus 12 is disposed within amniotic fluid contained within the amniotic cavity 14 . in accordance with the present invention , a system 19 detects for and initiates contractions of the uterus 11 . more specifically , the system 19 includes a detection and initiation unit 20 including a uterine contraction detector 31 and a source of electrical energy 33 . the system 19 further includes first and second leads 22 and 24 having first and second electrodes 26 and 28 respectively . the first and second electrodes are coupled directly to the uterus 11 to establish a current return path between the electrodes within the myometrium 16 . as will be seen with respect to fig2 , the electrodes 26 and 28 are coupled to both the detector 31 and energy source 33 of unit 20 . as can be clearly seen in fig1 , the electrodes 26 and 28 of leads 22 and 24 respectively are in direct contact with the myometrium 16 . the electrodes 26 and 28 are also preferably configured so as to be releasably anchored within the myometrium 16 as will be more particularly described subsequently . in the detection of contractions of the uterus 11 , the electrodes 26 and 28 provide an electromyographic signal ( emg ) representing the electrical activity of the myometrium 16 . because the electrodes 26 and 28 are within the myometrium 16 , the emg is very specific to the electrical activity of the myometrium 16 . when the emg satisfies a predetermined criteria to be explained subsequently , uterine contractions are determined to be present . conversely , when the emg fails to satisfy a predetermined criteria , uterine contractions are considered to be sufficiently absent to require uterine stimulation for uterine contraction initiation . when contractions of the uterus 11 are to be initiated , the electrical energy source 33 is activated by the detector 31 to provide , for example , trains of square wave voltage pulses . the electrical energy is applied directly to the myometrium 16 along the aforementioned current return path within the myometrium by virtue of the electrodes 26 and 28 being directly in contact with the myometrium 16 . because the electrodes 26 and 28 are fixedly anchored within the myometrium 16 , they will not be dislodged by the uterine contractions to enable the therapy to have its complete therapeutic effect . however , because the electrodes are releasably anchored , they may be readily removed in a noninvasive manner when no longer needed . to lend further understanding of the present invention , the electrical activity of the uterus can exhibit two distinct forms of activity . one form is that of a uterine contracture which is exhibited long before actual labor . contractures are represented by bursts of electrical activity which can last on the order of several minutes and which are widely spaced apart by separations of about an hour or more . contractures are disorganized muscle activity of the myometrium causing minimal , if any , physical manifestations of the myometrium . the other form is that of a uterine contraction . contractions are represented by relatively short bursts of electrical energy with the bursts being relatively closely spaced apart . for example , during labor , the uterine contraction electrical bursts of energy may have durations of thirty seconds or less with separations on the order of twenty minutes or less . contractions , as compared to contractures , are organized muscle activity of the myometrium causing pronounced physical manifestations of the myometrium . it is the occurrence of contractions that is most identified as labor . the electrical energy bursts of both contractures and contractions are made up of electrical waves having separations of , for example , three hundred milliseconds to nine hundred milliseconds ( 300 ms to 900 ms ). as will be seen subsequently , one or more characteristics of the emg electrical bursts are used to identify actual contractions or the lack thereof in need of initiation . referring now to fig2 , it illustrates in schematic form , the uterine contraction detection and initiation unit 20 of fig1 . the unit 20 includes the contractions detector 31 and energy source 33 within an enclosure 30 . the unit 20 is turned on by a switch 50 which connects a battery 51 to the various components of the unit 20 when contractions are to be initiated or maintained . within the enclosure 30 is also a microprocessor 32 which , in a manner well known in the microprocessor art , operates on operating instructions stored in an internal memory 52 or an external memory ( not shown ). as a result of such operation , the microprocessor 32 implements the contractions detector 31 including burst duration stage 39 , a first timer 41 , an inhibit stage 45 and a second timer 47 . also , stored in memory portion 53 of memory 52 , are preprogrammed contraction detection parameters or criteria . the contraction detector 31 further utilizes a sense amplifier 35 and a threshold circuit 37 . the sense amplifier 35 has a pair of inputs which are coupled to outputs 68 and 70 of the unit 20 . the outputs 68 and 70 are adapted to be coupled to the first and second electrodes 26 and 28 . the electrodes 26 and 28 provide the emg representing the electrical activity of the myometrium . the emg is amplified by the sense amplifier 35 . the amplified emg is then provided by the sense amplifier 35 to the threshold detector 37 . whenever an electrical wave from the sense amplifier 35 exceeds a threshold magnitude set by the threshold detector 37 , the threshold detector will provide an output to an interrupt input 43 of the microprocessor 32 . the burst duration stage 39 time stamps each interrupt input and stores each time stamp in memory 52 . it also , with timer 41 , starts keeping time from each interrupt input . when the timer 45 has timed a predetermined time period of , for example , five seconds without being reset by another interrupt , the burst duration stage 39 considers the current burst to be completed . the next interrupt will then represent the beginning of the next burst of electrical activity . the inhibit stage 45 precludes the energy source 33 from stimulating the uterus as long as contractions are sufficiently present . to that end , the second timer 47 starts keeping time from the beginning of each burst as determined by the duration stage 39 . as long as the second timer 47 is reset by the burst duration stage 39 before it times out , the inhibit stage 45 will continue to inhibit the energy source 33 . however , when a next burst fails to begin within the time out time period of the second timer 47 , the inhibit stage 45 activates the energy source 33 for stimulating the uterus to initiate the next contraction . the time out period of timer 47 may be , for example , on the order of two minutes . as a result , if a next burst does not occur within two minutes of its immediately preceding burst , the beginning the contraction detector 31 will consider the contractions to be insufficient and warranting uterine stimulation to initiate the next uterine contraction . hence , a new contraction will be initiated when a uterine contraction is undetected within a predetermined time from the beginning of an immediately preceding uterine contraction . as can be appreciated by those skilled in the art , the time out period may be tailored to an individual patient . the above time out period is provided as being exemplary only . the energy source 33 includes a charging circuit 34 , an analog to digital converter 36 , a storage capacitor 38 , and an h bridge 40 comprising field effect transistors 42 , 44 , 46 , and 48 . the electrical energy source 33 is activated by the inhibit stage 45 of the contractions detector 31 over a line 49 which causes the charge circuit 34 to charge capacitor 38 . the memory 52 has storage locations 54 , 56 , 58 , 60 , and 62 for storing preprogrammed energy delivery parameters such as pulse voltage , pulse polarity , burst duration , pulse interval , and pulse duration respectively . the foregoing parameters including the detection parameters may be stored in the memory 52 with a programming computer ( not shown ) of the type well known in the art . the charge circuit 34 charges the storage capacitor 38 to the pulse voltage programmed at memory location 54 . the output of the charge circuit 34 is monitored by the analog to digital connector 36 which provides the microprocessor with a digital representation of the output voltage of the charge circuit 34 . in this manner , the microprocessor is capable of regulating or controlling the charge circuit 34 to maintain the preprogrammed pulse voltage across the capacitor 38 . the h bridge 40 is of the type well known in the art which is controlled by the microprocessor 32 over control lines 64 and 66 which are provided with buffers 65 and 67 respectively to accommodate required voltage swings and higher voltage applied to h bridge 40 . the signals provided by the microprocessor over the control lines 64 and 66 cause the energy source 33 to provide a train of output pulses at the output terminals 68 and 70 having the pulse polarity , burst duration , pulse interval , and pulse duration as preprogrammed in memory locations 56 , 58 , 60 and 62 respectively of the memory 52 . the output terminals 68 and 70 of the unit 20 are coupled to the leads 22 and 24 respectively as shown in fig1 to provide the electrodes 26 and 28 with the preprogrammed electrical energy . fig3 - 5 illustrate a manner in which the electrodes 26 and 28 may be substantially non - invasively placed in direct contact with the uterus 11 through the abdomen 18 and more particularly in direct contact with the myometrium 16 in accordance with a preferred embodiment of the present invention . referring first to fig3 , there is illustrated , to an enlarged scale , the abdominal wall 18 and the myometrium 16 . the abdominal wall includes the skin 72 and the abdominal muscle 74 . in an initial step , a removable inner needle 76 is first inserted into an introducer tube 78 . the introducer tube 78 terminates in a conical surface 80 which matches the terminating conical surface 82 of the removable inner needle 76 . with the conical surfaces 82 and 80 aligned as shown in fig3 , the introducer tube 78 and removable inner needle 76 are moved in unison to pierce the skin 72 and abdominal muscle 74 . movement of the introducer tube 78 and removable inner needle 76 is terminated when the tip 84 of the needle 76 has entered the space 86 between the abdominal muscle 74 and myometrium 16 to such an extent that the conical surface 80 of the introducer tube 78 is within the space 86 . once the removable inner needle 76 and introducer tube 78 are positioned as shown in fig3 , the removable inner needle 76 is withdrawn from the introducer tube 78 . with the removable inner needle 76 thus removed from the introducer tube 78 , the introducer tube 78 is now ready to receive the electrode 26 at the distal end of its lead 22 as illustrated in fig4 . the lead 22 has a cylindrical lead body with an inner electrical conductor 23 which contacts a conductive collar 25 of the electrode 26 . the electrode 26 has a structure 27 secured to the collar 25 by welding , for example . the structure 27 is formed of a relatively rigid conductive wire 29 configured as a screw - in tip . more specifically , the electrode structure 27 is formed in the shape of a helix so that when the lead 22 is introduced through the introducer tube 78 to an extent permitting the electrode 26 to contact the myometrium 16 , rotation of the lead 22 as indicated by the arrow 88 causes the helical screw - in tip 29 of electrode 26 to screw into the myometrium 16 . when the lead 22 has been rotated a sufficient number of turns to fully embed the electrode tip 29 within the myometrium 16 , the lead will be securely , but releasably , anchored within the myometrium 16 . this is illustrated in fig5 where it can be seen that the helical tip 29 of the electrode 26 is fully embedded within the myometrium 16 . once this is accomplished , the introducer tube 78 may be removed to thus render the lead 22 passing through the abdominal wall 18 including the skin 72 and abdominal muscle 74 with the electrode 26 securely anchored to the uterus 11 and more specifically , the myometrium 16 . as a result , during the therapy of initiating contractions of the uterus 11 , the contractions of the uterus 11 will not dislodge the electrode 26 from the myometrium 16 . however , when therapy is no longer required and the electrode 26 is no longer needed , it may be readily withdrawn by just rotating the lead 22 in a direction opposite that shown at 88 in fig4 and pulling the lead from the patient when the tip 29 is disengaged from the myometrium . referring now to fig6 , it illustrates a further embodiment of the present invention . here it may be seen that the unit 20 is coupled directly to the myometrium through the lead 22 and electrode 26 as previously described while another lead 90 couples the unit 20 to a surface of the body of the patient 10 with a surface or patch electrode 92 . the patch or surface electrode 92 is in surface contact with a posterior portion of the body of the patient 10 and more specifically , on the back of the patient . with such an arrangement , a return current path is established between the electrodes 26 and 90 . the electrical energy from the energy source 33 of the unit 20 will remain concentrated in the myometrium given the large surface area of electrode 92 compared to electrode 26 . the fetus 12 and the body of the patient 10 will only be exposed to dispersed energy which will be well within safe limits for both the fetus 12 and mother 10 . while particular embodiments of the present invention have been shown and described , modifications may be made , and it is therefore intended to cover in the appended claims all such changes and modification which fall within the true spirit and scope of the invention .

a system and method for detecting for and initiating contractions of a uterus of a human patient employs a sensor for sensing electrical activity of the uterus of the patient . data from the sensed electrical activity is stored in memory . a processor accesses the stored data for analysis . electrical energy is applied to the uterus to initiate a uterine contraction when the analyzed data fails to satisfy predetermined detection criteria .

the power lawn mower 10 , according to the preferred embodiment of the invention as illustrated in fig1 and 2 includes a drive assembly 11 and a cutter assembly 12 . the drive assembly 11 includes an engine deck 13 for supporting a conventional gasoline engine 14 . a pair of drive wheels 15 and 16 are mounted on cutter deck 13 and generally on each side of the engine 14 . hydraulic motors 17 and 18 are mounted on wheels 15 and 16 , respectively . pumps 20 and 21 are mounted on engine deck 13 and are respectively connected to motors 17 and 18 through hydraulic conduits 23 and 24 . the pumps 20 and 21 are driven at the same speed from the engine 14 by any conventional means such as , for example , a belt drive ( not shown ). those skilled in the art will appreciate that such belt drives may include a belt which extends around a first pulley mounted on the engine shaft and pulleys mounted on shafts extending downwardly from pumps 20 and 21 . each pump 20 and 21 also has a pump control shaft 32 , extending therefrom and each has a pump control lever 33 fixed to its outer end . in particular , each lever 33 has an integral bushing 31 at its lower end and which is suitably fixed to shaft 32 extending from each pump 20 and 21 . the pump control levers 33 are mirror images and are shown more particularly in fig3 to be generally triangular with one corner fixed to shaft 34 . each lever 33 also has a short slot 35 formed adjacent the forward corner . at the third corner of the lever 33 there is a bushing 36 which supports a roller 37 as will be described more fully below . the cutter assembly 12 includes a cutter deck 38 suitably mounted at the front of the engine deck 13 . mounted below the cutter deck 38 is one or more cutter blades ( not shown ) which rotate in a horizontal plane on vertical shafts ( not shown ) coupled to the engine 14 in any suitable manner , such as a belt drive assembly ( not shown ). the cutter assembly 12 , its associated drive and the engine 14 are conventional and , accordingly , these parts will not be discussed in detail for the sake of brevity . a second pair of wheels 40 are mounted at the front of the cutter deck 38 by means of castor assemblies 41 which permit the mower to be turned by the rear wheels 15 and 16 as will be discussed more fully below . a handle assembly 43 is provided for handling and manipulating the mower 10 and consists of a pair of handle members 44 and 45 and a cross member 46 secured adjacent the upper end of handle members 44 and 45 to hold the same in a generally parallel , spaced - apart relation . each handle member is also suitably fixed , such as by bolts 47 to a u - shaped frame member 48 mounted on the engine deck 13 . the handle members 44 and 45 extend upwardly and rearwardly from frame member 48 and each has a downward curve at its remote end for receiving a handgrip member 49 . a speed control assembly 50 is located on the handle members 44 and 45 as shown more particularly in fig5 and includes a speed control lever 51 pivotally mounted on each handle member 44 and 45 and each is coupled to one of the pump control levers 33 by a control rod 53 . the levers 51 are generally bar - like and each is fixed to the lower end of a generally u - shaped bracket 54 the upper ends of which are pivotally mounted by means of a pin 56 received in a suitable opening in the handle members 44 and 45 and forwardly of the handgrip 50 . control rod 53 is elongate and its upper end 58 is bent laterally at right angles for being received in an opening 60 formed in an ear 62 fixed to and extending downwardly from the underside of control lever 51 and adjacent bracket 54 . a pin 63 is fixed to the lower end of rod 53 and extends laterally therefrom into the slot 35 . a control finger 64 is also mounted on control lever 51 and extends laterally outwardly therefrom at a point generally above ear 62 . the control lever 33 shown in fig3 is mounted on pump 20 . it will be appreciated that the lever 33 mounted on pump 21 is a mirror image of that mounted on pump 20 . mounted adjacent the control lever 51 on each of the handle members 44 and 45 is a speed control index 66 . the speed control indexes 66 on each side of the mower are identical except that each is a mirror image of the other . the right hand speed control index is shown in fig5 and will now be described . the left hand speed control index is shown in fig3 and corresponding parts have the same reference numerals as the index shown in fig4 . each speed control index 66 is a relatively flat , pear shaped member pivotally mounted on the outer side of the respective handles 44 or 45 by means of pins 68 with the control fingers 64 extending into the sectors 70 . a friction bushing ( not shown ) is disposed between each index 66 and the pins 68 to retain the indexes 66 in their respective positions unless manually reset . an indexing slot 70 is formed in index member 66 adjacent its larger end . a first edge 72 of slot 70 is generally linear and extends laterally relative to the pivot axis of pin 68 . the opposite side of slot 70 has a shaped configuration which defines pockets 74 and 75 which are complementary to the outer surface of the control fingers 64 . pocket 74 is located farther from the axis of pin 68 than the pocket 75 . the index 66 defines neutral , full forward , and reverse drive positions . in addition , the broken lines 77 and 78 define an arcuate neutral zone 79 spaced from edge 70 and pocket 74 and having its center of curvature at the axis of pin 68 and intersecting the neutral pocket 74 . the length of slot 35 on pump control lever 33 is equal to the width of the neutral zone 79 for reasons which will be discussed below . at the end of speed control index 66 opposite the slot 70 there is a thumb lever 80 . the speed control assembly 50 also includes a master speed control lever 84 pivotally mounted intermediate its ends on a support bracket 85 suitably fixed to one of the handles 44 or 45 , although preferably on the handle 44 at the right side of the apparatus as shown in fig3 . bracket 85 generally has an inverted u - shape and transverse cross - section with its sides embracing handle 44 . lever 84 is pivotally mounted by means of a pin 86 adjacent the lower end of bracket 85 . at the upper end of bracket 85 , there are a plurality of slots 88 which are equally spaced apart and arranged in an arc whose center of curvature is at the axis of pin 86 . a detent 90 is mounted adjacent the upper end of lever 84 and on the inner side thereof for cooperating with the slots 88 whereby lever 84 can be retained in each of a plurality of forward speed positions corresponding to the slots 88 . the lower end of lever 84 is coupled to a cam assembly 94 by an elongate rode 95 which is pivotally connected to the lower end of lever 84 by a pin 96 . cam assembly shown in fig2 and 6 includes a shaft 97 mounted for rotation about a horizontal axis by means of bushings 98 mounted on the sides of frame member 49 and about a pair of aligned openings formed therein . mounted on each of the ends of shaft 97 and adjacent the outer surface of the sides of member 48 are a pair of identical cams 100 . as seen more particularly in fig6 each cam 100 has a generally circular profile and is eccentrically mounted on shaft 97 . the rollers 37 on the pump control levers 33 bear against the surface of each cam 100 under the influence of a spring 102 extending between the end of the pump control rods 53 and the engine deck 13 . the rod 95 is pivotally connected at its end remote from lever 84 to an arm 105 extending from cam shaft 97 . the lever 84 controls the forward speed of the lawn mower by pivoting the pump control lever 33 through the agency of the cams 100 and the rollers 37 . with particular reference to fig3 and 6 , when the lever 84 is pivoted counterclockwise to its position shown in fig3 its lower end will move toward the right thereby rotating camshaft 97 and consequently rotating cams 100 counterclockwise from its position shown by full lines to its position shown by broken lines in fig6 . as a result , the roller 37 will move from a lower point on the profile of cam 100 to a higher point , thereby causing the lever 33 to pivot in a counterclockwise direction ( fig3 ) so as to increase the forward speed . conversely , pivotal movement of lever 84 in a counterclockwise direction will move the lower end of lever 84 toward the left as viewed in fig3 thereby rotating the cams 100 counterclockwise so as to rotate pump control lever 33 counterclockwise which reduces motor speed . the detent 90 and slots 88 permit the lever 84 to be resiliently maintained in a plurality of forward speed positions . in order to insure that the cams 100 will coact equally with pumps 20 and 21 , the rollers 37 are adjustable by means of an eccentric 117 . in particular , eccentric 117 includes a first eccentrically mounted pin 118 which is threaded ( not shown ) in a suitable opening in the lever 33 . a second pin 119 , which is axially positioned on eccentric 117 , rotatably supports the roller 37 . it can thus be seen that by securing eccentric 117 in different angular positions , the distance between the axis of roller 37 and cam 100 can be adjusted . the cams 100 on each side of the lawn mower are identical and interconnected so that both drive wheels 15 and 16 will be driven at the same forward speeds when lever 75 is repositioned . once a forward speed has been set , the operator can operate the mower safely at that speed without either of the wheels creeping and without further handling of lever 84 . in order to facilitate positioning of lever 84 , an extension arm 125 may be secured to the upper end of lever 84 and extending backwardly therefrom to a position adjacent the handgrips 49 . however , it is not necessary for the operator to maintain a hold on lever 125 once the desired speed position has been set . as seen in fig3 the line of action of spring 102 is generally along the axis of rod 53 . when the speed control lever 51 is in its full forward speed position , that is , with finger 64 in pocket 74 , spring 102 urges the forward end 58 of rod 53 into engagement with the forward end of slot 35 thereby tending to rotate the lever 33 clockwise as viewed in fig3 . however , when speed control lever 51 is in its neutral position , i . e . when finger 64 is in pocket 74 , the end 58 of rod 53 should be out of engagement with the ends of slot 35 . a neutral adjustment assembly 104 as seen in fig3 is provided for returning lever 33 to its neutral position and maintaining said position so that the end 58 of control rod 53 will be positioned intermediate the ends of slot 35 when lever 51 is in its neutral position or finger 64 is in pocket 74 . the assembly 104 includes a bar 105 pivoted at one end on frame member 49 by pivot pin 107 which is adjacent the upper edge of pump control lever 33 . lever 105 extends downwardly from its pivot pin 107 and has a v - shaped section 108 intermediate its ends . a spring 109 extends between the lower end of bar 106 and the engine deck 13 for urging the bar 106 clockwise around its pivot 105 . in addition , a short bar 110 is fixed to busing 34 and extends laterally therefrom . an eccentrically mounted roller 113 is rotatably mounted at the free end of bar 110 and its contact surface engages the flat sides of the v - shaped section 108 . in particular , roller 113 includes an outer race 114 and an inner race 115 having an eccentrically located opening formed therein . a bolt 116 extends through the opening in race 114 and through an aligned opening ( not shown ) in the end of bar 110 . as those skilled in the art will appreciate , caged balls are located between the races 114 and 115 . those skilled in the art will also appreciate that shafts 34 are coupled at their inner ends to flow control and directional valves ( not shown ) which are mounted within the housing of each pump . the internal control valves are conventional and need not be described in detail . it is sufficient to understand the invention to state that , for example , as the control lever 33 is pivoted clockwise as viewed in fig3 fluid pressure to the motor 20 will increase thereby increasing the rotational speed of wheel 15 . conversely , as the lever 33 is pivoted counterclockwise , fluid flow to pump 20 will decrease until such time as a neutral zone is reached wherein fluid flow to the motor 20 will cease . further pivotal movement in a clockwise direction will reverse fluid flow in conduits 23 and 24 so that the motor 20 will begin to rotate in the reverse direction and the reversal speed will increase as the lever 33 pivots further . pump 21 will be operated by its associated lever 33 in an identical manner . in operation , when the engine 14 is running , the pumps 20 and 21 will be driven at the same speed . hydraulic fluid under pressure will be delivered to motors 17 and 18 through conduits 23 and 24 . when the direction of fluid flow is to the motor 17 and 18 through conduits 23 and return flow to the pumps 20 and 21 is through conduit 24 , each of the motors will be driven in the forward direction so that the drive wheels 15 and 16 will be correspondingly driven . on the other hand , fluid flow in the opposite direction will cause the motor 17 and 18 to operate in the reverse direction whereby the respective wheels will be driven rearwardly . the force of spring 102 is larger than spring 109 so that spring 102 must be disconnected when the neutral position of lever 33 is being adjusted . initially , lever 33 is assembled to shaft 32 such that it will be in approximately the proper position wherein the roller 113 will be at the base of the v - section 108 of bar 106 when shaft 32 is in the neutral position of the internal control valves ( not shown ) and the pin 63 at the end of rod 53 is in slot 35 and spaced from its ends . by releasing the roller 113 and rotating the inner race 115 relative to the end of bar 110 , the position of the roller can be adjusted so that it will be at base of section 108 when the shaft 32 in its neutral position . it will be appreciated that the inner race 115 may then be fixed in its adjusted position by means of bolt 116 . it is extremely important that the pin 63 be located intermediate the ends of slot 35 when the control finger 64 is in the neutral zone 79 of index 66 and the shaft 32 is in its neutral position . the length of rod 53 may be adjusted by means of turnbuckles 121 which are disposed intermediate the ends of rods 53 . after the length of rods 53 have been adjusted , the assembly 104 will be operative to return the lever 33 to its neutral position so that the pin 63 is intermediate the ends of slot 35 when the finger 64 is in the neutral zone 79 or in the pocket 75 . by coupling the control rod 53 to lever 33 through slot 35 and by insuring that the pin 63 is out of contact with the edges of slot 35 when the lever 33 is in its neutral position , slight misalignment will not cause the lawn mower to begin moving in either the forward or reverse directions when the operator has set the indexing assembly in the neutral position . the operator must intentionally move the finger 64 out of the pocket 74 or the neutral zone 82 in order to commence operation of the forward or reverse direction . upon movement of finger 64 out of pocket 74 , rotation of the index 66 to a desired position , and release of the handle 51 , the pin 63 at the end of rod 53 will be free to be moved into engagement with the front edge of slot 35 by spring 102 . when the operator wishes to drive the wheels forwardly , for example , the control lever 51 will be pivoted counterclockwise as viewed in fig4 and about pin 56 thereby moving finger 64 from pocket 75 . the operator may then push on thumb lever 120 to pivot the index 66 until the pocket 74 is moved into alignment with pin 64 . the operator may then release the control lever 51 and the spring 94 acting through the rod 53 move the finger 64 into pocket 64 . forward speed of both wheels 15 and 16 will then be determined by the position of the lever 84 . when the index 66 is being moved between the neutral and forward positions , the pin 64 will be held in the neutral zone 77 so that the assembly 104 will return lever 33 to its neutral position whereby wheels 15 and 16 will not be driven during the shifting operation . if the wheels are being driven at any forward speed , the operator can , by pulling back on either of the levers 51 to move either or both of the pins 64 back into the neutral zones whereby the assemblies 104 will be free to reposition levers 33 in their neutral positions and the wheels will come to rest . if it is desired to drive either of the wheels 15 or 16 in the reverse direction when they are in any of their forward speeds , the appropriate lever 51 is pivoted counterclockwise to move its finger 64 through the neutral zone and into the reverse zone at the inner edge of slot 70 . the wheel will thus slow , come to rest , dwell in the neutral position and then reverse as the pin 63 at the end of rod 53 traverses the slot 35 and moves into engagement with the rear edge thereof . the edge 72 limits reverse speed . it will be appreciated that in order to operate wheel 15 in the reverse direction the operator must maintain pressure on lever 51 . if the operator should stumble or walk into an obstacle , so that he releases his grip on lever 50 , wheel 15 will begin to rotate in the forward direction and away from the operator . the speed controls at the opposite sides of the mower operate identically for driving wheels 15 and 16 in forward or reverse directions and at varying speeds . in normal operation , the operator will set the speed control indexes 66 at each side of the mower in forward or neutral positions . it is necessary that the wheels 15 and 16 be driven at the same speed for the mower to travel in relatively straight line . if a turn is desired , the wheel at the outside of the turn is driven at a faster speed than that at the inside of the turn or the inside wheel is stopped or driven in the opposite direction . the radius of the turn will be determined by the different relative speeds of the inside and outside wheels . therefore , in order to affect a turn , the operator will change the relative speeds of the inside and outside wheels by rotating the lever 51 at the inside of the turn . the speed control index 66 permits the mower to be driven at any forward speed without the necessity for the operator applying pressure to the control levers 51 and still permits different relative forward speeds of the wheels 15 and 16 so that turns of varying radii can be achieved . return of the pump control lever to its neutral position when the control lever 104 is moved to neutral is insured by the neutral control mechanism 104 . while only a single embodiment of the invention has been illustrated and described , it is not intended to be limited thereby but only by the scope of the appended claims .

a lawn mower has a hydraulic motor mounted on each drive wheel and each motor is independently driven by a separate pump . each pump includes a control lever for regulating fluid pressure and flow direction so that each wheel may be driven independently in the forward and reverse directions and at varying speeds . a speed control index is mounted on one side of the mower for releasably setting and maintaining the speed control levers in a plurality of equal forward speed positions so that the operator can preset the maximum forward speed . in addition , an individual speed control lever is mounted on each handgrip and each is independently coupled to one of the control levers for individually adjusting each wheel for speeds less than the preset maximum or for setting either wheel drive pump in neutral or reverse . a neutral control assembly returns the pump control levers to a neutral position when the control levers are moved into neutral .

in essence , the invention is directed to particulate and non - particulate compositions having a plasma - induced , graft polymerized , water - soluble coating . in preferred modes of the invention , the particulate material is selected from water - insoluble particles such as those used in cosmetic and shampoo compositions , soluble particles such as spray dried granules , agglomerates and mixtures thereof which are typically used in detergent compositions . the non - particulate compositions herein may also be used in laundry or dishwashing , for example , as a laundry or dishwashing tablet , block , cylinder , sheet , cube or other non - particulate configuration . the graft polymerization of the water - soluble coating by exposing the particulate or non - particulate material to an organic hydrophilic monomer after the particulate or non - particulate material is subjected to plasma . it is essential for the graft polymerization process step that the organic monomer be introduced after the plasma has been generated in the plasma chamber . preferably , the water - soluble coating is formed from an organic hydrophilic monomer , which is even more preferably selected from the group consisting of acrylates , methacrylates , acrylamides , methacrylamides , maleates , fumarates , vinyl ethers and mixtures thereof . more preferably , the organic monomer is selected from the group consisting of 2 - hydroxyethyl methacrylate , n , n - dimethylacrylamide , acrylic acid , methacrylic acid and mixtures thereof . most preferably , the organic monomer is acrylic acid . the water - soluble coating is on at least a portion of the compositions described herein . by “ at least a portion ”, it is meant that at least 1 %, preferably 90 % to 100 % of the particulate or non - particulate composition has a water - soluble coating on it . it should be understood that not all of the composition needs to be coated to be within the scope of the invention . to that end , a plasma coating process is used to place the water - soluble coating on the composition . as detailed hereinafter , this is accomplished by ionizing a gas , such as argon , using high frequency electricity in a plasma vacuum chamber . suitable gases may be selected from the group consisting of argon , helium , oxygen , nitrogen and mixtures thereof . as used herein , the phrase “ plasma - induced , graft polymerized ” means that which has been deposited , coated or otherwise layered using one or more of grafting deposition techniques wherein the material to be deposited reacts , grafts , attaches , bonds or otherwise binds with the free radicals formed on the surface of the material during generation of plasma in a plasma chamber . typical plasma chambers will have a “ plasma glow zone ” which can be the region between the two electrodes used to generate the high frequency electricity , and thus the plasma therebetween . the pressure inside the plasma chamber is typically maintained at a pressure of from about 5 mtorr to about 300 torr , more preferably from about 10 mtorr to about 1 torr , and most preferably from about 50 mtorr to about 250 mtorr . the power used in the plasma chamber is selected to be from about 0 . 1 watts to about 500 watts , more preferably from about 0 . 5 watts to about 100 watts , and most preferably from about 1 watt to about 10 watts . this application of a high frequency electric field to a gas to form a plasma of gas ions is a known technique used in polymerization of monomers such as organic hydrophilic monomers which are suitable for use herein to form the water - soluble coating on the detergent composition . this technique has been described , for example , in luster , u . s . pat . no . 2 , 257 , 177 . in general , this involves continuous contact of the polymerizing monomer in the vapor phase with the gas plasma until substantial completion of the graft polymerization on the substrate . this technique tends to form a cross - linked product as suggested by u . s . pat . no . 3 , 287 , 242 . due to the high cross - linking associated with plasma polymerization , that technique is generally employed for the purpose of forming water - insoluble thin films or coatings rather than the water - soluble coating currently contemplated by the present invention . the activation is confined to a region near the surface of the substrate at which links and cross - links are formed . one modification of the film / coating forming techniques in which the monomer is polymerized directly from the gas state is described in knox et al , u . s . pat . no . 3 , 475 , 307 . there , the substrate is cooled to condense a thin layer of liquid monomer on the substrate in order to increase the polymerization rate . however , in that technique , the ordinary skilled artisan must avoid condensing “ too much ” of the monomer on the surface because otherwise the incoming activated molecules from the gas phase would not reach the monomer removed from the gas liquid interface which is stated to cause a coating of little adherence ( col . 10 , lines . 54 - 60 ). the order of magnitude of condensed monomer prior to polymerization is indicated as being few molecules in thickness ( col . 4 , lines 1 - 4 ). another plasma coating technique is to initiate polymerization by use of a non - equilibrium ionized gas plasma and to complete the majority of the polymerization in the absence of the plasma . in this manner , a high molecular weight polymer is formed . the formation of the ionized gas plasma may be accomplished in any of the techniques known to produce such plasmas . for example , see j . r . hollahan and a . t . bell , eds ., “ techniques in applications of plasma chemistry ”, wyley , new york , 1974 and m shen , ed . “ plasma chemistry of polymers ”, dekker , new york , 1976 . in one technique , an ionizable gas is contained under vacuum between parallel plate electrodes connected to a radio frequency generator which is sold by international plasma corporation under the designation “ model 3001 ”. the plasma can be created with such parallel plates either external or internal to the plasma chamber . in another technique , an external induction coil creates an electric field which produces the plasma of ionized gas . in yet another technique , oppositely charged electrode points are placed directly into the plasma vacuum chamber in spaced apart relationship to create the plasma . any plasma formed by these techniques or any other one in which an electric field creates a path of electrical conduction totally within the gas phase is suitable for use in the invention . as used herein , the term “ plasma ” is to be distinguished from any liquid or solid environment in which an electric field is applied to create ions in a path through the solid or liquid . this is not to exclude the possibility that an electric field would also be applied across the non - vapor monomer . however , if it were , it is not believed that it would have any beneficial function ; instead , it would be extraneous to the vapor phase plasma . the operating parameters for the plasma vary from monomer to monomer . in general , it is preferable to employ reduced gas pressures to form a glow discharge by electron liberation which causes ionization in the gas phase . where a plasma is created in a chamber including a gas at a pressure below atmospheric pressure , the plasma is formed when the interelectrode potential exceeds a threshold value which is sufficient to ionize or “ breakdown ” the gas . this is a function of the composition of the gas , its pressure and the distance between the electrodes . after breakdown , the gas is conductive and a stable plasma may be maintained over a wide range of currents . although the exact composition of the plasma is not known , it is believed to include electrons , ions , free radicals , and other reactive species . in a related procedure , the creation of active sites on the substrate or particulate material may be facilitated by direct activation from the ionized gas . for this purpose , the presence of any ionizable gas under the conditions prevalent in the plasma may be employed . for example , water vapor may be ionized to create active polymerization sites for certain monomers . other gases which have been ionized by such plasmas include hydrogen chloride , carbon tetrachloride , and inert gases such as helium or neon . those gases which are ionizable in the plasma are well known to those in the field . the monomer to be deposited may be in the essentially pure monomeric state or in solution . in the latter instance , organic or inorganic solvents capable of complete dissolution of the monomer may be employed . typical organic solvents for certain monomers include benzene and acetone . for any given plasma deposition technique as described herein , the process may involve the use of high frequency microwaves to ionize the gas in the plasma chamber . alternatively , high frequency radio waves or direct current electricity can be used , for example to ionize the gas between two oppositely charged electrode points used to define the plasma glow zone in a plasma vacuum chamber . another option is to pulsate or otherwise intermittently ionize the gas in the plasma glow zone in the plasma chamber so as to control the plasma - induced deposition of the monomer onto the particulate detergent material . further control of plasma - induced deposition can be achieved in the process of the present invention by positioning the particulate detergent material to be coated with the hydrophilic monomer outside of the plasma glow zone . alternatively or additionally , the water - soluble hydrophilic monomer may be introduced outside of the plasma glow zone , as well , to provide further control of the deposition . the particulate or non - particulate material subsequent to being subjected to plasma is subsequently ( i . e ., after the plasma has been generated in the plasma chamber ) exposed to an organic hydrophilic monomer that is ultimately graft polymerized onto at least a portion of the particulate or non - particulate surface . so - called “ graft polymerization ” is known and has been used in the art with many graft copolymers such as abs ( acrylonitrile butadiene / styrene ) resins which have achieved considerable commercial success . it has also been known in the art that various vinyl monomers can be graft polymerized onto polymer substrates which have been first treated with ionizing radiation in the presence of oxygen or with ozone to form peroxy groups on the surface of said substrate . u . s . pat . nos . 3 , 008 , 920 and 3 , 070 , 573 teach the grafting of selected monomers onto ozonated surfaces . however , problems have also arisen when such a graft polymerization is carried out . for example , one serious complication involves graft polymerization of the vinyl monomer onto the substrate as desired , but with the simultaneous and undesired homopolymerization or crosslinking of the vinyl monomer which leads to a water - insoluble coating . by contrast , the present invention relates to a composition and process for modifying the surface characteristics of a particulate substrate with minimum of crosslinking to obtain a water - soluble coating . in that regard , operating the plasma chamber at the selected power and pressure levels described previously is important . typically , the graft polymerization of the organic monomer will take from about 1 minute to about 40 minutes , preferably 10 minutes to about 30 minutes . the organic monomer may be in the form of a liquid , a solid , or a solid - liquid mixture . for the liquid monomer , the monomer vapor is supplied by evaporation of monomer into the plasma which is facilitated by the application of a vacuum . similarly , for the solid monomer , such free radicals and / or ions are supplied by sublimed monomer vapor . for simplicity of description , the non - vapor monomer to be activated will be described herein as being in the liquid state unless otherwise specified . as mentioned previously , the water - soluble coating is formed from an organic hydrophilic monomer , some of which are mentioned above . the compositions preferably contain an effective amount of such monomer so as to achieve the desired solubility , flowability , chemical stability and / or other desired function for the particulate or non - particulate composition . in typical formulations , the coating which is formed of the monomer grafted onto the particulate or non - particulate composition will have a thickness in the range of from about 0 . 01 microns to about 1000 microns , more preferably from about 0 . 05 microns to about 50 microns and most preferably from about 0 . 1 microns to about 10 microns . suitable organic hydrophilic monomers include generally water soluble conventional vinyl monomers such as : acrylates and methacrylates of the general structure where r 2 is hydrogen or methyl and r 3 is hydrogen or is an aliphatic hydrocarbon group of up to about 10 carbon atoms substituted by one or more water solublizing groups such as carboxy , hydroxy , amino , lower alkylamino , lower dialkylamino , a polyethylene oxide group with from 2 to about 100 repeating units , or substituted by one or more sulfate , phosphate , sulfonate , phosphonate , carboxamido , sulfonamido or phosphonamido groups , or mixtures thereof ; where r 4 is lower alkyl of 1 to 3 carbon atoms and r 2 is as defined above ; where r 2 is as defined above and r 3 is as defined above with the proviso that r 3 is other than hydrogen ; and vinyl substituted heterocycles , such as vinyl pyridines , peperidines and imidazoles and n - vinyl lactams , such as n - vinyl - 2 - pyrrolidone . included among the useful water - soluble monomers are : 2 - hydroxyethyl -, 2 - and 3 - hydroxypropyl -, 2 , 3 - dihydroxypropyl -, polyethoxyethyl -, and polyethoxypropyl acrylates , methacrylates , acrylamides and methacrylamides ; acrylamide , methacrylamide , n - methylacrylamide , n - methylmethacrylamide , n , n - dimethylacrylamide , n , n - dimethylmethacrylamide ; n , n - dimethyl - and n , n - diethyl - aminoethyl acrylate and methacrylate and the corresponding acrylamides and methacrylamides ; 2 - and 4 - vinylpyridine ; 4 - and 2 - methyl - 5 - vinylpyridine ; n - methyl - 4 - vinylpiperidine ; 2 - methyl - 1 - vinylimidazole ; n , n - dimethylallyalamine ; dimethylarninoethyl vinyl ether , n - vinylpyrrolidone ; acrylic and methacrylic acid ; itaconic , crotonic , fumaric and maleic acids and the lower hydroxyalkyl mono and diesters thereof , such as the 2 - hydroxyethyl fumarate and maleate , sodium acrylate and methacrylate ; maleic anhydride ; 2 - methacryloyloxyethylsulfonic acid and allylsulfonic acid . preferred water soluble monomers include 2 - hydroxyethylmethacrylate ; n , n - dimethylacrylamide ; acrylic acid and methacrylic acid ; and most preferably 2 - hydroxyethyl methacrylate . the particulate and non - particulate compositions described herein can be in the form of detergent compositions which preferably contain a detersive surfactant and a detergent builder , and optionally , a variety of common detergent ingredients . the surfactant system of the detergent composition may include anionic , nonionic , zwitterionic , ampholytic and cationic classes and compatible mixtures thereof . detergent surfactants are described in u . s . pat . no . 3 , 664 , 961 , norris , issued may 23 , 1972 , and in u . s . pat . no . 3 , 919 , 678 , laughlin et al ., issued dec . 30 , 1975 , both of which are incorporated herein by reference . cationic surfactants include those described in u . s . pat . no . 4 , 222 , 905 , cockrell , issued sep . 16 , 1980 , and in u . s . pat . no . 4 , 239 , 659 , murphy , issued dec . 16 , 1980 , both of which are also incorporated herein by reference . nonlimiting examples of surfactant systems include the conventional c 11 - c 18 alkyl benzene sulfonates (“ las ”) and primary , branched - chain and random c 10 - c 20 alkyl sulfates (“ as ”), the c 10 - c 18 secondary ( 2 , 3 ) alkyl sulfates of the formula ch 3 ( ch 2 ) x ( choso 3 − m + ) ch 3 and ch 3 ( ch 2 ) y ( choso 3 − m + ) ch 2 ch 3 where x and ( y + 1 ) are integers of at least about 7 , preferably at least about 9 , and m is a water - solubilizing cation , especially sodium , unsaturated sulfates such as oleyl sulfate , the c 10 - c 18 alkyl alkoxy sulfates (“ ae x s ”; especially eo 1 - 7 ethoxy sulfates ), c 10 - c 18 alkyl alkoxy carboxylates ( especially the eo 1 - 5 ethoxycarboxylates ), the c 10 - 18 glycerol ethers , the c 10 - c 18 alkyl polyglycosides and their corresponding sulfated polyglycosides , and c 12 - c 18 alpha - sulfonated fatty acid esters . if desired , the conventional nonionic and amphoteric surfactants such as the c 12 - c 18 alkyl ethoxylates (“ ae ”) including the so - called narrow peaked alkyl ethoxylates and c 6 - c 12 alkyl phenol alkoxylates ( especially ethoxylates and mixed ethoxy / propoxy ), c 12 - c 18 betaines and sulfobetaines (“ sultaines ”), c 10 - c 18 amine oxides , and the like , can also be included in the surfactant system . the c 10 - c 18 n - alkyl polyhydroxy fatty acid amides can also be used . typical examples include the c 12 - c 18 n - methylglucamides . see wo 9 , 206 , 154 . other sugar - derived surfactants include the n - alkoxy polyhydroxy fatty acid amides , such as c 10 - c 18 n -( 3 - methoxypropyl ) glucamide . the n - propyl through n - hexyl c 12 - c 18 glucamides can be used for low sudsing . c 10 - c 20 conventional soaps may also be used . if high sudsing is desired , the branched - chain c 10 - c 16 soaps may be used . mixtures of anionic and nonionic surfactants are especially useful . other conventional useful surfactants are listed in standard texts . the detergent composition can , and preferably does , include a detergent builder . builders are generally selected from the various water - soluble , alkali metal , ammonium or substituted ammonium phosphates , polyphosphates , phosphonates , polyphosphonates , carbonates , silicates , borates , polyhydroxy sulfonates , polyacetates , carboxylates , and polycarboxylates . preferred are the alkali metal , especially sodium , salts of the above . preferred for use herein are the phosphates , carbonates , silicates , c 10 - 18 fatty acids , polycarboxylates , and mixtures thereof . more preferred are sodium tripolyphosphate , tetrasodium pyrophosphate , citrate , tartrate mono - and di - succinates , sodium silicate , and mixtures thereof ( see below ). specific examples of inorganic phosphate builders are sodium and potassium tripolyphosphate , pyrophosphate , polymeric metaphosphate having a degree of polymerization of from about 6 to 21 , and orthophosphates . examples of polyphosphonate builders are the sodium and potassium salts of ethylene diphosphonic acid , the sodium and potassium salts of ethane 1 - hydroxy - 1 , 1 - diphosphonic acid and the sodium and potassium salts of ethane , 1 , 1 , 2 - triphosphonic acid . other phosphorus builder compounds are disclosed in u . s . pat . nos . 3 , 159 , 581 ; 3 , 213 , 030 ; 3 , 422 , 021 ; 3 , 422 , 137 ; 3 , 400 , 176 and 3 , 400 , 148 , all of which are incorporated herein by reference . examples of nonphosphorus , inorganic builders are sodium and potassium carbonate , bicarbonate , sesquicarbonate , tetraborate decahydrate , and silicates having a weight ratio of sio 2 to alkali metal oxide of from about 0 . 5 to about 4 . 0 , preferably from about 1 . 0 to about 2 . 4 . water - soluble , nonphosphorus organic builders useful herein include the various alkali metal , ammonium and substituted ammonium polyacetates , carboxylates , polycarboxylates and polyhydroxy sulfonates . examples of polyacetate and polycarboxylate builders are the sodium , potassium , lithium , ammonium and substituted ammonium salts of ethylene diamine tetraacetic acid , nitrilotriacetic acid , oxydisuccinic acid , mellitic acid , benzene polycarboxylic acids , and citric acid . polymeric polycarboxylate builders are set forth in u . s . pat . no . 3 , 308 , 067 , diehl , issued mar . 7 , 1967 , the disclosure of which is incorporated herein by reference . such materials include the water - soluble salts of homo - and copolymers of aliphatic carboxylic acids such as maleic acid , itaconic acid , mesaconic acid , fumaric acid , aconitic acid , citraconic acid and methylenemalonic acid . some of these materials are useful as the water - soluble anionic polymer as hereinafter described , but only if in intimate admixture with the nonsoap anionic surfactant . other suitable polycarboxylates for use herein are the polyacetal carboxylates described in u . s . pat . no . 4 , 144 , 226 , issued mar . 13 , 1979 to crutchfield et al ., and u . s . pat . no . 4 , 246 , 495 , issued mar . 27 , 1979 to crutchfield et al ., both of which are incorporated herein by reference . these polyacetal carboxylates can be prepared by bringing together under polymerization conditions an ester of glyoxylic acid and a polymerization initiator . the resulting polyacetal carboxylate ester is then attached to chemically stable end groups to stabilize the polyacetal carboxylate against rapid depolymerization in alkaline solution , converted to the corresponding salt , and added to a detergent composition . particularly preferred polycarboxylate builders are the ether carboxylate builder compositions comprising a combination of tartrate monosuccinate and tartrate disuccinate described in u . s . pat . no . 4 , 663 , 071 , bush et al ., issued may 5 , 1987 , the disclosure of which is incorporated herein by reference . water - soluble silicate solids represented by the formula sio 2 . m 2 o , m being an alkali metal , and having a sio 2 : m 2 o weight ratio of from about 0 . 5 to about 4 . 0 , are useful salts in the detergent granules of the invention at levels of from about 2 % to about 15 % on an anhydrous weight basis , preferably from about 3 % to about 8 %. anhydrous or hydrated particulate silicate can be utilized , as well . any number of additional ingredients can also be included as components in the granular detergent composition . these include other detergency builders , bleaches , bleach activators , suds boosters or suds suppressors , anti - tarnish and anti - corrosion agents , soil suspending agents , soil release agents , germicides , ph adjusting agents , nonbuilder alkalinity sources , chelating agents , smectite clays , enzymes , enzyme - stabilizing agents and perfumes . see u . s . pat . no . 3 , 936 , 537 , issued feb . 3 , 1976 to baskerville , jr . et al ., incorporated herein by reference . bleaching agents and activators are described in u . s . pat . no . 4 , 412 , 934 , chung et al ., issued nov . 1 , 1983 , and in u . s . pat . no . 4 , 483 , 781 , hartman , issued nov . 20 , 1984 , both of which are incorporated herein by reference . chelating agents are also described in u . s . pat . no . 4 , 663 , 071 , bush et al ., from column 17 , line 54 through column 18 , line 68 , incorporated herein by reference . suds modifiers are also optional ingredients and are described in u . s . pat . nos . 3 , 933 , 672 , issued jan . 20 , 1976 to bartoletta et al ., and 4 , 136 , 045 , issued jan . 23 , 1979 to gault et al ., both incorporated herein by reference . suitable smectite clays for use herein are described in u . s . pat . no . 4 , 762 , 645 , tucker et al ., issued aug . 9 , 1988 , column 6 , line 3 through column 7 , line 24 , incorporated herein by reference . suitable additional detergency builders for use herein are enumerated in the baskerville patent , column 13 , line 54 through column 16 , line 16 , and in u . s . pat . no . 4 , 663 , 071 , bush et al ., issued may 5 , 1987 , both incorporated herein by reference . the compositions of the present invention can also be in the form of cosmetic compositions or components thereof . typically , such compositions contain insoluble particles at levels of from about 0 . 1 % to about 20 %, more preferably from about 0 . 25 % to about 15 %, and most preferably from about 0 . 5 % to about 10 %, based on the weight of the total composition . such insoluble particles are useful for enhancing the cleansing effect , when the compositions of the present invention are in the form of a cleansing composition . the term “ insoluble ”, as used herein , means that the particles are essentially insoluble in the compositions of the present invention . in particular , the insoluble particles should have a solubility less than about 1 gram per 100 grams of composition at 25 . degree . c ., preferably less than about 0 . 5 grams per 100 grams of composition at 25 . degree . c ., and more preferably less than about 0 . 1 grams per 100 grams of composition at 25 . degree . c . useful herein are both micronized and conventional size insoluble particles . the micronized particles , for the most part , are of a size that is below the tactile threshold and are essentially nonabrasive to the skin . the conventional size particles are tactilely perceptible and are added for the scrubbing and abrasive effect which they provide . the micronized particles have a mean particle size diameter and particle size distribution such that they are below the tactile perception threshold of most users , and yet are not so small as to be ineffective for aiding in oil , dirt , and debris ( e . g ., make - up ) removal . it is found herein that particles having a mean particle size diameter greater than about 75 microns are tactilely perceived during the cleansing process mid it is important to minimize the amount of these larger particles if it is desired that the particles not be felt by the user . conversely , it is found that particles having a mean particle size diameter of less than about 1 to about 5 microns are generally less effective for providing a cleansing benefit . without being limited by theory , it is believed that the micronized cleansing particles should be of a size that is on the order of the thickness of the dirt , oil , or debris layer to be cleaned away . this layer is believed to be on the order of a few microns in thickness in most instances . it is therefore found in the present invention that the micronized particles should have a mean particle size diameter from about 1 to about 75 microns , more preferably from about 15 to about 60 microns , and most preferably from about 20 to about 50 microns , so as to provide effective cleansing without being tactilely perceptible . particles having a wide range of shapes , surface characteristics , and hardness characteristics can be utilized herein provided the particle size requirements are met . micronized particles of the present invention can be derived from a wide variety of materials including those derived from inorganic , organic , natural , and synthetic sources . nonlimiting examples of these materials include those selected from the group consisting of almond meal , alumina , aluminum oxide , aluminum silicate , apricot seed powder , attapulgite , barley flour , bismuth oxychloride , boron nitride , calcium carbonate , calcium phosphate , calcium pyrophosphate , calcium sulfate , cellulose , chalk , chitin , clay , corn cob meal , corn cob powder , corn flour , corn meal , corn starch , diatomaceous earth , dicalcium phosphate , dicalcium phosphate dihydrate , fullers earth , hydrated silica , hydroxyapatite , iron oxide , jojoba seed powder , kaolin , loofah , magnesium trisilicate , mica , microcrystalline cellulose , montmorillonite , oat bran , oat flour , oatmeal , peach pit powder , pecan shell powder , polybutylene , polyethylene , polyisobutylene , polymethylstyrene , polypropylene , polystyrene , polyurethane , nylon , teflon ( i . e . polytetrafluoroethylene ), polyhalogenated olefins , pumice rice bran , rye flour , sericite , silica , silk , sodium bicarbonate , sodium silicoaluminate , soy flour synthetic hectorite , talc , tin oxide , titanium dioxide , tricalcium phosphate , walnut shell powder , wheat bran , wheat flour , wheat starch , zirconium silicate , and mixtures thereof . also useful are micronized particles made from mixed polymers ( e . g ., copolymers , terpolymers , etc . ), such as polyethylene / polypropylene copolymer , polyethylene / propylene / isobutylene copolymer , polyethylene / styrene copolymer , and the like . typically , the polymeric and mixed polymeric particles are treated via an oxidation process to destroy impurities and the like . the polymeric and mixed polymeric particles can also optionally be crosslinked with a variety of common crosslinking agents , nonlimiting examples of which include butadiene , divinyl benzene , methylenebisacrylamide , allyl ethers of sucrose , allyl ethers of pentaerythritol , and mixtures thereof . other examples of useful micronized particles include waxes and resins such as paraffins , carnuba wax , ozekerite wax , candellila wax , urea - formaldehyde resins , and the like . when such waxes and resins are used herein it is important that these materials are solids at ambient and skin temperatures . among the preferred water - insoluble , micronized particulate materials useful herein are the synthetic polymeric particles selected from the group consisting of polybutylene , polyethylene , polyisobutylene , polymethylstyrene , polypropylene , polystyrene , polyurethane , nylon , teflon , and mixtures thereof . most preferred are polyethylene and polypropylene micronized particles , with the oxidized versions of these materials being especially preferred . examples of commercially available particles useful herein include the acumist . tm . micronized polyethylene waxes available from allied signal ( morristown , n . j .) available as the a , b , c , and d series in a variety of average particle sizes ranging from 5 microns to 60 microns . preferred are the acumist . tm . a - 25 , a - 30 , and a - 45 oxidized polyethylene particles having a means particle size of 25 , 30 , and 45 microns , respectively . examples of commercially available polypropylene particles include the propyltex series available from micro powders ( dartek ). the conventional size insoluble particles are well - known to formulation chemists in the art . these particles typically have larger particle sizes than the micronized particles described herein . these particles generally have an average particle size diameter that is about 75 microns or greater , which is about the tactile threshold described above . these conventional size particles typically have average particle sizes ranging up to about 400 microns and larger . these particles can be made from the same materials as for the micronized particles just described . among the preferred conventional size particulate materials useful herein are the synthetic polymeric particles selected from the group consisting of polybutylene , polyethylene , polyisobutylene , polymethylstyrene , polypropylene , polystyrene , polyurethane , nylon , teflon , and mixtures thereof . most preferred are polyethylene and polypropylene micronized particles , with the oxidized versions of these materials being especially preferred . an example of a commercially available conventional size particle useful herein is acuscrub . tm . 51 , available from allied signal ( morristown , n . j .) having a mean particle size of about 125 microns . other product forms containing plasma - coated particles in accordance with the invention are also contemplated . by way of example , mcatee et al , u . s . pat . no . 5 , 665 , 364 , and lafleur et al , u . s . pat . no . 5 , 683 , 706 , disclose a cosmetic compositions and a variety of particulate ingredients suitable for plasma coating with a water - soluble coating according to the invention . the following examples are presented for illustrative purposes only and are not to be construed as limiting the scope of the appended claims in any way . a dishwashing tablet having the formula set forth in table i below is placed on the bottom electrode of a vacuum chamber of plasma discharge unit ( commercially available from aps inc ., model d ). the plasma chamber is depressurized to 20 mtorr . a carrier gas mixture ( argon / oxygen at 1 / 1 ratio ) is continuously introduced into the chamber at a constant rate ( 10 sccm ), so the pressure inside the chamber is maintained at 63 mtorr by the balance of continuous evacuation and introduction of the carrier gas . while maintaining the above - noted conditions , low temperature plasma is generated inside the chamber for a period of 5 minute by supplying high frequency electricity ( 200 watts ) at a frequency of 40 khz so as to expose the surface of the tablet to the low temperature plasma . thereafter , an organic hydrophilic monomer ( acrylic acid ) is introduced into the chamber at a constant rate to maintain constant pressure in the chamber at 200 mtorr for 10 minutes during which no plasma is generated and deposited onto the tablet . the chamber is evacuated ( 30 mtorr ) and flooded with atmospheric air . the resultant tablet has a water - soluble coating formed of the deposited monomer . the water solubility of the tablet is unexpectedly equal to uncoated tablets and superior to tablets coated by means other than plasma deposition . several detergent compositions made in accordance with the invention and specifically for top - loading washing machines are coated with an acrylic monomer . specifically , a prototype apparatus is configured using a modified , rotational vaporator with a 12 inch ( 30 . 5 cm ) quartz tube for the treatment chamber and an external coil electrode wrapped over a 6 inch ( 15 . 25 cm ) length . a 50 gram sample of detergent composition is placed in the plasma glow zone , and argon gas is introduced into the plasma chamber which is maintained at 200 mtorr for 15 minutes min . at the output of 100 watts by the inductive coupling system using a radio frequency power system of 13 . 6 mhz while rotating the cylinder of the reactor at 10 rpm . the detergent compositions are then plasma treated with oxygen for 15 minutes at the output of 100 watts by the inductive coupling system using a radio frequency power system of 13 . 6 mhz while rotating the cylinder of the reactor at 10 rpm . after the plasma treatment , acrylic acid vapor is introduced into the chamber which is maintained at 500 mtorr and graft polymerization on the detergent compositions occurs for 20 minutes . the resulting compositions are exemplified below . the base granule is prepared by a conventional spray drying process in which the starting ingredients are formed into a slurry and passed though a spray drying tower having a countercurrent stream of hot air ( 200 - 300 ° c .) resulting in the formation of porous granules . the admixed agglomerates are formed from two feed streams of various starting detergent ingredients which are continuously fed , at a rate of 1400 kg / hr , into a lödige cb - 30 mixer / densifier , one of which comprises a surfactant paste containing surfactant and water and the other stream containing starting dry detergent material containing aluminosilicate and sodium carbonate . the rotational speed of the shaft in the lödige cb - 30 mixer / densifier is about 1400 rpm . the contents from the lödige cb - 30 mixer / densifier are continuously fed into a lödige km - 600 mixer / densifier for further agglomeration . the resulting detergent agglomerates are then fed to a fluid bed dryer and to a fluid bed cooler before being admixed with the spray dried granules . the remaining adjunct detergent ingredients are sprayed on or dry added to the blend of agglomerates and granules . 2 made according to u . s . pat . no . 5 , 415 , 807 , issued may 16 , 1995 to gosselink et al the resulting detergent compositions unexpectedly have improved chemical stability and flowability . the following detergent compositions accordance with the invention are especially suitable for front loading washing machines and are coated with an acrylic acid monomer as described in example ii . the compositions are made in the manner of examples ii - iv . the resulting detergent compositions unexpectedly have improved chemical stability , flowability , and excellent dissolution characteristics . accordingly , having thus described the invention in detail , it will be obvious to those skilled in the art that various changes may be made without departing from the scope of the invention , and the invention is not to be considered limited to what is described in the specification .

a composition having a plasma - induced , graft polymerized , water - soluble coating for controlling solubility , chemical stability and physical properties is disclosed . a process for making such a composition is also disclosed which involves subjecting a particulate material to plasma after which a water - soluble organic monomer is graft polymerized onto at least a portion of the particulate material . the compositions are particulate or non - particulate in form and can be used in shampoos , skin care and other cosmetic products , deodorant products , laundry , dishwashing , carwashing or other similar detergent products .

the following is a detailed description of my new variety of sugar maple . the chart used in identification of colors is that of the royal horticultural society ( r . h . s . colour chart ). common color terms are to be accorded their ordinary dictionary meaning . the description is based on a test planting of the new variety at new madrid , mo . and on the 20 year old tree shown in the photographs . parentage : chance seeding of acer saccharum of unknown origin found growing in a cultivated area in tullahoma , tenn . the seedling was notably shorter and had smaller leaves than the other seedlings around it . tree shape : upright , oval with layered very dense branch structure . size : smaller than standard acer saccharum of same age ; almost semi - dwarf . the height is almost 25 feet and breadth is about 15 feet at 20 years . the mature size should be no more than 35 feet . growth : moderate when young ; very slow after 10 years . trunk : generally straight and upright and trunk diameter is 8 inches measured 4 feet from the base . bark : gray group 201c , fan 4 grey ( r . h . s .). branches : on a typical sugar maple measuring the same height as ‘ hawkersmith 1 ’, a branch measured 8 feet from ground level was 5½ inches in caliper measured 6 inches from main trunk and was 15 feet in length . texture is smooth and coloration was found to match fan 4 page 200 a brown group ( r . h . s .). ‘ hawkersmith 1 ’ has a branch caliper of 2⅛ inches and a length of 8 feet , 4 inches , both being measured by the same specifications as was the typical sugar maple . texture is smooth and coloration matches fan 4 , page 199 b grey / brown group ( r . h . s .). leaves : much smaller , slightly darker and slightly thicker than standard sugar maple . on a typical sugar maple the leaf shape is simple and palmate . the length is 3 inches , the width is 6 inches , the apex is acuminate , the base is cordate , and the margin is lobed . ‘ hawkersmith1 ’ leaf shape is simple and palmate . the length is from 2 1 / 16 inches to 4 1 / 16 inches . the width is from 2⅜ inches to 4 15 / 16 inches . the apex is acuminate , the base is cordate , and the margin is lobed . visually the leaf is heavier and thicker as can be noted in the photos . color : the new growth and fall color of the leaves of the instant tree is dark red to bronze . the summer color is darker green than standard acer saccharum . the leaves turn their fall color 2 - 3 weeks later than standard sugar maples . bud sets : vary from ¼ ″ apart at the ends of the branches to about 2 ″ apart toward the trunk . the buds are brown and scaly . the bud shape is conical ⅛ inch long , 1 / 16 inch wide and the color was found to match fan 4 , page 200 c , brown group ( r . h . s .). reproductive organs and fruit : no seed , fruit or flowers have yet been observed . petiole : the petiole length is from 1⅜ inches to 5⅜ inches . the diameter is from 1 / 32 inch to 1 / 16 inch . ability to withstand head : the tree is tolerant of summer heat in the south and is very drought tolerant compared to standard sugar maple . cold hardiness : the tree has no winter die back . it also has withstood high winds and ice in usda zones 4 - 8 . disease resistance : no disease or insect problems have been noted . leaf and petiole color comparison with the royal horticultural society colour chart : new petiole — fan 3 yellow - green group 146 b . new leaf upper surface — fan 4 greyed - purple group 185 b . new leaf lower surface — fan 4 greyed - purple group 186 c . summer petiole — fan 3 yellow - green group n 144 d . summer leaf upper surface — fan 3 yellow - green group 147 a . summer leaf lower surface — fan 3 yellow - green group 144 a . fall petiole — fan 4 greyed - green group 197 c . fall leaf upper surface — fan 4 greyed - purple group 184 c . fall leaf lower surface — fan 4 greyed - purple group 185 d .

a new culivar of sugar maple tree having a compact oval appearance , dark red to bronze new growth and fall foliage , small , dark and slightly thicker leaves , good summer heat and drought resistance and cold hardiness . the tree is beautiful , compact , tought , colorful and functional as an ornamental shade tree .

the detailed description set forth below in connection with the appended drawings is intended as a description of various and preferred embodiments of the present disclosure , and is not intended to represent the only forms that may be developed or utilized . the description sets forth the various functions in connection with the illustrated embodiments , but it is to be understood , however , that the same or equivalent functions may be accomplished by different embodiments that are also intended to be encompassed within the scope of the present disclosure . it is further understood that the use of relational terms such as first and second and the like are used solely to distinguish one from another entity without necessarily requiring or implying any actual such relationship or order between such entities . referring now to the drawings , specifically , fig1 - 4 , there is depicted a cap 10 having a selectively adjustable visor 12 . more specifically , the visor 12 includes a slit visor body 14 ( fig5 - 9 ) having a proximal portion 16 ( fig5 - 9 ) and distal portion ( s ) 18 ( fig5 - 9 ) selectively moveable relative to the proximal portion 16 . the distal portion 18 may be adjusted to modify the amount of shade provided by the visor 12 and / or to make apparent of the artwork ( not shown ) on visor cover 34 . referring now specifically to fig5 - 9 , there is depicted a unitary visor body 14 defining the proximal portion 16 and the distal portion ( s ) 18 , preferably formed from a single piece of material . the visor body 14 includes a first ( upper ) surface 20 and an opposing second ( lower ) surface 22 , preferably defining a uniform thickness , although it is understood that the visor body 14 may also define a non - uniform thickness . according to one embodiment , a slit 24 is formed within the visor body 14 and extends from the first surface 20 to the second surface 22 . the slit 24 is formed to allow the distal portion 18 to articulate relative to the proximal portion 16 between a first position and a second position . the slit 24 terminates at a first slit end 26 and an opposing second slit end 28 . in this regard , the slit 24 is contained within the visor body 14 and does not completely dissect the visor body 14 which would result in separate proximal and distal portions 16 , 18 . accordingly , the visor body 14 includes a pair of connector portions 30 where the proximal portion 16 meets the distal portion 18 . in this regard , the distal portion 18 may be integrally connected to the proximal portion 16 via the connector portions 30 . the connector portions 30 may be flexible enough to allow the distal portion 18 to easily adjust up or down between the first and second positions . in a variation of the invention , the slit ( s ) 24 may extend from the periphery of the visor body 14 into the middle of the visor body 14 , which may result in a connector portion 30 , which is medial to the laterally disposed slit ( s ) 24 ( see fig1 ). for instance , the visor body 14 may include a single medial connector portion 30 disposed between a pair of lateral slits 24 extending into the visor body 14 from the periphery of the visor body 14 . in another variation of the invention , a straight slit can terminate at slit ends 26 and 28 ( see fig8 and 9 ). in this configuration , the slit 24 may only extend partially between the first surface 20 and the second surface 22 . along these lines , the slit 24 may extend partially from the first surface 20 toward the second surface 22 ( which may facilitate bending of the distal portion 18 about the second surface 22 ), or from the second surface 22 toward the first surface 20 ( which may facilitate bending of the distal portion 18 about the first surface 20 ). it is further contemplated that as an alternative to , or in conjunction with , the slit 24 in the visor body 14 , various polymer materials may be selected for visor body 14 to form fixed configurations of the distal portion 18 or to form curvature on first and second surfaces 20 , 22 on the distal portion 18 . for example , the polymer materials may include , but are not limited to , abs plastic , polyurethane , polyester , or vinyl , or a combination thereof . in operation , before and / or after the visor cover 34 is disposed about the visor body 14 , heat and pressure is applied to induce the polymer visor body 14 to soften and reshape into optimal configuration . upon subsequent cooling , the polymer visor body 14 solidifies and retains the new shape . the first and second surfaces 20 , 22 extend across both the proximal portion 16 and the distal portion 18 , such that when the distal portion 18 is disposed in the first position ( see fig3 , 4 , 5 and 7 ), the distal most tip 36 is disposed down , or towards the second side of the plane defined by the proximal portion 16 . when the distal portion 18 is disposed in the second position ( as shown in phantom in fig3 ), the distal most tip 36 is disposed up , or towards the first side of the plane defined by the proximal portion 16 . it is contemplated that the distal portion 18 may additionally be disposed in a planar position relative to the proximal portion 16 , wherein the distal portion 18 is substantially co - planar with the proximal portion 16 . the slit 24 and connector portion 30 allow the distal portion 18 to articulate is relative to the proximal portion 16 without requiring the use of a hinge or other pivoting members . in this regard , the visor body 14 may be safer and more aesthetically pleasing than a visor having a hinge connected thereto . more specifically , a hinged visor may present a risk of getting the wearer &# 39 ; s hair caught in the hinge . therefore , by providing a visor 12 which is moveable without a hinge , such a risk is mitigated . furthermore , a hinge may detract from the overall appearance of the cap . therefore , a slit visor may be seamlessly integrated into a conventional cap design without detracting from the overall appearance of the cap . one embodiment of the visor 12 includes a visor cover 34 disposed about the visor body 14 and connected to a crown 32 . the visor cover 34 may include a fabric , leather , plastic vinyl , or other materials known by those skilled in the art . the lack of hinges or other pivoting elements on the visor body 14 allows the visor cover 34 to be seamlessly disposed about the visor body 14 to enhance the aesthetic appeal of the cap 10 . furthermore , the lack of hinges or pivoting elements allows a needle on a conventional sewing machine to puncture / stitch / sew without any modification or need to avoid certain areas on the visor body 14 ( such as hinges ), which may break the needle . the visor cover 34 may include one or more layers of stretchable or non - stretchable material and may contain various sections that are disposed adjacent to the first surface 20 and / or the second surface 22 of the visor body 14 to account for the movement of the distal portion 18 between the first position and the second position . the visor cover 34 may include designs or other artwork displayed adjacent the distal portion 18 , such that when the distal portion 18 is disposed in the first or second position , the artwork becomes more readily apparent . as used herein , the term “ cap ” may refer to a conventional baseball cap , sun visor , golf hat or any other headwear known by those skilled in the art having a visor connected thereto . the visor 12 may extend from a portion of the crown 32 , as depicted in fig1 - 4 , or may completely circumnavigate the crown 32 ( not shown ). in this regard , the visor body 14 may include a plurality of slits 24 extending around the visor body 14 . it is also contemplated that the visor body 14 may include a plurality of overlapping slits 24 formed therein to allow for multiple angular dispositions of the visor 12 ( see fig1 ). in this regard , the term “ overlapping ” refers to slits 24 which intersect a common axis . overlapping slits 24 may enable greater degree of adjustment by the wearer . the slit 24 may additionally be curved ( see fig2 ), straight , zig - zag , waved , and the like , which is distinguishable from hinged visors , which cannot achieve their purpose with a curved slit . the slit 24 may be configured to be a gap , a cut , aperture , or any other suitable shape . the visor body 14 may be formed from a material capable of facilitating movement of the distal portion 18 relative to the proximal portion 16 . exemplary materials include , but are not limited to , cardboard , abs plastic , sheet metal or other suitable materials known by those skilled in the art . the visor body 14 may also be formed from a simple manufacturing process , i . e ., cutting the visor body 14 from a sheet of material , and forming / cutting the slit 24 within the visor body 14 . in this manner , the visor body 14 may be formed without injection molding , which tends to result in increased material , tooling , and labor costs . while the invention has been described with reference to various and preferred embodiments , it should 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 essential 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 embodiments disclosed herein contemplated for carrying out this invention , but that the invention will include all embodiments falling within the scope of the claims .

a headwear having a selectively adjustable visor is disclosed . the headwear includes a crown for covering at least a portion of a wearer &# 39 ; s head . a visor is attached to the crown and includes a visor cover disposed over a unitary visor body . the visor body has a first surface and an opposing second surface to define a uniform thickness . the visor body is configured with at least one slit formed therein . the at least one slit defines a proximal portion and a distal portion . the distal portion is transitional relative to the proximal portion between a first position and a second position . the slit allows the distal portion of the visor to adjust relative to the proximal portion , thereby to enhancing the visor appearance of the headwear and providing a better shade to the wearer .

this application concerns a method referred to in non - elected claims of the “ parent ” utility patent application ser . no . 09 / 907 , 781 , filed jul . 18 , 2001 . turning now to fig1 – 11c , preferred embodiments of a unique method that use an impedance spectroscopy system 10 , with catheters 12 a – 12 d , for monitoring ischemic mucosal damage monitoring in hollow viscous organs , will now be given . the catheters 12 a – 12 d are generally similar , in that each one has two or four electrodes with annular side surfaces positioned at a distal end of the catheter . for example , the catheter 12 a comprises a flexible tube 14 and two or four generally cylindrical electrodes 16 a – 16 d disposed at one end thereof . the electrodes 16 a – 16 d are electrically connected , via leads 18 a – 18 d extending up through the tube 14 , to an impedance spectrometer 20 portion of the system 10 . the spectrometer 20 is used in conjunction with a signal processing device 22 , such as an appropriately - programmed general purpose computer , for processing the complex impedance spectrum to detect tissue damage . to monitor mucosal damage , the catheter is placed in one of a patient &# 39 ; s hollow viscous organs 24 , and current is injected by two of the electrodes 16 a , 16 d at a range of frequencies . the other two electrodes 16 b , 16 c measure the resulting voltage spectrum , which is subsequently processed and analyzed by the spectrometer 20 and signal processing device 22 . fig2 a – 2c show a first embodiment 12 a of the preferred catheter , used in the preferred method . the catheter 12 a comprises the flexible plastic tube 14 that can be inserted in any hollow viscous organ ( e . g ., 14 – 16 french ). at the distal end or tip of the tube 14 are located the two or four electrodes 16 a – 16 d ( i . e ., the catheter can be provided with either two electrodes or four electrodes ) that function as ionic - current - to - electronic - current transducers , such as ag / agcl electrodes . the electrodes are substantially identical . as best shown in fig2 b , each has a cylindrical central portion ( e . g ., 24 a ) having a first diameter and two annular side surfaces ( e . g ., 25 a , 25 b ), and two cylindrical extensions ( e . g ., 26 a , 26 b ) attached to the ends of the central portion and coaxial therewith . each extension ( e . g ., 26 a , 26 b ) has a second , reduced diameter , and each electrode 16 a – 16 d has an axial through - bore . the electrodes 16 a – 16 d are spaced equally apart from one another along the distal tip of the catheter 12 a , and are separated by spacers ( short lengths of tubing ) 27 a – 27 d . as best seen in fig2 a , the annular side walls of the central portions 24 of the electrodes 16 a – 16 d are the only portions thereof that are exposed to the outside of the catheter 12 a . thus , each electrode 16 a – 16 d is ring - like in functionality , and the distal end of the catheter ( with the electrodes ) is generally radially symmetric . the catheter , therefore , will provide the same measurements regardless of its radial orientation in an organ . the diameters of the central electrode portions ( e . g ., 24 a ) are about the same as the outer diameter of the tube 14 . this ensures that the outer surface of the catheter 12 a is relatively smooth , e . g ., that it has no more than minor surface roughness or undulations . the electrodes 16 a – 16 d are respectively electrically connected to the leads 18 a – 18 d ( via soldering , welding , or the like ) in the electrodes &# 39 ; axial through - bores . the leads from the distal three electrodes 16 b – 16 d extend through the axial through - bores of the other electrodes , as applicable . the electrodes 16 a – 16 d , leads 18 a – 18 d , and short portions of tubing are kept in place and stabilized via an epoxy or plastic fill 28 . the catheter 12 a may be a stand alone sensor catheter , or it may be provided as part of a feeding / sump tube or some other type of life support tube or catheter . for example , as shown in fig2 a , the catheter 12 a doubles as a feeding tube . more specifically , the end of the catheter 12 a is provided with the electrodes 16 a – 16 d , while the remainder of the tube 14 is left hollow to act as a feeding line 29 . additionally , the catheter tube 14 may include a second lumen for sampling and feeding , like a levin type gastric catheter , and / or a third lumen for a vented feeding / sump tube , as in a salem type gastric catheter . for example , as shown in fig2 c , the electrical leads 18 a – 18 d extend down through a side wall portion of the tube 14 having a vent lumen 30 and a feeding / sump lumen 32 . to manufacture the catheter 12 a , the leads 18 a – 18 d are fed through the tube 14 , if needed ( since the leads may be provided as part of the tube 14 during the tube &# 39 ; s manufacturing process ), and through the electrode through - bores , as applicable . the leads are subsequently electrically connected to the respective electrodes . then , the proximate electrode 16 a is inserted in the end of the tube 14 , one of the short lengths of tubing is affixed to the proximate electrode 16 a , and so on . adhesive may be used to hold the components together in this manner . finally , the plastic or epoxy fill 28 is injected into the space between the tubing portions , electrodes , and partially into the tube 14 , and is allowed to set . the end of the fill 28 is rounded , as shown in fig2 a , to ease insertion of the catheter into a patient . as will be appreciated by those of skill in the manufacturing arts , the catheter 12 a can be manufactured according to a number of different methods and / or steps . for example , the catheter could be extruded from a machine . if the catheter 12 a is provided with four electrodes , the two outer ring electrodes 16 a , 16 d inject a current into the tissue , and the two inner electrodes 16 b , 16 c measure the resulting voltage , as shown schematically in fig7 . in the two electrode configuration ( not shown ), the electrodes are used for both current source and voltage measurement . as mentioned above , the electrodes 16 a – 16 d are respectively connected to the leads 18 a – 18 d that provide an electrical connection to the other end of the catheter along the wall of the tubing or in the lumen . at the other , proximal end of the catheter , the leads 18 a – 18 d end in an electrical multi - channel connector 34 that can be plugged into the impedance spectrometer 20 . fig3 shows a second , alternative embodiment of the catheter 12 b . here , the catheter 12 b has four tubular or ring - like electrodes 36 a – 36 d simply placed over ( and adhered to ) the exterior surface of the tubing 14 , with the leads extending from the electrodes down through the tube wall . in this case , the electrodes would have to be as thin as possible to minimize surface roughness . fig4 a – 4c show a third embodiment of the catheter 12 c . the catheter 12 c is generally similar to the catheter 12 a , but has spacers ( e . g ., 42 a , 42 b , 42 c ), provided with annular internal sockets or spacer lips ( e . g ., 52 a , 52 b ), into which flanged electrodes ( e . g ., 44 a , 44 b ) lock into place . in this sample interlocking means , each flanged electrode ( e . g ., 44 a , 44 b ) has a cylindrical central portion ( e . g ., 46 a , 46 b ) having a first diameter and two annular side surfaces , two extensions ( e . g ., 48 a , 48 b ) attached to the ends of the central portion and coaxial therewith , and an axial through - bore . the extensions ( e . g ., 48 a , 48 b ) each have a second , reduced diameter , but instead of being purely cylindrical , the extensions ( e . g ., 48 a , 48 b ) have annular electrode lips ( e . g ., 50 a , 51 a ) that face towards the central portion 46 . additionally , the spacers ( e . g ., 42 a – 42 c ) are made of flexible plastic tubing ( i . e ., a relative non - conductor of electricity ) or the like . each spacer has two annular , inwardly - facing shoulders , in this embodiment , which form the sockets ( e . g ., 52 a , 52 b ). the shoulders are spaced back a bit from the open ends of the spacers . as shown in fig4 b , the electrode extensions ( e . g ., 48 a , 48 b ) are dimensioned to fit within the spacers ( e . g ., 42 a , 42 b ), such that the electrode lips ( e . g ., 50 a , 50 b ) abut the shoulders , locking the flanged electrodes ( e . g ., 44 a , 44 b ) to the spacers ( e . g ., 42 a – 42 c ). the catheter 12 c is assembled similarly to the catheter 12 a , as described above . more specifically , the leads are electrically connected to the electrodes ( e . g . 44 a , 44 b ) and are threaded through the spacers and electrodes , and the electrodes ( e . g ., 44 a , 44 b ) are locked into successive spacers ( e . g ., 42 a , 42 b ) to form an assembly of two or four electrodes . as should be appreciated , since the electrodes ( e . g ., 44 a , 44 b ) simply snap into the spacers ( e . g ., 42 a , 42 b ), assembly is much quicker . finally , the assembly is filled with the epoxy or plastic fill 28 to further hold the assembly together and to provide a rounded tip , e . g ., as shown in fig2 a . also , the ends of the leads are connected to the multi - channel connector 34 . to give the catheter 12 c a smooth , low - friction outer surface , the diameter of the central portions ( e . g ., 46 c ) of the electrodes ( e . g ., 44 a ) may be initially slightly greater than the outer diameter of the spacers ( e . g ., 42 a , 42 b ), as shown in fig4 c . then , once the catheter 12 c is assembled , the outer surface of the catheter is sanded , remove the portions ( e . g ., 54 ) of the electrodes that extend past the spacers . fig5 a – 5c show a fourth embodiment of the catheter 12 d . the catheter 12 d comprises : an injection - molded , plastic tip 60 ; two or four electrodes 62 a – 62 d ; one or three spacers 64 a – 64 c ( i . e ., in the case of two electrodes , one spacer is needed , while three spacers are needed for a four electrode catheter ); dual - lumen tubing 66 or the like ; and the cables or leads 18 a – 18 d . as best shown in fig5 b , the plastic tip 60 comprises a rounded fore portion 68 and a rounded , trough - like projection 70 that extends back from the fore portion 68 . as indicated , the tip 60 can be injection molded , or it can be made via another suitable manufacturing process . the electrodes 62 a – 62 d and spacers 64 a – 64 c are generally similar in shape . each has a small , cylindrical passageway ( e . g ., 72 a , 72 b , 72 c , 72 d ) for the cables 18 a – 18 d , as well as a rounded through - bore ( e . g ., 74 a , 74 b , 74 c , 74 d ) through which the trough - like projection 70 of the tip 60 is dimensioned to fit ( i . e ., the rounded through - bores , e . g ., 74 a , 74 b , 74 c , 74 d , and projection 70 are complementary in shape ). additionally , the outer diameters of the electrodes and spacers are the same as the outer diameter of the tip 60 , which has the same outer diameter as the tubing 66 . to assemble the catheter 12 d , the cables 18 a – 18 d are respectively electrically connected to the electrodes 62 a – 62 d , and alternating electrodes 62 a – 62 d and spacers 64 a – 64 c are slid over the projection 70 . simultaneously , the cables 18 a – 18 d are inserted through the passageways ( e . g ., 72 a , 72 b , 72 c , 72 d ), as applicable . then , the portion of the projection 70 not covered by electrodes and spacers is slid into the tubing 66 , as shown in fig5 a . appropriate fastening means , such as a solvent or an adhesive , are used to hold the components of the catheter 12 d together . as should be appreciated , the rounded through - bores 74 and projection 70 can be provided in any of a number of complementary shapes . for example , the projection and through - bores can be v - shaped , square , or circular . however , having a v - or trough - shaped projection , or a projection with another shape where the electrodes and spacers have to be oriented in a particular manner to be positioned over the projection , facilitates assembly and enhances structural stability . referring back to fig1 , the system 10 generally consists of three elements : any of the catheters 12 a – 12 d ; the impedance spectrometer 20 ; and the signal processing device 22 . the impedance spectrometer 20 is an electronic instrument that includes electrical patient isolation and can measure the impedance spectrum of the mucosa in the range of 10 hz ( or thereabouts ) to 10 mhz ( or thereabouts ). the spectrum may be obtained by a frequency sweep from a synthesizer or by a pulse , and processed by such methods as synchronous demodulation or fast fourier transform , or any other similar method . the output of the spectrometer 20 is the complex impedance spectrum measured in digital form . spectrometers and processing methods suitable for adaptation for use in the present invention are well known to those of skill in the art , for example , as shown in u . s . pat . no . 5 , 807 , 272 to kun et al ., u . s . pat . no . 5 , 633 , 801 to bottman , and u . s . pat . no . 5 , 454 , 377 to dzwonczyk et al . the entireties of these patents are hereby incorporated by reference . once the complex impedance spectrum is obtained , the results are processed by the signal processing device 22 . the signal processing device 22 may be an appropriately - programmed general purpose computer , or a dedicated analog and / or digital device , both of which are well known to those of ordinary skill in the art . for processing the complex impedance spectrum obtained by the spectrometer 20 , the signal processing device 22 may graph or plot the spectrum for visual analysis , as discussed in further detail below . alternatively , the signal processing device 22 may utilize a pattern recognition algorithm or system ( e . g ., running as software ) or the like for analyzing the complex impedance spectrum itself . the pattern recognition system uses a previously trained or calibrated algorithm to classify the impedance spectrum measured and provided by the spectrometer 20 . the output of this system is a numerical score ( or other reference point ) in an ischemic damage index scale 80 validated experimentally via mri &# 39 ; s , chemical analysis , biopsy samples , or the like . in other words , the signal processing device 22 , implementing the pattern recognition system , analyzes the impedance spectrum to determine to what extent the impedance spectrum of the analyzed tissue deviates from that of normal tissue . the degree and character of deviation provides an actual measure of tissue damage , which translates into the ischemic damage index scale 80 , as validated experimentally ( e . g ., heavily damaged tissue , as determined experimentally , will have a certain pattern , and slightly damaged tissue , as also determined experimentally , will have a different pattern ). more specifically , as discussed above , the impedance spectrum of the analyzed tissue is obtained by making multiple complex impedance measurements at different frequencies over the range of interest . at each frequency , an amplitude , z , and a phase , φ , of the tissue response are obtained . these values are then plotted as a function of frequency , or combined and plotted in the complex plane ( resistance vs . reactance ) in a nyquist or a cole - cole plot ( this latter term applies specifically to tissue impedance spectra plots ), where resistance ( r ) and reactance ( x ) are defined as : analysis of these plots shows that normal tissue spectra have a characteristic shape or pattern . according to the cole - cole electric model of biological tissues , this shape is the arc of a circle when plotted in the complex plane . however , if tissue is damaged after an extended period of ischemia , the spectra of the damaged tissue loses this characteristic shape . in fact , when plotted in the complex plane , the spectra of the damaged tissue become sigmoid - or s - shaped , deviating significantly from the normal tissue spectra . fig8 a – 11c show averaged experimental data obtained in the small intestine of a group of test subjects subjected to a period of intestinal ischemia followed by a period of reperfusion ( restored blood flow ), in comparison to a group of test subjects in which normal perfusion and oxygenation was maintained . the data is presented in both the frequency plots and in the complex plane . for the nyquist plots ( complex plane ), the data has been normalized so that the shapes of the curves can be more easily compared , e . g ., the point at the highest measurement frequency ( 300 khz ) has a dimensional impedance of 1 and a phase angle of 0 . fig8 a – 8c show the impedance spectra of intestine with less than ten minutes of reduced blood flow , wherein the intestine is already ischemic , with associated rising acidity . in particular , fig8 a and 8b show the average amplitude and phase impedance spectra , respectively , of both normal intestine and the intestine subjected to reduced blood flow , while fig8 c shows the normalized nyquist plot of the normal and ischemic intestinal tissue . as can be seen , although the intestine with reduced blood flow is ischemic , the tissue is not yet damaged , and the spectra are not easily distinguishable from the spectra of the normally perfused intestines . note that the spectra contain some noise , but resemble the circular arc predicted by the cole - cole model . fig9 a and 9b show the average amplitude and phase impedance spectra , respectively , of both normal intestine and intestine after 1 . 5 hours of severe ischemia , while fig9 c shows the normalized nyquist plot of the normal and ischemic intestinal tissue . here , the ischemic tissue has suffered moderate damage , and the spectra have become clearly distinguishable b the ischemic tissue spectra have lost their circular shape and have taken on a sigmoidal shape with several inflection points . fig1 a – 10c show similar plots for normal intestines and intestines after two hours of severe ischemia . by now , the damage is even more severe , and the spectra have become even more distorted . fig1 a – 11c show the spectra of normal intestines and intestines after an hour of ischemia followed by 1 . 5 hours of reperfusion . after an hour of ischemia , the tissue has suffered some damage . however , after being reperfused , most of this damage has been reversed , and the spectra of the damaged tissue have largely regained their characteristic shape , although they are still somewhat abnormal and are still moderately distinguishable from the spectra of the normal tissue . as should be appreciated , a plot or graph of the complex impedance spectrum of potentially damaged tissue versus the spectrum of normal tissue , e . g ., as shown in fig8 a – 11c , can be used by appropriately - trained personnel to determine the level of damage due to ischemia , by way of a visual comparison . accordingly , the signal processing device 22 may be configured to graph or plot the spectrum for visual analysis , accordingly the general guidelines given above , on a screen or monitor , or by way of a print - out . alternatively , the signal processing device 22 can be configured to automatically determine tissue damage , by way of the pattern recognition system or other standard signal processing techniques , such as filtering , or smoothing and extracting inflection points by analysis of derivatives . another alternative is the use of principal component decomposition or any other method of extracting a characteristic vector describing the shape of the spectrum . such a characteristic vector can then be analyzed by a classifying or pattern recognition algorithm to provide a score in a predetermined tissue damage scale . such an algorithm can use one of many standard techniques for classification and / or pattern recognition , such as bayesian statistics , neural networks , fuzzy logic , statistical classifiers , expert systems , or any combination of these . further detail regarding a pattern recognition system suitable for use or adaptation for use in the present invention can be found in u . s . pat . no . 5 , 807 , 272 to kun et al ., previously incorporated by reference . although the preferred catheters have been illustrated as having ag / agcl electrodes , one of ordinary skill in the art will appreciate that other types of electrodes could be used instead without departing from the spirit and scope of the invention . although the electrodes and spacers of the fourth embodiment of the catheter have been illustrated as having separate passageways and through - bores , one of ordinary skill in the art will appreciate that the passageways and through - bores could be connected , i . e ., they do not have to be separate openings , as long as there is a space for the leads . since certain changes may be made in the above described impedance spectroscopy system and catheter for ischemic mucosal damage monitoring in hollow viscous organs , without departing from the spirit and scope of the invention herein involved , it is intended that all of the subject matter of the above description or shown in the accompanying drawings shall be interpreted merely as examples illustrating the inventive method herein and shall not be construed as limiting the invention .

alternate embodiments of an impedance spectroscopy method are disclosed for monitoring ischemic mucosal damage in hollow viscous organs . in each embodiment , a sensor catheter is placed inside a patient &# 39 ; s hollow viscous organ . afterwards , the catheter is electrically driven to obtain a complex impedance spectrum by causing two electrodes in the tip of the catheter to inject a current into the mucosal tissue at different frequencies , while two other electrodes measure the resulting voltages . a pattern recognition system is then used to analyze the complex impedance spectrum and to quantify the severity of the mucosal injury . alternatively , the complex impedance spectrum can be appropriately plotted against the spectrum of normal tissue , allowing for a visual comparison by trained personnel .

this invention provides a method for using one or more telephones as control input devices for controlling the activities of a network connected computer . the telephones use only the basic functionality of a conventional telephone . such basic functionality is that which any conventional telephone , without modifications or without regard to features offered by specific telephone device models , such as the capability to process and run special purpose software that is incompatible with other telephone makes or models , or features and functionality proprietary to the capabilities of one or several makes or models of telephone devices . the method includes ( a ) dialing a specific telephone number connected via telecommunications networks to a telephony gateway such as a vxml gateway that interprets and processes audio signals generated by the individual telephones and ; ( b ) using the interpreted audio signals to generate a data message containing information about the specific telephone &# 39 ; s automatic number identification ( ani ) and the specific dialing number keys pressed by that telephone , and ; ( c ) transmitting the data message over telecommunications networks to a data processing unit such as a network connected computer that contains software programs that interpret the data message and changes the behaviors of software running on the networked connected computer according to the interpreted semantics of the data message . the teachings of this invention provide in one aspect an entertainment application utilizing the controlled key presses of a plurality of individual telephones in a coordinated fashion to interactively control an entertainment game experience running as software on a network connected computer . the results of these controlled key presses is to change the state or character of the game as depicted on either or both of a visual display and audio output system connected to the networked computer . the teachings of this invention provide in another aspect an improved user interface application by which a telephone device , such as a cellular or mobile telephone , is able to control the general state of a network connected computer , through the delivery of signals generated by those key presses over telecommunications networks . the teachings of this invention provide in another aspect a method for capturing and logging in a persistent storage and retrieval mechanism , such as an information database , the telephone calls &# 39 ; ani &# 39 ; s and the sequence of controlled key presses for individual telephones . such captured and logged information pertaining to the activities of participants may be used to extend the features of the game across multiple game sessions , or to provide mechanisms for fulfilling game rewards . in another aspect of the method of this invention , the telephony gateway and the data processing unit may be a single combined unit such as the state of the art in technology affords such capabilities . the following description is presented to enable any person skilled in the art to make and use the invention , and is provided in the context of a particular application and its requirements . various modifications to the disclosed embodiments will be readily apparent to those skilled in the art , and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the present invention . thus , the present invention is not intended to be limited to the embodiments shown , but is to be accorded the widest scope consistent with the principles and features disclosed herein . in the following description of the preferred embodiment , reference is made to the accompanying drawings which form a part hereof , and which show by way of illustration various embodiments in which the invention may be practiced . it is to be understood that other embodiments may be utilized and structural and functional modifications may be made without departing from the scope of the present invention . fig1 illustrates a telephony solution in accordance with the primary embodiment of the present invention . the system includes telephone 101 , telephony network gateway 102 , data processing unit 103 , audio output system 104 , visual display output system 105 , a telecommunications network 106 , a telecommunications network 107 , and a user 108 who operates telephone 101 . for the purposes of clarity , fig1 indicates a single user 108 with access to a single telephone 101 . in the preferred embodiment , there may be a plurality of users each with access to their own individual telephones . telephone 101 can be any telephone including cellular telephones and their associated cellular mechanisms or any ip - based telephony device such as a voice over ip ( voip ) terminal that can be connected to the telephony network gateway 102 . telephony network gateway 102 can be any system that bridges the network communication link from telephone 101 to data processing unit 103 , including a voip gateway or vxml gateway . telecommunications network 106 can be any network link that can connect telephone 101 to telephony gateway 102 , including a public switched telephone network ( pstn ), cellular telephone network , or ip networks such as the internet . telecommunications network 107 can be any network link that can connect telephony network gateway 102 to data processing unit 103 , including ip networks such as the internet . the system operates generally as follows , and as illustrated in fig1 . an individual or plurality of users , indicated as a single user 108 , each initiate a telephone call using their telephone , indicated as a single telephone 101 in fig1 . the initiation of the call connects telephone 101 to telephony network gateway 102 . telephony network gateway 102 can be directed to send control messages to data processing unit 103 based upon the dial pad keys that user 108 presses on telephone 101 while telephone 101 is connected to telephony network gateway 102 . similarly , telephony network gateway 102 can be directed to send control messages to data processing unit 103 based upon the articulation of speech by user 108 into telephone 101 . based on the interpreted semantics of these control messages , data processing unit 103 will adjust either or both of the visual display output system 105 and audio output system 104 , through the capabilities of software programs that run on data processing unit 103 . these software programs may also send control messages back to telephony gateway 102 which can be further directed to produce an audio signal on telephone 101 in response to the input or based upon the state of the software programs . fig2 . illustrates an alternative embodiment in which telephony network gateway 202 is linked to a data storage mechanism 209 , such as a relational database management system ( rdbms ) that persists the sequence of key presses for individual telephone calls into the system , including the automatic number identifier ( ani ) linked to that sequence of key presses . a similarly related alternative embodiment would contain an rdbms attached to either or both telephony network gateway 202 and data processing unit 203 to perform similar functionality as aforementioned . fig3 . illustrates another alternative embodiment in which data processing unit 303 runs software that interfaces with one or a plurality of peripheral devices 304 , such as mechanisms to control other aspects of the entertainment experience , such that control inputs initiated by user 408 through telephone 301 may control the behavior of those peripheral devices . such peripheral devices might include systems to control lighting displays , for example . this aforementioned peripheral device can be linked to data processing unit 303 through a variety of communications links such as afforded by the current state of the art , such as ieee1394 “ firewire ” network communication protocols or rs232 serial communications protocols . in alternative embodiments , the system does not include the audio output system 104 or audio output system 204 or the visual display output system 105 or the visual display output system 205 , but retains the other system features . the foregoing and other problems of the current methods and systems are over - come , and other advantages are realized , in accordance with the presently preferred embodiments of these teachings . a method is herewith provided to deliver to a data processing unit over telecommunications networks the control input derived from speaking into a telephone , or pressing a numeric or symbolic key on a telephone with optimally minimized delay , such that the generic and conventional functionality of telephone is sufficient to execute such control . the foregoing entertainment applications used to describe the primary embodiments are intended to be merely representative of the utility of this invention , and are in no way to be viewed as limitations on the use of the invention . those skilled in the game programming arts are assumed to have the expertise to create alternative game applications , scenarios and entertainment experiences that are executed by the data processing unit ( e . g . 103 in fig1 in fig2 and 303 in fig3 ). the specifics of the play of the game or entertainment experiences are not germane to an understanding of this invention , except as to the use of the aforementioned method and embodiments for interacting with the game application . while the invention has been described with respect to specific examples including presently preferred modes of carrying out the invention , those skilled in the art will appreciate that there are numerous variations and permutations of the above described system and methods that fall within the spirit and scope of the invention as set forth in the appended claims .

a method and system is disclosed for interacting in a game or entertainment experience in which participants in the game are located in the same physical space and use telecommunications networks and telephones . the game consists of actions initiated by game participants through their pressing numerical or symbolic keys on their telephones , or speaking into their telephones , so as to control or initiate action within the game .

although it is well known that naturally occurring anthocyanins are highly colored and that the color is greatly influenced by ph , it is also known that as the ph is raised the anthocyanins are converted to very unstable purplish anhydro bases that are almost immediately converted to colorless carbinol bases . a typical property of anthocyanins is that they lose their color at ph values above 3 . 0 consequently , we were surprised to find that the anthocyanin from the morning glory , ipomoea tricolor cav cv heavenly blue provided stable colors in food and beverage products at ph values ranging from about 2 . 0 to about 8 . 0 . this display of stability , especially when the anthocyanin was incorporated into food and beverage products , was completely unexpected . the recent delisting by the food and drug administration of red dye # 2 and red dye # 4 and the uncertainty about red dye # 40 presents the food processing industry with a serious problem regarding the coloring of such products as beverages , gelatin desserts , maraschino cherries , ice cream and confections . in view of these problems , our invention is an important contribution to the art and could be a much needed substitute for the artificial coloring agents now in use . the colorant of the present invention is stable in the ph range where practically all anthocyanins are colorless . in the ph range of 2 . 0 to 5 . 0 , colors that match very closely those of cherry , strawberry , raspberry , and grape are obtained . when refrigerated , the color range is extended to the blue colors by increasing the ph to 8 . 0 this colorant is suitable for use in beverages , gelatin desserts , toppings , icings , and various dairy products including ice cream , sherbert , and yogurt . the stability of the colors obtained when the anthocyanin from ` heavenly blue ` morning glory is used in food and beverage products , especially over a wide range of ph values , is a key element of this invention . anthocyanin from other natural sources are known to color food and beverage products , but only at low ph values since , for the most part , they are virtually colorless above ph 3 . 0 . as will be evident in the following exemplification of the invention ; the colors , although stable , do show some fading by spectrophotometric determination . however , this fading is not detectable by the human eye . in fact , it is known that fading also occurs with polymeric food colors ( food technology 31 , 34 - 38 , 1977 ). the color designations in the exemplification are according to the iscc - mbs ( inter - society color council - national bureau of standards ) color - name charts , also known as kelly &# 39 ; s notations or the iscc - mbs method of designating colors and dictionary of color names , kenneth l . kelly et al , national bureau of standards , washington , d . c ., november , 1955 . the anthocyanin from the morning glory , ipomoea tri - color cav cv heavenly blue was obtained by the process described in phytochemistry 16 , 1118 - 1119 , 1977 , which description is incorporated into this specification . the anthocyanin , cyanidin 3 , 5 - diglucoside , from ` better times ` rose was obtained by the process described in the journal american society horticultural science 96 , 770 - 773 , 1971 . the stability , under conditions of light and darkness , of colors produced in a colorless commercially available carbonated soft drink by the anthocyanin from ` heavenly blue ` morning glory and by that from ` better times ` rose was determined at two ph levels . seven - up was suitable for our purposes ; however , any colorless beverage may be used . 9 . 0 mg . of each anthocyanin were added to individual 50 ml . volumes of colorless carbonated beverage . this concentration gave an acceptable color intensity and is considered to be an effective coloring amount of the anthocyanin . the ph of each solution was 3 . 35 . the ph of duplicate solutions of each anthocyanin was adjusted with 0 . 1 m sodium citrate solution to 5 . 45 . half of the solutions at each ph value were placed in a dark environment ( a closed drawer or cabinet ) and half in an environment of diffused light ( exposure to ordinary artificial and natural light in a laboratory or other room ). the average temperature to which the solutions were exposed was from 23 ° to 26 ° c . absorption spectra of the solutions exposed to diffused light were measured peroidically over a period of three weeks while those of the samples stored in the dark environment were measured at the beginning of the experiment , after three weeks and after 11 months . the following results were obtained . the recorded colors were determined at the end of each experiment . 1 . the colors of the solutions having a ph of 3 . 35 were stable both in light and in darkness . according to kelly &# 39 ; s notations the color of each was # 27 , deep yellow pink . after 11 months there was only a 25 . 0 % loss of color . 2 . the solutions in which the ph was adjusted to 5 . 45 were unstable and both those which were exposed to light and those kept in the dark became virtually colorless . according to kelly &# 39 ; s notations the color of each was # 252 , pale purplish pink . 1 . the color of the solutions having a ph of 3 . 35 was stable both in light and in darkness . according to kelly &# 39 ; s notations , the color of each was # 254 , vivid purplish red . after 11 months there was only an 11 . 0 % loss of color . 2 . the solutions in which the ph was adjusted to 5 . 45 remained highly colored . both these solutions exposed to light and those kept in darkness lost approximately one - third of their original absorbance at the λ maximum after three weeks . however , the color loss was not perceptible to the human eye . according to kelly &# 39 ; s notations , the color of each was # 238 , deep reddish purple . after 11 months the color loss was 50 . 0 %. the stability under conditions of light and darkness , of colors produced in colorless citrate - phosphate buffer at a ph range of from 2 . 0 to 8 . 0 by the anthocyanin from ` heavenly blue ` morning glory and by that from ` better times ` rose was determined . the citrate - phosphate buffer was made by mixing the following stock solutions in various proportions to obtain the proper or desired ph value : ( a ) 0 . 5 m sodium phosphate , debasic ( 71 . 01 g . dissolved and deluted to make 1 liter ), and ( b ) 0 . 5 m citric acid ( 105 . 6 g . dissolved and deluted to make 1 liter ). 0 . 6 mg . of each anthocyanin were added to individual 4 . 0 ml . volumns of citrate - phosphate buffer at ph levels ranging from 2 . 0 to 8 . 0 . this concentration gave an acceptable color intensity and is considered to be an effective coloring amount of the anthocyanin . each solution was sealed with parafilm in a 1 . 0 cm . pathlength disposable cuvette , the cuvette placed in a clear plastic container , and the container placed in a dark environment . a duplicate set of solutions was made up as just described and placed in an environment of diffused light as in example 1 . the average temperature to which the solutions were exposed was from 23 ° to 26 ° c . absorption spectra of the solutions exposed to diffused light were measured periodically over a period of three weeks while those of the solutions stored in the dark environment were measured at the beginning and at the end of the three week experiment . the following results were obtained . the recorded colors were determined at the end of each experiment . 1 . the colors of the solutions at ph 2 . 0 were stable both in light and in darkness . according to kelly &# 39 ; s notations the color of each was # 34 , vivid reddish orange . 2 . the colors of the solutions at ph 3 . 0 were essentially stable . the solutions exposed to light and those kept in darkness lost only 16 % and 9 %, respectively , of the absorption at the λ maximum . according to kelly &# 39 ; s notation , the color was # 26 , strong yellowish pink . 3 . all solutions at ph values of 4 . 0 , 5 . 0 , and 6 . 0 were colorless . 4 . all solutions at ph values of 7 . 0 and 8 . 0 had an initial deep blue color , but the color rapidly decomposed and became colorless . 1 . the color of the solutions at ph 2 . 0 was stable both in light and darkness . the color was darker and slightly bluer than kelly &# 39 ; s notation # 3 , deep pink . 2 . the color of the solutions at ph 3 . 0 was stable both in light and in darkness and was slightly bluer than kelly &# 39 ; s notation # 254 , vivid purplish red . 3 . the color of the solutions at ph 4 . 0 was stable both in light and in darkness . the color , according to kelly &# 39 ; s notations , was # 255 , strong purplish red . 4 . the solutions at ph 5 . 0 were highly colored and according to kelly &# 39 ; s notation the color was # 237 , strong reddish purple . however , the solution exposed to light and that kept in darkness lost 31 % and 24 %, respectively , of the absorption at the λ maximum . 5 . there was a perceptible loss of color from the solutions at ph 6 . 0 . the solution exposed to light and that kept in darkness lost 70 % and 67 %, respectively , of the absorption at the λ maximum . according to kelly &# 39 ; s notations the color was # 238 , deep reddish purple . 6 . the colors of the solutions at ph 7 . 0 were highly colored initially and according to kelly &# 39 ; s notations were # 194 , vivid purplish blue . however , after two days the color faded rapidly and at the end of three weeks both the solution exposed to light and that kept in darkness lost 93 % of the absorption at the λ maximum . 7 . the colors of the solutions at ph 8 . 0 were highly colored initially and according to kelly &# 39 ; s notations were # 179 , deep blue . after two days the color faded rapidly and at the end of three weeks both the solution exposed to light and that kept in darkness lost 90 % of the absorption at the λ maximum . the stability of colors produced in gelatin at a ph range of from 2 . 0 to 8 . 0 by the anthocyanin from ` heavenly blue ` morning glory and by that from ` better times ` rose was determined . 0 . 6 mg . of each anthocyanin were added to individual 4 . 0 ml . volumes of hot citrate - phosphate buffer ranging in ph from 2 . 0 to 8 . 0 and then 60 mg . of a colorless gelatin was added . this concentration gave an acceptable color intensity and is considered to be an effective coloring amount of the anthocyanin . each solution was placed in a 1 cm . pathlength disposable cuvette and the absorption spectra of each obtained prior to gelation . the solutions were placed in a refrigerator at 40 ° c . and allowed to gel . absorption spectra of each gel was obtained periodically . the followign results were obtained . the recorded colors were determined at the end of 320 hours . 1 . the only gels in which the color was stable were those at ph 2 . 0 and ph 3 . 0 . according to kelly &# 39 ; s notations , the colors for the gels at ph 2 . 0 and ph 3 . 0 , respectively , were # 34 , vivid reddish orange and # 26 , strong yellowish pink . 1 . the color of all of the gels in the ph range of this example , 2 . 0 - 8 . 0 , was stable for the 320 hours of this experiment . there was virtually no loss in color . according to kelly &# 39 ; s notations , the colors were as follows :

a colorant from a natural source which produces a wide range of stable colors in food and beverages which have a ph range of 2 . 0 to about 8 . 0 is added to foods and beverages in effective proportion . the colorant is the anthocyanin from ` heavenly blue ` morning glory , peonidin 3 -- 5 - glucoside .

as described above , typical inflatable boats ( or baby boats ) are used for young children for entertainment and safety purposes . fig1 shows a typical inflatable boat which may include a bottom 102 affixed to and surrounded by a ring - like flotation tube 104 . the bottom 102 may include apertures 106 through which a child &# 39 ; s legs may be inserted . the bottom 102 functions as a seat , and in cooperation with the flotation tube 104 , supports the weight of the child in a sitting position and keeps the child afloat while the flotation tube 104 rests on top of the water . while useful for the safety of a child in water , the inflatable boat does not play a role in teaching a child how to swim . another type of flotation device is a swimming board or a kickboard , which is normally used as a training device to teach older children how to swim . a typical kickboard may include a flat rectangular body having a front and a back portion . the front portion may be rounded to provide smoother movement through water and the back portion may be contoured to fit around a child &# 39 ; s torso . the front portion may include apertures or slits used as hand holds . in using the kickboard , the child typically lies on top of the kickboard in a swimming position while holding on to the front portion of the kickboard , and the child &# 39 ; s legs kick to propel the child through the water . the front portion of the kickboard emerges from the water , while the back portion supports the weight of the child , keeping the child afloat . the transition from sitting in the water to using the kickboard to learn how to swim can be challenging for a child . therefore , embodiments described herein and illustrated in fig2 - 8 , include a recreational flotation device that is a combination of a baby boat and a kickboard . the combined baby boat and kickboard helps to transition the child from a stationary sitting position into an active swimming position . when the child is younger , the child can use the recreational flotation device as an inflatable boat . as the child &# 39 ; s comfort level , age and skill in the water grows , the child can lean forward on the kickboard portion and use the combined boat and kickboard to feel more comfortable in the swimming position . finally , when the child grows more comfortable in the swimming position , the kickboard portion can be removed from the boat portion and used independently . both the boat portion and the kickboard portion can be easily stored and transported . fig2 - 8 illustrate one example of a recreational flotation device 200 during various stages of assembly including a “ boat stage ,” an “ extended stage ” and a “ separation stage .” fig2 illustrates one example of the flotation device 200 , including a kickboard 202 and a boat portion 204 , in the boat stage of assembly . the kickboard 202 is detachably coupled to the boat portion in the various stages of assembly . in some embodiments , both the kickboard 202 and the boat portion 204 are inflatable and can support the weight of a child in the water . in other embodiments , the kickboard may not be inflatable and may be made from a foam or plastic material , such as for example eva or hdpe material . the boat portion 204 includes a well 206 having apertures 208 , an upper support 220 , a flotation tube 210 , and fastening straps 212 . as shown in this example , the kickboard 202 includes two pairs of apertures or slits 216 , which can be used as hand - holds as further described below . in the boat stage , the child &# 39 ; s legs fit through the apertures 208 and the child sits in the well 206 . the well 206 is submerged in water while the flotation tube 210 supports the weight of the floating child . the flotation tube 210 has an elongated shape forming a “ u - shape ” with a rounded front portion , which partially surrounds the well 206 and the upper support 220 ( shown in fig4 and 5 ), and two extensions 218 on a back portion of the flotation tube 210 extending from the front portion . as shown in fig4 and 5 , the extensions 218 may be substantially parallel to each other and together with the upper support 220 form a space for the kickboard 202 to be placed within the bounds of the boat portion 204 . according to one embodiment , the flotation tube 210 may include one or more inflatable chambers , with each of the chambers including a separate valve that allows each chamber to be inflated and / or deflated independently . in one example , the length of the flotation tube 210 is approximately 26 inches while the width of the flotation device is 25 . 5 inches . the flotation tube 210 may include one or more arches 214 forming hand - holds , as shown in fig3 . the arches 214 may be used to carry the recreational device 200 when outside the water and may be used for stability when the recreational device 200 is placed in water . the well 206 is contoured and includes the apertures 208 . the well 206 functions as a seat in the boat stage of assembly and supports the weight of the child in a sitting position . the apertures 208 may have an oval shape with a diameter large enough to easily allow the legs of a child to fit through in both the boat stage and in the extended stage of assembly . in one example , the length of the apertures is approximately 4 . 5 inches and the width of the apertures is approximately 3 . 25 inches . the upper support 220 is contoured in a way as to allow a portion of the kickboard to rest uniformly on top of the upper support 220 , in the boat stage of assembly or when the kickboard is stored within the boat portion 204 . in one example , the well 206 can extend below the bottom plane of the flotation device . however , in other examples , the well 206 can be flush with the bottom plane of the flotation device . in one embodiment , the well 206 and the upper support 220 are smaller than the total length of the flotation tube 210 . according to other embodiments , the well 206 , together with the upper support 220 , can extend through the length of the flotation tube 210 , as shown in fig8 . for example , the diameter of the well 206 is 10 inches and the length of the upper support 220 is 5 inches , as shown in fig3 , while the total length of the flotation device 200 is 26 inches . in another embodiment , as shown in fig8 , the well 206 , without the support 220 , can extend the entire length of the flotation device 200 . although the well 206 is shown as circular in shape , in other embodiments the well 206 may be elongated or oval in shape . in other embodiments , the well 206 may be rectangular or square in shape . in one example , the kickboard 202 has an elongated shape and further includes a front end 224 and a rear portion 226 . in one embodiment , as shown in fig5 , the edge of the rear portion 226 is contoured to fit around a child &# 39 ; s torso , while the edge of the front end 224 is extends outside of the extensions 218 of the flotation tube 210 . in another embodiment , as shown in fig3 , the edge of rear portion 226 is contoured to fit to the shape of the child &# 39 ; s torso , while the edge of the front end 224 of the kickboard 202 may form a substantially straight edge . the kickboard shown in fig3 is substantially rectangular with the front end 224 having a smaller width than the width of the rear portion 226 . in one embodiment , the kickboard includes two pairs of apertures or slits 216 which are disposed in the front end 224 and the rear portion 226 of the kickboard 202 ; first pair of slits in the front end 224 and second pair in the rear portion 226 . in one example , the first pair of slits may be disposed perpendicular to the length of the kickboard and the second pair of slits is disposed parallel to the length of the kickboard . it is appreciated that the slits can be included in other orientations on the flotation device 200 . the slits serve can dual functions . first , in one example , the slits can be configured to allow the fastening straps 212 to couple the kickboard 202 to the flotation tube 210 , as shown in fig2 and 5 . second , the slits can also serve as hand holds for the child in the extended and the separation stages of assembly . in an alternative embodiment , the kickboard 202 is uniform in shape and does not include slits 216 or fastening straps 212 . illustrated in fig3 , in this embodiment , the kickboard is fastened to the boat portion 204 by using velcro ® hook - and - loop fasteners . the hook and loop fasteners may be disposed on both sides of the kickboard 202 and on the inner side of flotation tube 210 . for example , one portion of the hook and loop fasteners is placed on the upper support and another portion of the hook and loop fasteners is placed on one side of the kickboard . as shown in fig4 , the fasteners can also be used to position and secure the kickboard 202 entirely inside the boat portion 204 for easy storage . it is appreciated that other releasable fastening mechanisms may be used to attach the kickboard 202 to the boat portion 204 , including a snap , a clip , a button , a buckle , or a reusable adhesive . referring again to fig2 , in one embodiment , the proportions of the kickboard are configured such that the kickboard 202 can slide within the extensions 218 of the u - shape flotation tube 210 and rest on the upper support 220 . the width of the front end 224 may match the outer width of the flotation tube 210 . in another embodiment , the width of the front end 224 may match the inner width of the flotation tube . in one embodiment , the width of the rear portion 226 may match the inner width of the flotation tube 210 , with the front end 224 being proportionally wider than the rear portion 226 . in addition , front end 224 may be proportionally shorter than the length of the rear portion 226 , and with the front end 224 extending beyond the extensions 218 of the u - shape flotation tube 210 . in one example , the width of the front end 224 is approximately 10 inches . in one example , the length of the front end 224 is approximately a third of the length of the rear portion 226 . in various examples , the length of the entire kickboard is approximately 15 inches . in at least one embodiment , as shown in fig2 and 5 , the fastening straps 212 are attached to the flotation tube 210 and fit through one pair of the slits 216 on the kickboard 202 . the fastening straps 212 can keep the kickboard 202 secured to the flotation tube 210 in the boat stage and the extended stage of assembly , as shown in fig2 and 5 and discussed further below . in the boat stage , shown in fig2 , the fastening straps 212 attach to the first pair of slits 216 and in the extended stage , shown in fig5 , the fastening straps 212 attach to the second pair of slits . in another embodiment , as shown in fig3 , 4 and 6 , the hook and loop fasteners are configured to releasably attach the kickboard 202 to the boat portion 202 . according to one embodiment , elements of both the kickboard 202 and the boat portion 204 as described herein may be constructed of plastic material . for example , in one embodiment , the plastic material is polyvinyl chloride ( pvc ), reinforced pvc , pvc mesh , laminated pvc or any other plastic material . fig5 illustrates one example of the flotation device 200 in the extended stage of assembly . in the extended stage , the kickboard 202 is extended away from the boat portion 204 while still attached to the extensions 218 of the flotation tube 210 . as shown , fastening straps 212 are attached to flotation tube 210 and fit around the second pair of slits of the kickboard . the kickboard 202 can be situated relative to the flotation tube 210 based on the child &# 39 ; s size and comfort in the water . for example , as the child grows taller , the child can extend the kickboard may be placed farther away from the upper support 220 to match the child &# 39 ; s height . in use , the child lays down in a swimming position on top of the kickboard 202 while the child &# 39 ; s legs protrude through the apertures 208 . in one example , the child can use the first pairs of slits as hand - holds , while the boat portion serves to support the weight of the child . illustrated in fig6 , in an alternative embodiment , the flotation device 200 is shown in the extended stage of assembly . in this embodiment , the kickboard 202 has a uniform shape and does not include slits 216 or fastening straps 212 . in this embodiment , the kickboard 202 can be attached to the boat portion 204 by using velcro ® hook - and - loop fasteners 222 . one portion of the fasteners may be disposed on the side of the kickboard ( not shown ), while the second portion may be disposed on the inner surface of the boat portion 204 , as shown in fig6 . in this embodiment , the fasteners are disposed starting at the well 206 , continuing through the length of the flotation tube 210 , and ending at the extensions 218 . however , it is appreciated that one or more hook and loop fasteners may be disposed on any portion of the upper support 220 . in this embodiment , the kickboard 202 can be placed in any position in relation to the boat portion 204 and can be progressively secured further away from the well 206 to accommodate for the growing size of the child . the hook and loop fasteners 222 provide enough strength to keep the kickboard in place , while a child is placed onto the kickboard . as shown in fig6 , the flotation device 200 is in the extended stage of assembly with the kickboard 202 extending away from the boat portion 204 . fig7 illustrates one example of the flotation device 200 in the separation stage of assembly . in the separation stage , the kickboard 202 is separated from the boat portion 204 and can be used by the child independently of the boat portion 204 . as shown , the fastening straps 212 are unfastened , but remain attached to the flotation tube 210 . the boat portion 204 can be removed , deflated and stored . in this stage , the child feels more comfortable in the water and does not need the support of the boat portion 204 . fig8 illustrates another embodiment , where the kickboard attaches to the boat portion using hook and loop fasteners and is shown in the separation stage of assembly , where the kickboard is removed from the boat portion 204 . one portion of the hook and loop fasteners is shown and the upper support portion 220 is exposed . as described above , children can sometimes feel cautious transitioning from a fully supportive , sitting flotation device to a less supportive kickboard . but through use of flotation device 200 in the various stages as described above , the child can gradually become accustomed to the swimming position . the flotation device 200 can be transformed from the boat stage to the extended stage and then to the separation stage to fit the child &# 39 ; s stages of growth and comfort in the water . it is to be appreciated that embodiments of the methods and apparatuses discussed herein are not limited in application to the details of construction and the arrangement of components set forth in the following description or illustrated in the accompanying drawings . the methods and apparatuses are capable of implementation in other embodiments and of being practiced or of being carried out in various ways . examples of specific implementations are provided herein for illustrative purposes only and are not intended to be limiting . in particular , acts , elements and features discussed in connection with any one or more embodiments are not intended to be excluded from a similar role in any other embodiments . also , the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting . any references to embodiments or elements or acts of the systems and methods herein referred to in the singular may also embrace embodiments including a plurality of these elements , and any references in plural to any embodiment or element or act herein may also embrace embodiments including only a single element . references in the singular or plural form are not intended to limit the presently disclosed systems or methods , their components , acts , or elements . the use herein of “ including ,” “ comprising ,” “ having ,” “ containing ,” “ involving ,” and variations thereof is meant to encompass the items listed thereafter and equivalents thereof as well as additional items . references to “ or ” may be construed as inclusive so that any terms described using “ or ” may indicate any of a single , more than one , and all of the described terms . any references to front and back , left and right , top and bottom , upper and lower , and vertical and horizontal are intended for convenience of description , not to limit the present systems and methods or their components to any one positional or spatial orientation . having thus described several aspects of at least one embodiment , it is to be appreciated various alterations , modifications , and improvements will readily occur to those skilled in the art . such alterations , modifications , and improvements are intended to be part of this disclosure and are intended to be within the scope of the invention . accordingly , the foregoing description and drawings are by way of example only , and the scope of the invention should be determined from proper construction of the appended claims , and their equivalents .

a recreational floatation device is disclosed . in one example , the recreational floatation device comprises a main body having a front portion and members extending substantially parallel from the front portion , a seat portion attached to the main body between the two parallel members and adjacent to the front portion , for receiving and supporting a user of the recreational flotation device in a seated portion , and a floating board removably attachable to said main body , when positioned between the parallel members .

referring to fig1 - 4 , the preferred embodiment of the pole - supporting pole of the invention consists of three elongate members 2 , 4 , and 6 disposed in telescoping relation with one another , with the member 2 being the outermost member , the member 6 being the innermost member , and the member 4 being an intermediate member that slidably extends within member 2 and surrounds and is in sliding relation with member 6 ( from the perspective of using to support a growing plant , the members 2 and 6 may be viewed as being the bottom and top pole members respectively ). elongate pole member 2 is formed in two component halves or parts 10 and 12 ( fig5 - 11 ), elongate intermediate member 4 is formed in two halves or parts 14 and 16 ( fig1 - 19 ), and elongate member 6 is a solid one - piece part ( fig2 - 24 ). all of the parts 6 , 10 , 12 , 14 , and 16 are molded of a polymer material . by way of example but not limitation , they may be made of polyethylene , polypropylene , or some other suitable moldable material capable of providing a suitable combination of resiliency and adequate strength against breaking . referring now to fig1 - 9 , component part 10 comprises an elongate shaft section 20 and an elongate stake section 22 . shaft section 20 has a generally u - shaped configuration in cross - section . as seen best in fig7 - 9 , shaft section 20 comprises a flat base wall 26 and stepped side walls 28 that terminate in outwardly - projecting flanges 30 . the latter are interrupted at several spaced locations with l - shaped locking tabs 32 that project outwardly away from flanges 30 , as shown best in fig5 , 7 and 9 . the junction of shaft section 20 with stake section 22 is demarcated by a relatively large radially projecting flange 34 that extends through an angle of 180 ° and is terminated by straight edge 36 . the edge 36 is interrupted by a co - planar and projecting key section 38 . as seen best in fig5 , 8 , 25 and 26 , the flat base wall 26 of component part 10 is formed with a u - shaped slot 40 that borders a relatively large locking tab 42 on three sides . tab 42 is essentially tongue - like , having one end formed integral with base wall 26 and its other end free and characterized by a lock projection 44 and a lip 46 . tab 42 is formed so that at its free end it projects outwardly of base wall 26 but with its lock projection 44 extending inwardly of the inner surface of base wall 26 . the inner end surface of lock projection 44 is inclined as shown in fig2 to facilitate a locking interaction with the intermediate pole member 4 as described hereinafter . shaft section 20 also is formed with a plurality of mutually spaced notches 48 in its two flanges 30 . the stake section 22 of component part 10 comprises four like blade - shaped fins 50 , with each fin extending at an angle of 90 ° to each adjacent fin . the fins are tapered longitudinally as shown , having expanded tapered sections at their top ends and terminating at their bottom ends in a narrow more tapered tip 52 . the upper end of one of the fins projects laterally of flange 34 as seen in fig7 . referring to fig6 , 7 , 10 and 11 , the second component part 12 of the outermost pole member 2 comprises a shaft section that is generally u - shaped in cross - section and is characterized by a flat base wall 58 and stepped side walls 60 that terminate in outwardly - projecting flanges 62 . the stepped side walls 60 and flanges 62 are formed with a series of spaced openings 64 that are sized to receive the l - shaped locking tabs 32 of component part 10 . the bottom end of component part 12 also is formed with a relatively large radially projecting flange 66 that extends through an angle of 180 ° and is terminated by a straight edge 68 . the bottom end of component part 12 also is formed with a pair of tabs 69 ( fig6 , 10 and 11 ) that extend forwardly from base wall 58 below the level of flange 66 . component part 12 also is formed with a plurality of mutually spaced notches 70 ( fig5 and 7 ) in its two outwardly - projecting flanges 62 . the two parts 10 and 12 are secured to one another by squeezing one of the component parts 10 or 12 enough to insert the l - shaped locking tabs 32 through the openings 64 in the flanges 62 . it is to be noted that the two component parts 10 and 12 are made with a sufficient resiliency to allow them to flex to the extent required to allow locking tabs 32 to be inserted in openings 64 and to have the tabs tightly engage component part 12 when the squeezing force is removed . the component parts 10 and 12 also are stiff enough to form a rigid pole member as described . when this is done , the key 38 of part 10 fits into and engages the inner surface of base wall 58 and also portions of the inner surfaces of stepped side walls 60 , the tabs 69 underlie the key 38 , the flanges 34 and 66 are in a co - planar relationship with the straight edge of flange 66 with and engaging the straight edge of flange 34 , and the notches 70 are aligned with the notches 32 of part 10 . when so assembled , the two parts 10 and 12 form a substantially rigid pole member , and the matching notches 32 and 70 constitute areas adapted to receive flexible metal or organic string plant ties and keep them from slipping down on the outermost pole member . also , when so assembled , the base walls 26 and 58 and stepped side walls 28 and 60 of component halves 10 and 12 respectively , define a channel for slidably receiving intermediate member 4 . the key section 38 and tabs 69 coact to provide radial strength to pole member 2 . referring to fig8 a , a top ( extended position ) stop is provided for limiting the extent to which intermediate member 4 can be extended relative to outermost member 2 . one half of that top stop is provided by reducing the spacing between the two stepped side walls 28 of component part 10 for a selected distance extending down from the outer ( top ) end of member 2 , whereby to provide shoulders as indicated at 29 in fig8 a . although not shown , it is to be understood that the other half of the top stop for intermediate member 4 comprises a like reduction in the spacing between the stepped side walls 60 of component part 12 for a like distance extending down from the outer ( top ) end of outermost member 2 . referring now to fig1 and 14 - 16 , the first part 14 of intermediate pole member 4 consists of an elongate shaft section with a generally u - shaped configuration in cross - section that is similar to that of component part 10 of outermost pole member 2 . as seen best in fig1 and 14 - 16 , component part 14 comprises a flat base wall 80 and stepped side walls 82 that terminate in outwardly - projecting flanges 84 . the latter are interrupted at several spaced locations with outwardly projecting l - shaped locking tabs 86 . the top and bottom ends of component part 14 terminate in substantially flat surfaces . the flat base wall 80 is formed with a u - shaped slot 88 that borders a relatively large locking tab 90 on three sides . tab 90 is similar to tab 42 , being essentially tongue - like , with one end formed integral with base wall 80 and its other end free and characterized by a lock projection 92 essentially the same as locking projection 44 of locking tab 42 . like the latter tab , locking tab 90 is formed so that at its free end it projects outwardly of base wall 80 but with its lock projection 92 extending inwardly of the inner surface of base wall 80 . the inner end surface of the lock projection of locking tab 90 is intended to make a locking interaction with the innermost ( top ) pole member 6 as described hereinafter . the outer surface of base wall 80 also is formed with a series of indentations or cavities 96 ( fig1 , 15 and 26 ) that are characterized by inclined bottom surfaces so that the upper ends of the cavities are deepest at their top margin and are flush with that outer surface base wall 80 at their bottom ends , i . e ., the depth of recesses 96 increases with increasing distance from the stake - like section of pole member 2 . at their deepest ends , recesses 96 are terminated by a wall 98 ( fig1 ) that extends perpendicular to the longitudinal axis of pole member 4 . these indentations or cavities 96 are sized to receive the lock projection of locking tab 42 , as shown in fig2 . referring now to fig1 - 19 , component part 16 of the intermediate pole member also is in the form of an elongate shaft section that is generally u - shaped in cross - section and is characterized by a flat base wall 100 and stepped side walls 102 that terminate in outwardly - projecting flanges 104 . the stepped side walls 102 and flanges 104 are formed with a series of spaced openings 106 that are sized to receive the l - shaped locking tabs 86 of component part 14 . both component parts 14 and 16 are formed with substantially flat end surfaces . the two parts 14 and 16 are secured to one another by squeezing one of them enough to insert the l - shaped locking tabs 86 into the openings 106 in flanges 104 . like the component parts 10 and 12 , the two parts 14 and 16 have sufficient resiliency to allow them to flex to the extent required to allow tabs 86 to be inserted in openings 106 . when this is done , the flanges 84 and 104 are engaged tightly with each other and the assembly forms a substantially rigid intermediate pole member . referring again to fig1 , 15 and 17 , the flanges 84 and 104 of component parts 14 and 16 are sized in width so as to make a close sliding fit with adjacent portions of stepped side walls 28 and 60 of outermost pole member 2 , except that a short distance from their lower ( inner ) ends flanges 84 and 104 are enlarged in width so as to form shoulders 85 and 105 respectively that will be interrupted by the shoulders ( see 29 in fig8 a ) of the top stop described hereinabove . referring again to fig1 and 18 , a narrow rib 107 is formed on the inner surface of base wall 100 of component part 16 . rib 107 commences at the top ( outer ) end of base wall and extends longitudinally for a selected distance . as explained hereinafter , rib 107 functions as a top ( extended position ) stop for innermost member 6 . referring now to fig2 - 24 , the top or innermost member 6 is formed as a solid rod with a polygonal cross - sectional configuration . preferably , as shown , elongate member 6 is formed with a number of longitudinally - extending grooves 110 and 111 , ribs 112 and 113 , a number of transversely - extending ribs or wall sections 114 and 115 that extend across grooves 110 and 111 between ribs 112 and 113 respectively , and a longitudinally - extending center wall section 116 . in the illustrated preferred embodiment of the invention , innermost member 6 is formed with four ribs 112 and 113 , but the number of ribs and grooves may be varied . the presence of grooves 110 and 111 helps to reduce the amount of material required to form innermost member 6 . at multiple locations along their length , the two inner ribs 112 a and 112 b are cut back at an angle adjacent selected transversely - extending wall sections 114 , as shown at 120 in fig2 and 24 , so as to form tapered recesses or slots 126 for receiving the locking projection of large locking tab 90 pf component part 14 of intermediate pole member 4 a . at their deepest ( top end ), recesses 126 are terminated by an end wall 128 ( fig2 ) that extends perpendicular to longitudinally - extending wall section 116 . the top ( outer ) end of elongate member 6 is preferably enlarged so as to form a knob 118 for grasping that member and pulling it out axially in a telescoping movement relative to member 4 a . as seen in fig2 , on the side of pole member 6 opposite to the side that has locking tab recesses 126 , the two centermost ribs 113 a and 113 b project outwardly of the body of that pole member . additionally adjacent the inner end of pole member 6 a transverse wall section 117 extends between and is joined to ribs 113 a and 113 b . wall member 117 projects beyond the outer edges of wall sections 115 so as to engage rib 107 when innermost pole member 6 is extended , thereby acting as a top ( extended position ) stop for pole member 6 . preferably a through hole 130 is provided in knob 118 to accommodate a string for tying the top of the pole to a growing plant . referring now to fig1 - 4 , 18 and 25 - 27 , intermediate pole member 4 and innermost pole member 6 are sized to make a close sliding fit inside of pole members 2 and 4 respectively . the base and side walls of component halves 14 and 16 of intermediate pole member 4 are aligned with the corresponding walls of component halves 10 and 12 of pole member 2 , and the exterior surfaces of innermost pole member 6 slidably engage the inner surfaces of component parts 14 and 16 , with ribs 113 a and 113 b disposed in a longitudinally extending recess 101 ( fig1 ) formed by the junction of base wall 100 and stepped side walls 102 of component part 16 , and stop rib 107 disposed in groove 111 a between ribs 113 a and 113 b . the pole is assembled by first positioning innermost pole member 6 between component parts 14 and 16 of pole member 4 and then securing the latter parts to each other by inserting locking tabs 86 into holes 106 . innermost member 6 is oriented so that the center groove 111 a is aligned with and slidably accommodates rib 107 and so that its ribs 113 a and 113 b make a sliding fit in recess 101 formed in the inner surface of base wall 100 ( fig1 ). thereafter the component parts 10 and 12 of outermost pole member 2 are assembled around intermediate member 4 so that their base walls 26 and 58 are aligned with the base walls 80 and 100 of component parts 14 and 16 respectively , as shown in fig2 . component parts 10 and 123 are then secured to one another by inserting locking tables 32 into openings 64 . as it is obvious from the foregoing description , when pole member 2 , 4 and 6 are assembled in telescoping relation , the intermediate member 4 cannot rotate on its axis relative to the outermost member 2 , and the innermost ( top ) member 6 cannot rotate on its axis relative to intermediate member 4 . the lengths of the three pole members may be varied . preferably the length of innermost member 6 is set so it can be telescoped into member 4 far enough for its knob 118 to be relatively close to but spaced from the top ( rearward ) end of intermediate member 4 in the manner shown in fig2 , while the length of intermediate member 4 is set so that all but a short top end portion , e . g ., 2 - 5 inches long , can be telescoped into elongate member 2 . in this preferred embodiment , the actual depth to which pole members 4 and 6 can be telescoped into fully retracted position is determined by interlocking of locking tabs 42 and 90 with the perpendicular end walls 98 and 128 of the uppermost recesses 96 and 126 of pole members 4 and 6 respectively . by way of example , but not limitation , members 2 , 4 and 6 have such that when the three pole sections are locked in fully extended position , the pole will have an overall length of approximately 72 inches . assuming that the pole is in its fully retracted position , it is extended by pulling one or both of pole members 4 and 6 outwardly from pole member 2 . locking tabs 42 and 90 ride on the exterior surfaces of pole members 4 and 6 respectively until their locking projections fall into locking relation with one of the locking recesses 96 and 126 respectively . preferably intermediate member 4 and innermost member 6 are provided with at least two recesses 96 and 129 spaced along their lengths so as to allow the assembled pole to be locked in a variety of extended positions . in practice , the stake section of pole member 2 is inserted into the soil surrounding a growing plant by pushing down on it , with the flange sections 30 and 66 limiting the depth of penetration and stabilizing the pole in a vertical position . assuming that locking tabs 42 and 90 are positioned in one of the recesses 96 and 126 respectively , the end walls 98 and 128 of those recesses will act on those large locking tabs to prevent the pole from collapsing from a full or partially extended position to a retracted position as the pole is pressed into the soil . if locking tabs 42 and / or 90 are interlocked with recesses 96 and / or 126 respectively , all that is required to move pole member 4 and / or 6 from a given extended position to a more retracted position is for the user to grasp locking tab 42 and / or 90 outwardly far enough to clear recesses 96 and 126 respectively , after which those pole members may be retracted to a different tab locking position . the foregoing construction offers a number of advantages . a primary advantage resides in the fact that the stake portion 22 of pole member 2 facilitates penetration of the earth adjacent to a growing plant , while its flanges 34 and 66 serve to limit the depth of penetration and also to stabilize the pole so as to hold it in a vertical position , as is desired in order to adequately support the growing plant . a second advantage of the invention is that the pole has a variable length , plus means for releasably locking the elongate members in several different telescoped positions . a further advantage is that the pole is made of a plastic material , so that unlike a wooden stake , it will not degrade with continued presence in the ground . the specific construction of the invention as herein described and illustrated offers the further advantage that the parts can be injection molded with precision . in this connection it should be noted that making each of the elongate members 2 and 4 in two parts is an economical advantage since the molds required to make them are less complex and costly than a mold required to make an elongate tubular member , particularly if the tubular member is required to have an internal or external surface that is not cylindrical . the component parts of pole members 2 and 4 are readily made by injection molding , and that mode of manufacturing is preferred although some other method , e . g ., compression molding , may be used . while poles made according to this invention are especially useful in supporting growing plants that produce food , e . g ., tomato plants , they also are useful in supporting growing other plants , e . g . flowering plants of a purely ornamental or aesthetic value , shrubs and small trees . furthermore the poles of this invention may be molded in different colors and may be used to support plants are indoors or outdoors . still other advantages and uses will be obvious to persons of ordinary skill in the art . it is to be appreciated that the invention is subject to changes that are obvious to persons skilled in the art . thus , for example , the pole may be made with only two pole members or with more than three pole members . additionally , the cross - sectional shape of each of the elongate members may be varied , e . g ., the inner and or outer surfaces of the telescoping pole members may have a different configuration than the configurations disclosed herein , provided , however , that the telescoping members are limited in their ability to rotate on their axes so as to assure , for example , that the relatively large locking tabs 42 and 92 will remain in alignment with the complementary locking recesses 96 and 126 as herein described . also the number of locking recesses 96 and 126 in pole members 4 and 6 respectively may be varied according to the desired number of possible extended pole positions . another possible alternative construction is to form the stakes section in two mating halves , one half section including flange 34 on the part 10 and the other half section including flange 66 on the part 12 . however , for strength purposes , the stake construction illustrated in figure is 1 - 5 is preferred . another possible modification is to replace the solid innermost pole member 6 with a tubular pole member . it also is contemplated that a glue may be applied to the mating surfaces of component parts 10 and 12 and also to mating surfaces of component parts 14 and 16 to assure that they will not separate from one another . still other modifications obvious to a person of ordinary skill in the art may be made without departing from the essence of the invention .

a telescoping pole for supporting growing plants comprises two or more elongate pole members , one of which has a pointed stake section at one end to facilitate insertion into the ground . the pole includes means for locking the elongate pole members in a number of different telescoped positions , whereby to allow for adjustment of the effective length of the pole according to the height of the plant that it supports . the telescoping members are made of a polymer material , with at least one of the telescoping members comprising two injection - molded component parts that are mechanically attached to one another .

activated t cell - induced liver injury in viral and autoimmune hepatitis involves multiple tnfsf members and various signaling pathways . tempering such injury by a single treatment has been difficult . relieving the staggering worldwide burden of liver diseases requires new understanding of pathogenesis and new treatments . the multiple dimensions of ltβr ( and tnfr ) signaling revealed its focal responsibility for integrating distinct hepatocyte injury signaling pathways . the dependence of distinct hepatitis models on ltβr and tnfr signaling was shown ; murine hepatitis was induced by stimulation of tnfsf members fas , cd137 , light , or even cona , a general t cell activator . surprisingly , use of genetic knockout and soluble protein systems revealed that relevant ltβr signaling in cona pathogenesis depends on membrane lt complex signaling directly on hepatocytes . tnfr and ltβr - dependent pathogenic mechanisms involve both the induction of hepatocyte apoptosis and the regulation of inflammation by neutrophil recruitment . a single treatment with soluble ltβr fusion protein ( ltβr - ig ) blocked liver injury from a variety of insults encompassing multiple signaling pathways . these new insights open a new dimension for achieving dynamic control of hepatic immune pathology with treatment implications for hepatitis and multiple forms of liver injury . a recent study using a monoclonal antibody that limited light binding to ltβr , while minimally affecting the binding of lt , suggested an independent role of light in the pathogenesis of hepatitis , presumably acting through ltβr ( anand et al ., 2006 ). in contrast , an independent study suggested light works through hvem signaling in cona - induced hepatitis ( an et al ., 2006 ). however , hvem - deficient mice show a greater susceptibility to cona - induced inflammation that calls into question the importance of hvem signaling in light - mediated hepatitis ( wang et al ., 2005 ). ltβr signaling from the surface lt ligand has a non - redundant role in the development of hepatitis . furthermore , analysis of conditional ltβr - deficient mice was interpreted to mean that ltβr expression specifically on hepatocytes is essential for cona - induced liver injury . lt - ltβr - dependent pathogenic mechanism likely involves both regulation of inflammation by neutrophil recruitment and induction of hepatocyte apoptosis . the role of ltβr in neutrophil recruitment is novel and intriguing since no defect in neutrophil development is reported in lt - or ltβr - deficient mice . gene microarray analysis revealed that expression of several neutrophil specific genes , such as myeloperoxidase and lactoferrin , were reduced in ltα −/− spleen compared to wt mice ( shakhov et al ., 2000 ). reduced numbers of neutrophils in the livers of ltβr - deficient mice following cona administration compared to wt mice and increased numbers when ltβr was stimulated with adenovirus - delivered light have been observed . cxcl2 are ccl3 are potent chemokines controlling neutrophil recruitment to the liver ( nakamura et al ., 2001 ; ramos et al ., 2006 ; bajt et al ., 2001 ; rawaiah et al ., 2007 ). previous studies showed that blocking cxcl2 or ccl3 with specific antibodies or inhibitors effectively protected mice from cona - induced hepatitis ( ajuebar et al ., 2004 ; okamoto et al ., 2005 ). the present disclosure supports that ltβr signaling regulates cxcl2 and ccl3 expression thus promoting neutrophil recruitment to the liver after cona administration . how ltβr signaling promotes hepatocyte apoptosis is not entirely clear . in contrast to tnfri or fas receptors , ltβr lacks the death effector domains known to trigger caspase activation and apoptosis ( ware , 2005 ). however , there is evidence that light - induced ltβr signaling can rapidly recruit traf3 , traf2 , ciap1 , and smac adaptors ( kuai et al ., 2003 ; kim et al ., 2005 ). traf3 activation via ltβr signaling appears to induce apoptosis in some adenocarcinoma cell lines , whereas traf2 signaling promotes nf - κb and jnk activation ( kim et al . 2005 ). several recent studies suggest that traf3 inhibits the noncanonical nf - κb activation pathway by suppressing p100 processing through induction of nik degradation . another report shows pretreatment of human primary hepatocytes with light induces nf - κb activation and blocks apoptosis induced by tnf / actinomycin - d but not fas - induced apoptosis . cell context and balance between nf - kb and apoptotic pathways all appear to influence cell fate . furthermore , ltβr −/− mice were protected from fas and cona - induced liver injury , suggesting collaboration of ltβr and fas signaling pathways leading to liver injury . ltβr - dependent up - regulation of neutrophil recruiting cxcl2 and ccl3 chemokines after fas and cona stimulation promotes liver injury . in line with this , both cxcl2 and ccl3 are known to be transcriptionally activated by nf - kb signaling , which is induced following fas and ltβr stimulation . in contrast to a hepatitis model , previous work by the inventors demonstrated that ltβr signaling promotes liver regeneration after partial hepatectomy . these similar seemingly paradoxical relationships exist for other members of the tnf superfamily of cytokines , fas and tnf for instance . injection of fas agonistic antibody induced massive liver injury in wt , but not in tnfri / ii −/− mice , while the same treatment promoted liver regeneration after partial hepatectomy . ltβr signaling may be constantly maintained by lt and such tuning will coordinate with other tnfrsf members to control homeostasis of liver regeneration and injury . tnf , ifn - γ , and fasl are all induced after cona administration . therefore , it is possible that stimulation of hepatocyte ltβr by lt - expressing t and nkt cells causes apoptosis depending upon the presence of inflammatory cytokines such as tnf , ifnγ , fasl . therefore , inhibitors of tnf or lt , such as soluble receptors for tnf or lt , could be used as a treatment to reduce liver injuries by rather broad insults . an integrative role of ltβr ( and tnfr ) likely exists in connecting various pathways that control hepatocyte apoptosis and survival . understanding the mediators of t cell - mediated liver injury provides targets for difficult - to - treat human liver diseases such as autoimmune and viral hepatitis inhibition of ltβr signaling is effective in preventing both acute cona - induced fulminant hepatitis and a subacute hepatitis induced by cd137 stimulation in fas - deficient mice . in contrast , experimental approaches using stimulation of ltβr signaling are being pursued to improve liver regeneration , or anti - tumor therapy . selective elimination of ltβr “ side effects ”, such as neutrophil - induced liver inflammation may improve efficacy of these treatments . this could also be achieved through inhibition of cxcl2 and cll3 activity using neutralizing antibodies . current therapeutics in development that may result in hepatic liver damage that could be alleviated by inhibition or antagonism of the tnf and / or lt pathways include bms - 663513 , a cd137 agonistic antibody . other antibody therapies that may result in liver damage that could be alleviated by inhibition or antagonism of the tnf and or lt pathways include those that target coinhibitory and costimulatory t cell receptors . coinhibitory and costimulatory molecules include cytotoxic t - lymphocyte antigen - 4 ( ctla - 4 ), glucocorticoid - induced tumor necrosis factor family receptor ( gitr ), b7 - h1 , programmed death [ pd ]- 1 , b7 - h3 and b7x . agonistic antibodies for cd137 are being developed for the treatment of cancer , autoimmune and other immune related diseases , viral disease , by enhancing the response to vaccines and alleviating inflammatory disease . cancer broadly refers to cellular - proliferation and / or cellular growth disease states . the cancer may be breast , prostate , ovarian , brain , melanoma , colorectal , liver , lymphoma , lung , oral , head , neck , spleen , lymph node , small intestine , large intestine , blood cells , stomach , pancreatic , endometrium , testicle , skin , esophagus , bone marrow , blood , cervical , bladder , ewing &# 39 ; s sarcoma , thyroid , a glioma , and / or gastrointestinal cancers . cancer also includes but is not limited to : sarcoma , myxoma , rhabdomyoma , fibroma , lipoma and teratoma , bronchogenic carcinoma , alveolar ( bronchiolar ) carcinoma , bronchial adenoma , chondromatous hamartoma , mesothelioma , squamous cell carcinoma , colorectal adenocarcinoma , leiomyosarcoma , carcinoma of the stomach , pancreatic ductal adenocarcinoma , insulinoma , glucagonoma , gastrinoma , pancreatic carcinoid tumors , vipoma , cancers of the small bowel cancers of the large bowel , colorectal adenocarcinoma , kidney adenocarcinoma , wilm &# 39 ; s tumor , nephroblastoma , bladder and urethra carcinomas , prostate adenocarcinoma and sarcoma , testicular cancers , hepatoma , hepatocellular carcinoma , cholangiocarcinoma , hepatoblastoma , angiosarcoma , hepatocellular adenoma , hemangioma , osteosarcoma , fibrosarcoma , malignant fibrous histiocytoma , chondrosarcoma , malignant lymphoma ( reticulum cell sarcoma ), multiple myeloma , malignant giant cell tumor chordoma , osteochrondroma ( osteocartilaginous exostoses ), benign chondroma , chondroblastoma , chondromyxofibroma , osteoid osteoma and giant cell tumors ; granuloma , xanthoma , osteitis defornians , meningioma , meningiosarcoma , gliomatosis , astrocytoma , medulloblastoma , glioma , ependymoma , germinoma ; pinealoma , glioblastoma multiformae , oligodendroglioma , schwannoma , retinoblastoma , congenital tumors , neurofibroma , breast cancer , endometrial carcinoma , cervical carcinoma , pre - tumor cervical dysplasia , ovarian carcinoma ; serous cystadenocarcinoma , mucinous cystadenocarcinoma , unclassified carcinoma ; granulosa - theca cell tumors , sertoli leydig cell tumors , dysgerminoma , malignant teratoma , vulval cancer , vaginal cancer fallopian tube carcinoma , chronic and acute myeloid leukemia , acute lymphoblastic leukemia , chronic lymphocytic leukemia , myeloproliferative diseases , multiple myeloma , myelodysplastic syndrome , hodgkin &# 39 ; s disease , non - hodgkin &# 39 ; s lymphoma , malignant lymphoma , endothelioma , malignant melanoma , basal cell carcinoma , squamous cell carcinoma , kaposi &# 39 ; s sarcoma , moles dysplastic nevi , lipoma , angioma , dermatofibroma , keloids , psoriasis , and neuroblastoma . the invention is applicable to other cancers discussed herein , including pre - cancers . immune related diseases include systemic lupus erythematosis , rheumatoid arthritis , osteoarthritis , juvenile chronic arthritis , spondyloarthropathies , systemic sclerosis , idiopathic inflammatory myopathies , sjögren &# 39 ; s syndrome , systemic vasculitis , sarcoidosis , autoimmune hemolytic anemia , autoimmune thrombocytopenia , thyroiditis , diabetes mellitus , immune - mediated renal disease , demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis , idiopathic demyelinating polyneuropathy or guillain - barré syndrome , and chronic inflammatory demyelinating polyneuropathy , hepatobiliary diseases such as infectious , autoimmune chronic active hepatitis , primary biliary cirrhosis , granulomatous hepatitis , and sclerosing cholangitis , inflammatory bowel disease , gluten - sensitive enteropathy , and whipple &# 39 ; s disease , autoimmune or immune - mediated skin diseases including bullous skin diseases , erythema multiforme and contact dermatitis , psoriasis , allergic diseases such as asthma , allergic rhinitis , atopic dermatitis , food hypersensitivity and urticaria , immunologic diseases of the lung such as eosinophilic pneumonias , idiopathic pulmonary fibrosis and hypersensitivity pneumonitis , transplantation associated diseases including graft rejection and graft - versus - host - disease . in addition to soluble receptors for tnf , a wide variety of inhibitors or antagonists of tnf are contemplated in this patent for reducing liver injury induced by various agents , including cd137 . these tnf inhibitors include infliximab ( remicadea ®), mouse - human chimeric anti - hutnf mab ; d2e7 ( humira ™), fully human anti - hutnf mab ; etanercept ( enbrel ®), p75stnf - rii - fc ( dimeric ); peg - p55stnf - ri ( monomeric ); lenercept , p55stnf - ri - igg1 ( dimeric ), cdp571 ( cdr - grafted anti tnf ab ) and cdp870 / certolizumab ( peg - linked anti tnf fab ). other inhibitors of tnf include small molecules ( e . g ., those described by he et al ., 2005 science 310 : 1022 - 1025 ; haraguchi et al ., aids res ther . 2006 ; 3 : 8 . published online 2006 mar . 31 . doi : 10 . 1186 / 1742 - 6405 - 3 - 8 ; strachan et al ., 2000 j . immunol . 164 : 6560 - 6565 ; and u . s . patent application ser . no . 10 / 833 , 871 entitled “ preparation of hymenialdisine derivatives and use thereof .” other tnf inhibitory antibodies include those described in u . s . pat . no . 7 , 160 , 542 ; u . s . patent application ser . nos . 10 / 043 , 436 , and 11 / 180 , 219 inhibitors of tnf , inhibitors of tnf include soluble tnf receptor polypeptides or inhibitors of tnf receptors . other inhibitors include competitive tnf antagonists , including those described in u . s . pat . no . 5 , 795 , 967 . other inhibitors include nucleic acids such as sirnas that are specific for inhibiting tnf expression . in addition to soluble receptors for lt , a wide variety of inhibitors or antagonists of lt are contemplated in this patent for reducing liver injury induced by various agents , including cd137 . inhibitors of lt include soluble forms of the ltβr extracellular domain . this can be achieved , for example , by fusing the extracellular domain of ltβr to an immunoglobulin constant heavy chain domain or to a human igg fc domain . other inhibitors include antibodies that bind to ltβr or lt . competitive antagonists of lt and nucleic acids inhibitors such as sirnas that are specific for inhibiting lt expression are also contemplated . ltβr is credited with developing lymphoid tissues but its role in other tissues has not been fully explored . ltβr &# 39 ; s high expression in liver and ltβr - deficient mice exhibiting reduced survival after partial hepatectomy suggest an active role of ltβr in promotion of hepatocyte proliferation or prevention of hepatic apoptosis . a question explored was whether ltβr signaling influences the liver injury induced by various tnfsf members . first , to investigate whether fas - induced hepatocyte injury is dependent upon the ltβr signaling , wt and ltβr - deficient mice were injected with anti - fas agonistic antibody ( fig1 a - 1g ). this treatment induces severe hepatitis in wild type ( wt ) mice by directly targeting hepatocytes , leading to super - acute liver failure . unexpectedly , almost all ltβr −/− mice survived , whereas wt mice died within 12 h after treatment ( fig1 a ). serum alanine aminotransferase ( alt ) levels , as an indicator of liver injury , were significantly reduced in ltβr mice at 3 h after anti - fas treatment ( fig1 b ). reduced liver injury in ltβr −/− mice was not due to an intrinsic resistance of ltβr −/− hepatocytes to fas - mediated apoptosis because ltβr −/− hepatocytes were sensitive to fas - mediated apoptosis in primary hepatocytes in vitro . to define which cells could influence fas - induced hepatitis , liver lymphoid cells were analyzed by flow cytometry . increased numbers of neutrophils were observed in wt mice injected with anti - fas antibody ( fig1 c ). however , neutrophil numbers were significantly reduced in ltβr −/− mice , which correlated with reduced myeloperoxidase ( mpo ) positive cells and liver injury compared to wt mice at 2 h after anti - fas antibody injection ( fig1 , c and d ). the reduced recruitment of neutrophils to the liver of ltβr −/− mice after fas stimulation was not attributable to defective neutrophil development since nave ltβr −/− mice contained normal neutrophil numbers in the liver and spleen ( fig1 c ). to define how ltβr controls neutrophil recruitment to the liver after fas stimulation , expression of chemokines cxcl2 , cxcl1 , and ccl3 that control neutrophil recruitment to the liver was analyzed ( fig1 e , fig1 f , fig1 g ). cxcl2 and cxcl1 are rapidly induced in the liver after fas stimulation and significantly contribute to neutrophil - mediated inflammation in the liver . reduced expression of cxcl2 ( mip - 2 ) and ccl3 was found in the liver of ltβr −/− mice , while expression of cxcl1 ( kc ) was not significantly different between wt and ltβr −/− mice ( fig1 e ). these results support that ltβr promotes pathogenic recruitment of neutrophils to the liver after fas stimulation by controlling expression of neutrophil attracting chemokines . fas and ltβr signaling are linked and likely coordinate since fas activation cannot fully induce liver injury in the absence of ltβr signaling . inhibition of ltβr signaling prevents hepatitis in a novel fas - independent liver injury model to define whether ltβr signaling is also involved in regulation of fas - independent liver injury agonistic anti - cd137 antibody , a strong t cell activator , was injected into fas −/− mice . cd137 ( 4 - 1bb ) is a member of the tnfr superfamily and primarily expressed on activated t cells . in wt mice this agonistic antibody induces subacute hepatitis within 7 days after injection that abates by day 14 ( fig2 , a and b ). this detailed analysis of intrahepatic lymphocytes in this severe hepatitis model parallels viral hepatitis in humans , in which there is heavy infiltration of cd8 + cells that secrete large amounts of ifn - γ , tnf , and chemokines are observed ( fig2 c , and fig3 , a and 3 c ). cd137 - induced hepatitis appears to be rich in cd8 + t cells , which represented the largest cell population in the liver of treated mice , whereas cd4 + t cells showed a lesser increase ( fig2 c ). however , unlike in cona - induced hepatitis model ( 3 ), cd4 cells do not appear to play an essential role , since fas −/− cd4 −/− double deficient mice were susceptible to cd137 - induced liver injury ( fig2 d and fig3 e ). in contrast , fas −/− cd8 −/− mice were essentially resistant to cd137 - induced liver injury ( fig2 e and fig3 f ). thus , activation of t cells by the cd137 costimulation pathway in fas - deficient mice results in development of a subacute cd8 - dependent hepatitis in mice . to test if inhibition of ltβr signaling could prevent hepatitis in the cd137 - induced hepatitis and thus uncover a potential treatment , the effect of soluble ltβr fusion protein ( ltβr - ig ) was tested . ltβr - ig given immediately before and again two days after anti - cd 137 administration resulted in markedly attenuated hepatitis with reduced serum alanine alt levels and minimal histological evidence of liver injury in fas −/− recipient mice ( fig2 , f - g ). ltβr - ig treatment also reduced the number of infiltrating lymphocytes in the liver compared to control rat - igg treated mice ( fig3 g ) inhibition of ltβr signaling by injection of ltβr - ig prevents the development of cd8 - dependent , fas - independent liver injury in cd137 stimulated mice . to test whether tnf is also involved in such t cell mediated hepatitis , the mice were treated with anti - cd137 as before , but 100 ug of tnfr - ig and ltβr - ig ( fig4 a ) was added . interestingly , both tnfr - ig and ltβr - ig can greatly reduce alt , supporting that tnf and lt are involved in liver injury . to test the role of light , another ligand for ltβr , hvem - ig that binds to light was used , but the blocking effect is limited ( fig4 b ). therefore , it is likely that both lt and tnf are required , but not light . ltβr signaling by membrane lt complex is essential for cona - induced liver injury to determine whether ltβr signaling is required for liver injury induced by cona , a strong and broader t cell activator that utilizes distinct ligands and cytokines that may each directly and indirectly cause liver injury , wt , ltβ −/− , ltβr −/− , and tnfr −/− mice were injected with a sublethal dose of cona ( fig5 and 5b ). quantitative serum alt at 24 hours after cona injection indicated significantly less hepatocyte injury in ltβ −/− , and ltβr −/− mice compared to wt mice ( fig5 a ). examination of liver tissue harvested 24 hours after cona administration revealed wt mice with geographic coagulative hepatocellular necrosis not seen in ltβ −/− and ltβr −/− mice ( fig5 b ). residual liver injury present in ltβ −/− compared to ltβr −/− mice ( fig5 a - b ) suggests that light signaling , the only other known ligand for ltβr , may additionally contribute to liver injury . this data demonstrates a distinct role of lt specifically in the pathogenesis of hepatitis that is not redundant . using a genetic knockout system , the inventor found that ltβ −/− mice , lacking surface lt , were protected from cona - induced liver injury even though unaltered light signaling persists ( fig5 a - 5b ). thus , this data demonstrates that ltβr deficiency confers resistance to cona - induced liver damage and that signaling by the ltα 1 β 2 through ltβr is necessary for developing cona - induced liver injury . therefore , blockade of lt or tnf by soluble receptors , or other inhibitors of lt or tnf expression or activity , will have broad impact on controlling liver injuries by various causes . inhibition of lt and ltβr signaling protects mice from cona - induced liver injury to determine whether inhibition of ltβr signaling could potentially protect mice from a broader form of liver injury induced by cona , wt mice were pretreated i . v . with 200 μg of control human igg or soluble ltβr fusion protein ( ltβr - ig ), which blocks ltβr signaling , 2 hours prior to cona injection ( fig6 a - 6d ). control human igg i . v . 2 hours prior to cona treatment in wt mice resulted in the expected marked alt elevations at 8 and 24 hours post - injection , whereas ltβr - ig resulted in substantially reduced alt levels ( fig6 b ). the ltβr - ig treatment markedly limited hepatocellular injury ( fig6 a - 6b ). to determine the influence on liver apoptosis , livers were harvested at 8 hours post cona administration and histological sections were assessed for tunel positive hepatocyte nuclei . wt mice treated with ltβr - ig had significantly fewer tunel positive nuclei ( fig6 c ). these data indicate that a pharmacologic blockade of ltβr reduces cona - induced hepatocyte injury , raising the possibility of treating broader forms of liver insults . since ltβr - ig blocks signaling through the ltβr from both light and the membrane lt complex ltα1β2 , the next test was whether specific inhibition of membrane lt reduces cona - induced hepatocyte injury ( fig6 d ). anti - ltβ antagonistic antibody given to wt mice 2 h prior to cona administration reduced liver injury relative to treatment with a control hamster antibody ( fig6 d ). together these data show that inhibition of ltβr signaling through ltα1β2 prevents cona - induced liver injury and illuminate a new direction for treatment of hepatitis through blockade of lt or tnf by soluble receptors , or other inhibitors of lt or tnf expression or activity . the ltβr pathway indeed plays a central and integral role in mediating the injury induced by different tnfsf members . this insight prompted the investigation of lt in t cell - mediated hepatitis , wherein multiple tnfsf pathways appear to coordinate the attack . chronic hepatitis c ( hcv ) viral infection induces t cell - mediated hepatitis , a chronic inflammation associated with an increased production of inflammatory cytokines leading to liver injury ( guidotti and chisari , 2006 ; mengshol et al ., 2007 ). studies in mice demonstrated that ectopic lt overexpression promotes similar chronic inflammation ( drayton et al ., 2006 ). however , whether lt has a significant role in hcv mediated liver injury remains largely unknown . to determine the role of lt in the pathogenesis of hcv - induced hepatitis , the inventor measured ltα mrna expression by real - time rt - pcr in liver tissue from human patients chronically infected with hepatitis c virus ( fig7 ). livers with chronic hcv infection showed significantly increased levels of ltα mrna expression when compared to uninfected controls ( fig7 ). these data suggest that lt may be involved in the pathogenesis of human hcv induced hepatitis and that blockade of lt by soluble receptors , or other inhibitors of lt expression or activity , will have broad impact on controlling hcv induced hepatitis . human samples . liver tissue samples were collected from chronically infected hcv patients at the time of liver transplantation according to approved procedures at johns hopkins school of medicine . active chronic hepatitis was confirmed by hematoxylin and eosin staining and ast levels (& gt ; 50 u / 1 ). all patients were diagnosed chronic hepatitis c virologically and serologically . all healthy donors were negative for hcv , hepatitis b virus ( hbv ), and human immunodeficiency virus ( hiv ). mice . c57bl / 6 male mice 8 - 10 weeks of age and fas −/− mice were purchased from the jackson laboratory ( jackson labs bar harbor , me ). fas −/− mice were crossed with cd4 −/− and cd8 −/− mice to generate fas −/− cd4 −/− and fas −/− cd8 −/− double deficient mice , respectively . ltβr −/− mice were kindly provided by k . pfeffer ( technical university of munich , germany ) lck - light transgenic mice ( light - tg ), ltβ −/− mice were genotyped as described ( wang et al ., 2001 ; tumanov et al ., 2002 ). all 8 - 10 weeks aged male mice were on c57bl / 6 background and were housed under specific pathogenfree conditions at the university of chicago . animal care and use were in accordance with institutional and nih protocols and guidelines , and all studies were approved by the animal care and use committee of the university of chicago . cona and antibody treatments . cona ( vector laboratories ) was administered i . v . to the mice at the indicated doses . sera were collected at the indicated times for measurement of cytokines and liver enzymes . inhibitors of lt and ltβr signaling : anti - ltβ blocking antibody ( bbf6 , 100 μg ) or soluble ltβr fused to human fc portion of igg ( ltβr - ig , 100 μg ) were injected i . v . 2 hours prior to cona injection . the ltβr - ig used in this study has been previously described . briefly , cdna encoding the extracellular domain of murine ltβr was fused with the fc portion of human igg , transfected into bhk / vp16 cell , and the supernatant collected . induction of hepatitis in fas −/− mice by administration of anti - cd137 . fas −/− mice were treated with 200 μg agonistic anti - cd137 ( 2a , rat igg2a ) by i . p . injection . the generation of 2a has been described previously ( wu et al ., 1999 ) and ascites were produced in scid mice and purified by passage over a protein g - coupled sepharose ® column . rat igg was purchased from sigma - aldrich and served as a control . rt - pcr analysis . total rna was extracted by rneasy ® mini kit from qiagen . for cdna synthesis , rnas were digested with dnase i and reverse transcribed using random primers with amv reverse transcriptase ( promega ) ( amv - rt ®). the concentration of the target gene was determined using the comparative c t ( threshold cycle number at a cross - point between amplification plot and threshold ) method and normalized to gapdh or hprt . cdna were amplified using taqman ® pcr master mix ( applied biosystems ) and run on abi 7900 cycler ( applied biosystems ). pcr primers and probes used : for human ltα : forward 5 ′- tggtgttggcctcacacct ( seq id no : 1 ), reverse 5 ′- ccaggagagaattgttgctc ( seq id no : 2 ), probe 5 ′- fam - ccacagcaccctcaaacctgc - tamra ( seq id no : 3 ); for human gapdh , forward 5 ′- gaaggtgaaggtcggagt ( seq id no : 4 ), reverse 5 ′- gaagatggtgatgggattt ( seq id no : 5 ), probe 5 ′- caagcttcccgttctcagc ( seq id no : 6 ); for murine mip - 2 ( cxcl2 ): sense 5 ′- ccaccaaccaccaggctacaggggc ( seq id no : 7 ), antisense 5 ′- aggctcctcctttccaggtcagttagc ( seq id no : 8 ); for murine hprt : forward : 5 ′- cagaggactagaacacctgc ( seq id no : 9 ), reverse : 5 ′- gctggtgaaaaggacctct ( seq id no : 10 ); for murine kc ( cxcl1 ): forward 5 ′- ccacccgctcgcttctc ( seq id no : 11 ), reverse 5 ′- cactgacagcgc agctcatt ( seq id no : 12 ); for murine mip - 1α ( ccl3 ): forward 5 ′- ccttgctgttcttctctgtaccatg ( seq id no : 13 ), reverse 5 ′- gcaatcagttccaggtgagtgatg ( seq id no : 14 ). histology and tunel labeling . tissues were fixed in 10 % buffered formalin and processed either for routine hemotoxylin and eosin staining or tunel and immunohistochemical studies . hematoxylin and eosin staining on sections of embedded tissues was performed according to standard procedure in the university of chicago pathology histology laboratory . tunel staining was performed on paraffin - embedded , formalin - fixed tissue using the apoptag ® plus peroxidase in situ apoptosis detection kit ( chemicon international ) according to the manufacturer &# 39 ; s directions . anti - gr - 1 ( rb6 - 8c5 clone ) ( bd biosciences ) and anti - myeloperoxidase ( mpo ) ( neomarkers ) antibody staining was performed on paraffin - embedded , formalin - fixed tissue . transaminase activity and cytokines analyses . blood was collected by retro - orbital puncture , following iacuc approved procedures . plasma alanine aminotransferase ( alt ) and aspartate aminotransferase ( ast ) activities were determined using a reflotron ® plus chemistry analyzer according to the manufacturer &# 39 ; s procedure ( roche diagnostics corp .). concentrations of cytokines in sera were determined by cytokine bead assay ( bd biosciences ) following the manufacturer &# 39 ; s recommendations . flow cytometry analysis . intrahepatic leukocytes were purified from the liver by pressing the liver through a steel sieve ( sigma , 190 μm ) into pbs , centrifuged at 800 g for 5 min with the resulting pellet suspended in a 35 % percoll ®- pbs - heparin ( 100 u / ml ) solution and centrifuged at 800 g for 20 min at room temperature . the pellet of mononuclear cells was cleared of rbc with a 5 - min osmotic lysis ( 0 . 15 m nh 4 cl , 1 mm khco 3 , 0 . 1 mm na 2 edta , ph 7 . 3 ) and washed twice in pbs . lymphocytes were stained with antibodies ( bd biosciences ) and analyzed by flow cytometry ( facscanto , bd biosciences ). statistical analysis . data are expressed as means ± sd . statistical significance was determined by a two - tailed student &# 39 ; s t - test (* p & lt ; 0 . 05 , ** p & lt ; 0 . 01 , *** p & lt ; 0 . 001 ), ns - not significant ( p & gt ; 0 . 05 ). abbreviations used : lt , lymphotoxin ; light , t - cell - restricted ligand , homologous to lymphotoxin , exhibits inducible expression , competes with herpesvirus glycoprotein d for herpesvirus entry mediator on t - cells ( tnfsf14 ); alt , alanine aminotransferase these publications are incorporated by reference to the extent they relate materials and methods disclosed herein . ajuebor , m . n ., c . m . hogaboam , t . le , a . e . proudfoot , and m . g . swain . 2004 . ccl3 / mip - 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one side - effect arising from the use of antibodies against tnf receptor family members as therapeutics can be liver damage which precludes the completion of clinical trial . a novel lt - dependent pathway is described that mediates liver cell injury in several disease models .

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 , devices , and materials are now described . however , before the present materials and 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 . accordingly , 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 . however , in case of conflict , the present specification , including definitions below , will control . the words “ a ”, “ an ” and “ the ” as used herein mean “ at least one ” unless otherwise specifically indicated . thus , for example , reference to an “ opening ” is a reference to one or more openings and equivalents thereof known to those skilled in the art , and so forth . the term “ proximal ” as used herein refers to that end or portion which is situated closest to the user of the device , farthest away from the target surgical site . in the context of the present invention , the proximal end of the powered percussive device includes the hub region . the term “ distal ” as used herein refers to that end or portion situated farthest away from the user of the device , closest to the target surgical site . in the context of the present invention , the distal end of the powered percussive device includes the axially movable distal element optionally configured for penetration of a bony surface . in the context of the present invention , the term “ cannula ” is used to generically refer to the family of elongate lumened surgical instruments that facilitate access across tissue to an internally located surgery site . the terms “ tube ” and “ tubular ” are interchangeably used herein to refer to a generally round , long , hollow component having at least one central opening often referred to as a “ lumen ”. the terms “ lengthwise ” and “ axial ” as used interchangeably herein to refer to the direction relating to or parallel with the longitudinal axis of a device . the term “ transverse ” as used herein refers to the direction lying or extending across or perpendicular to the longitudinal axis of a device . the term “ lateral ” pertains to the side and , as used herein , refers to motion , movement , or materials that are situated at , proceeding from , or directed to a side of a device . the term “ medial ” pertains to the middle , and as used herein , refers to motion , movement or materials that are situated in the middle , in particular situated near the median plane or the midline of the device or subset component thereof . the term “ rotational ” as used herein refers to the revolutionary movement about the center point or longitudinal axis of the device . in the context of the present invention , the inner assembly is rotated relative to the outer assembly , which typically is held in a stationary position , or vice versa . in either case , the rotary motion results in an energy potential that is stored and then subsequently transformed into an axial percussive force having clinical utility . in the summary above and the examples below , the present invention makes reference to the use of a linear spring to store and subsequently release kinetic energy in the form of a percussive force . however , the present invention contemplates other compressible and / or elastomeric configurations for potential energy storage , i . e ., alternative mechanisms , such as a bow or torsional spring , that may be deformed under pressure , tension or compression ( i . e ., stressed ) and then subsequently released from stress , thereby transforming the stored energy into a kinetic energy that may be directed to a target location or component as a percussive force . in the examples below , the present invention makes reference to various lock - and - key type alignment mechanisms that serve to establish and secure the arrangement of the various device components , such as the outer assembly to the arthroscopy handpiece . it will again be readily understood by the skilled artisan that the position of the respective coordinating elements ( e . g ., mating slots and protrusions ) may be exchanged and / or reversed as needed . in the summary above and the examples below , the present invention makes reference to a “ cam ” and “ cam surfaces ”. in the context of the present invention , a cam is a rotating or sliding piece in a mechanical linkage used especially in transforming rotary motion into linear motion or vice - versa . it is often a part of a rotating wheel ( e . g . an eccentric wheel ) or shaft ( e . g . a cylinder with an irregular shape ) that strikes a lever at one or more points on its circular path . the cam can be a simple tooth , as is used to deliver pulses of power to a steam hammer , for example , or an eccentric disc or other shape that produces a smooth reciprocating ( back and forth ) motion in the follower , which is a lever making contact with the cam . the present invention contemplates the use of alternative cooperating elements for automatically transmitting relative axial movement when the inner and outer hubs are relatively rotated , in particular cooperating elements disposed on or within the inner and outer hubs . examples of such cooperating elements include , but are not limited to , screw threads , worm gears , worm wheels , pneumatic devices , hydraulic mechanisms , magnetic assemblies , ratchet - and - pawl assemblies , and push - pull connectors . the instant invention has both human medical and veterinary applications . accordingly , the terms “ subject ” and “ patient ” are used interchangeably herein to refer to the person or animal being treated or examined . exemplary animals include house pets , farm animals , and zoo animals . in a preferred embodiment , the subject is a mammal . hereinafter , the present invention is described in more detail by reference to the figures and examples . however , the following materials , methods , figures , and examples only illustrate aspects of the invention and are in no way intended to limit the scope of the present invention . for example , while the present invention makes specific reference to arthroscopic procedures , it is readily apparent that the teachings of the present invention may be applied to other minimally invasive procedures and are not limited to arthroscopic uses alone . as such , methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention . fig1 through 6 depict an outer assembly 200 for a surgical percussive driver constructed in accordance with the principles of this invention . assembly 200 has a polymeric proximal portion forming a hub 202 with alignment key 203 for mounting in an arthroscopy shaver handpiece . a tubular cam element 204 having a helically formed proximal surface is mounted in the proximal end of hub 202 . outer assembly 200 has a distal tubular portion 206 terminating in a distal sub - assembly having a fixed portion 208 mounted to the distal end of tubular portion 206 and an axially movable portion formed of distal penetrating element 210 together with tubular retaining element 212 mounted to the proximal end of element 210 that acts as a stop mechanism , preventing the dislodgment or removal of the penetrating element 210 from the lumen of tubular portion 206 . distal penetrating element 210 can move axially distance 220 within element 208 . fig7 through 16 depict an inner assembly 300 for a surgical percussive driver constructed in accordance with the principles of this invention . assembly 300 has a proximal portion including a polymeric hub 320 with a proximal end drive portion 324 for transmitting rotational motion provided by an arthroscopy shaver handpiece , and a distal portion 322 in which is mounted the proximal end 312 of metallic distal rod element 310 , distal rod element 310 having a distal end 314 . hub 320 has mounted to its proximal drive portion spring 340 which has an initial compression supplied by , and is maintained in its position by spring retainer 350 . hub 320 has a helical distal - facing surface 326 having a pitch equal to that of the helical proximal surface of cam element 204 ( fig1 through 6 ). fig1 through 18 depict a surgical percussive driver 100 formed in accordance with the principles of this invention and formed of outer assembly 200 and inner assembly 300 . distal rod portion 310 of inner assembly 300 is positioned within tubular distal portion 206 of outer assembly 200 such that inner assembly 300 may be moved axially and rotationally , the axial motion being provided by cooperative interaction of the helical surface of cam 204 of outer assembly 200 and distal helical surface 326 of inner hub 320 . the respective helical surfaces ( 204 and 326 ) are formed such that rotation of inner assembly 300 within outer assembly 200 causes proximal axial motion of inner assembly 300 a predetermined distance whereupon inner assembly 300 is allowed to return to its distal - most position as depicted in fig1 through 18 . in this distal - most advanced position , metallic distal rod portion forces pointed penetrating element 210 to a distal position , though not its distal - most position . fig1 through 25 present a schematic representation of surgical percussive driver 100 ( formed through the coordination of inner and outer assemblies , 300 and 200 respectively ) mounted in a conventional arthroscopy shaver handpiece , wherein only those portions of the handpiece essential to the understanding of the operation of device 100 are depicted . accordingly , fixed element 402 with keyway 403 , and rotatable element 404 with keyway 405 are distal elements of a shaver handpiece . in use , rotatable element 404 is positioned such that keyways 403 and 405 are aligned and hub 202 with alignment key 203 can be inserted and positioned as shown in fig2 , whereupon rotatable element 404 is repositioned such that keyways 403 and 405 are not aligned and the axial position of hub 202 is maintained in the handpiece . element 410 corresponds to the rotational drive element of the shaver handpiece . as best seen in fig2 proximal end drive portion 324 of hub 320 is engaged by slot 412 of drive element 410 , and the tapered proximal portion of spring retainer 350 engages the tapered distal portion of drive element 410 such that inserting device 100 into the handpiece causes compression of spring 340 . the compression of spring 340 is depicted at its near maximum in fig1 through 25 wherein , as best seen in fig2 , the helical proximal surface of cam 204 in cooperative action with helical distal surface 326 of hub 320 has positioned inner assembly 300 at its maximum proximal deflection . referring to fig2 , distal rod portion 310 of inner assembly 300 is positioned proximally a distance 520 from the proximal end of penetrating element 210 and retaining element 212 . as shown in fig2 , penetrating element 210 is in its proximal - most position with distance 510 between the distal - most surface of retaining element 212 and the proximal - most surface of element 208 . distance 520 is less than the maximum proximal deflection of inner assembly 300 caused by the cooperative action of cam 204 and surface 326 of hub 320 . distances 510 and 520 together are greater than the maximum proximal deflection of inner assembly 300 caused by the cooperative action of cam 204 and surface 326 of hub 320 . fig2 through 30 depict the same elements as fig1 through 25 except that , as best seen in fig2 , inner assembly 300 has been rotated such that the helical proximal surface of cam 204 and helical surface 326 of hub 320 are disengaged and inner assembly 300 has traveled to its distal - most position as determined by cam 204 and inner hub 320 . when helical surface 326 of hub 320 is rotated past the angular limit of the helical proximal surface of cam 204 , force exerted by the ( now released ) spring 340 causes inner assembly 300 to rapidly travel to its distal limit . potential energy stored in spring 340 ( i . e ., kx where k is the spring constant and x is the spring deflection ) is converted to kinetic energy ( i . e ., ½ mv 2 where m is the mass of the inner assembly and v is the velocity of the inner assembly ). as best seen in fig2 , the distal end of distal rod 310 of inner assembly 300 contacts the proximal end of penetrating element 210 forcing it distally distance 530 . in use , the pointed distal end of penetrating element 210 is positioned against a bony surface to be penetrated . the shaver handpiece is activated such that inner assembly 300 is rotated , with cam 204 and helical surface 326 of hub 320 causing inner assembly 300 to be repeatedly deflected proximally and allowed to “ snap ” back to its distal position , in the process transferring its kinetic energy to the penetrating element so as to cause iterative penetration of the bony surface . device 100 depicts only two such cycles per revolution of inner assembly 300 . however , this is meant to be illustrative only ; as such other embodiments are contemplated wherein the axial cycles per revolution may range from 1 to 5 , preferably 2 to 4 , more preferably 2 to 3 . the energy transferred to penetrating element 210 is determined by the spring constant of spring 340 . accordingly , the spring constant can be increased to maximize the energy transferred , the maximum spring constant being determined by the torque required to rotate the inner so as to result in compression of spring 340 . the torque required will be determined by the spring constant and by the helical pitch of cam 204 and helical surface 326 of hub 320 . this pitch can be minimized by having a single compression of the spring per rotation of inner assembly 300 . to increase the rate of penetration of penetrating element 210 into a bony surface , the speed of the handpiece can be increased . the mass of inner assembly 300 ideally should not affect the transfer of the stored spring energy since a lower mass would result in a correspondingly higher velocity ; however , the efficiency of the transfer of the kinetic energy and penetration of the bony surface at high velocities may be less efficient . accordingly , the velocity may be decreased by increasing the mass of distal rod 310 of inner assembly 300 either through maximizing its diameter and length , or by forming it from a high - density metal . in the embodiment above , spring 340 is retained on inner hub 320 by spring retainer 350 . in other embodiments a spring is incorporated in the shaver handpiece and spring 340 and spring retainer 350 are eliminated . in the illustrative embodiment herein depicted , the penetrating element 210 and distal rod 310 are coaxial . however , other embodiments are anticipated in which the axis of the penetrating element 210 is angularly offset from the axis of distal rod 310 , thereby allowing surgeons to penetrate bony surfaces in locations which do not allow coaxial alignment . in such embodiments , the proximal - most surface of penetrating element 210 and retaining element 212 will not be normal to the elements &# 39 ; axis , but rather formed at a predetermined angle such that striking this surface with distal rod 310 produces a penetrating force that is not coaxial with rod 310 . fig3 depicts surgical percussive driver device 100 positioned for the microfracture treatment of an articular lesion 602 in bone 600 . in form , lesion 602 has a form resembling that of a pot - hole . in preparation for treatment , the walls of the “ pot - hole ” have been cleared back to stable articular cartilage and surface 604 has been abraded using a powered device or curette . as seen in fig3 , the distal end of element 210 is placed in contact with surface 604 . rotation of hub 320 and cooperative action between element 204 and surface 324 of hub 320 causes compression of the proximal spring such that distal end 314 of element 310 is displaced proximally from element 312 and the proximal end of element 310 . referring now to fig3 and 34 , continued rotation of hub 320 allows inner assembly 300 to travel distally as stored spring energy is converted to kinetic energy . as best seen in fig3 , distal end 314 of rod 310 impacts the proximal end of element 210 and element 212 thereby percussively transferring energy to element 210 causing penetration of surface 604 . continued activation of the shaver handpiece causes repeated percussive transfer of energy to element 210 thereby causing continued penetration of element 210 into surface 604 until element 210 has reached a predetermined depth as depicted in fig3 and 36 creating conical void 606 . the process is repeated so as to form a plurality of conical voids 606 as depicted in fig3 . percussive surgical devices of the present invention may be advantageously used for a variety of applications and is thus not limited to the application described above . for instance , in an alternate embodiment 1000 depicted in fig3 and 39 , the construction and operation of which are identical to percussive surgical driver device 100 except as described hereafter , distal element 210 with its conically pointed distal portion is replaced by planar elongate distal element 1210 having a sharpened distal edge 1211 . element 1210 functions as a chisel , the percussive energy transferred to it allowing the sharpened distal end 1211 to remove material from bony surfaces so as create flat surfaces . fig4 depicts the distal portion of a similar embodiment in which the elongate element 1210 has a curved cross - section and sharpened distal edge 1211 so as to allow device 1000 to create grooves in bony surfaces . the use of implants to affix tissue grafts to bone is well known . common procedures in which such implants ( also called “ anchors ”) are used include the repair of rotator cuff tears , and the repair of torn ligaments in the knee , among others . in these procedures , a socket is drilled or punched in the bone at the attachment site and a graft is secured to the bone using an implant placed in the socket . the graft may be secured to the implant by sutures , or an end of the graft may be placed in the socket and secured directly by an implant . such implants may be threaded and placed in the socket by torque applied to the anchor . alternatively , the anchor may be an interference plug - type that is not rotated for insertion , but rather forced into the socket by percussive energy that is conventionally supplied by a mallet applied to the anchor driver proximal end . the placement of an interference plug - type anchor in a prepared socket may be advantageously accomplished using a percussive surgical device of the instant invention . fig4 through 45 depict device 2000 with interference plug - type anchor 2700 loaded to the distal end thereof in preparation for placement of anchor 2700 in a prepared socket for the purpose of securing a graft . in all aspects of construction and function , device 2000 is identical to device 100 except as subsequently described . as best seen in fig4 , distal element 2210 has an elongate cannulated distal portion 2211 on which implant 2700 is positioned , and a proximal lateral opening 2209 in communication with the central lumen of distal portion 2211 . loading loop 2702 is formed from a suitable wire and has formed on its proximal end pull - tab 2704 . by placing sutures in loading loop 2702 and withdrawing the loop proximally using pull tab 2704 , sutures may be loaded into elongate portion 2211 of distal element 2210 such that the distal portion of the sutures extend beyond the distal end of distal element 2210 and implant 2700 , and the proximal portion extends proximally from lateral opening 2209 . fig4 through 49 depict device 2000 with sutures 2800 so loaded there to . distal portions 2802 of sutures 2800 extend distally beyond the distal end of anchor 2700 and distal portion 2211 of distal element 2210 , and proximal portions 2804 extend proximally from lateral opening 2209 of distal element 2210 . illustrative steps for placing anchor 2700 in prepared socket 2902 of bone 2900 to affix graft 2910 are depicted in fig5 through 53 . referring first to fig5 , sutures 2800 have been passed through graft 2910 in the usual manner , and loaded into device 2000 in the manner previously herein described such that distal portions 2802 of sutures 2800 are secured to graft 2910 , and proximal portions 2804 of sutures 2800 extend proximally from distal element 2210 to outside of the joint space where they may be tensioned by the surgeon . device 2000 is positioned as depicted in fig5 such that the distal end of anchor 2700 is adjacent to the top of socket 2902 . in fig5 , the surgeon has applied tension to proximal portions 2804 of sutures 2800 so as to draw graft 2910 into positioned a predetermined distance from socket 2902 , the distance being determined such that when implant 2700 is placed in socket 2902 , graft 2910 will be in the desired position for fixation . while maintaining tension on sutures 2800 so as to maintain the graft position , the distal end of anchor 2700 is inserted into the socket and , while maintaining slight distal force , the shaver handpiece is activated so as to percussively force implant 2700 into socket 2902 . when graft 2910 is at the desired fixation location and implant 2700 is inserted such that its proximal end is below the proximal end of socket 2902 , the handpiece is deactivated and anchor placement is complete as depicted in fig5 , suture distal portions 2802 being trapped between anchor 2700 and the wall of socket 2902 . fig5 depicts the fixation using anchor 2700 with sutures 2800 trimmed just proximal to anchor 2700 . anchor 2700 is of a type known as a “ knotless anchor ”. when a graft is secured using a knotless anchor , suture are passed through the graft prior to anchor placement and the tying of knots to secure fixation of the graft is not required . percussive driver device 2000 may also be used for placing anchors in which the sutures are loaded into the anchor before it is placed in the socket , the sutures being subsequently passed through the graft and fixation of the graft achieved through the tying of knots proximal to the anchor and graft . in the exemplary fixation of graft 2910 using implant 2700 previously herein described , fixation of sutures 2800 is achieved by trapping the sutures between anchor 2700 and the wall of socket 2902 . in other embodiments , fixation is achieved by trapping a portion of graft 2910 between anchor 2700 and the wall of socket 2902 , a technique known as bio - tenodesis . the placement of anchor 2700 for bio - tenodesis differs from the technique previously herein described in that , instead of leaving a predetermined length of distal suture portions 2802 between the distal end of anchor 2700 and graft 2910 , graft 2910 is drawn to the distal end of anchor 2700 by tension applied to proximal portions 2804 of sutures 2800 . thereafter , anchor 2700 and a portion of graft 2910 are inserted into socket 2902 in the manner previously herein described . embodiments of the instant invention heretofore described are configured for use with standard shaver handpieces , particularly arthroscopic shavers , wherein the devices of the instant invention convert the rotational motion ( and torque ) native to the handpiece to axial percussive energy that may be applied to the distal end device component ( s ). the hubs described herein are standard shaver hubs on which cooperating cam and follower geometries have been formed . the inner assembly is propelled distally by the spring ( or other compressible element ) that is part of the device assembly . the travel of the inner assembly relative to the outer assembly is limited by the engagement between the inner hub proximal torque transmitting portion and the driving element of the shaver handpiece . the percussive energy transmitted to the distal element of the outer assembly may be increased by increasing the spring constant of the device spring . the maximum percussive energy which may be applied to the distal element is therefore limited by characteristics of the device , i . e . the maximum axial travel of the inner assembly , and the maximum spring constant which the shaver handpiece has sufficient torque to compress . the present invention contemplates embodiments that utilize a handpiece for driving the device that is not a standard shaver handpiece but rather a handpiece which provides percussive energy rather than rotational energy and is constructed in accordance with principles of the instant invention . because percussive energy is supplied to the device by the handpiece rather than by conversion of rotational energy to percussive by the device , the amount of percussive energy supplied to the distal element may be much greater . this , in turn , allows the use of larger distal elements that require higher levels of percussive energy to achieve clinical effects . fig5 through 60 depict such an alternate embodiment device 3000 configured for use with a handpiece that supplies percussive energy to the proximal end of the inner assembly of the device , the handpiece and device 3000 together forming a percussive surgical system constructed in accordance with the principles of the instant invention . referring to the figures , device 3000 is alike in construction to embodiments previously herein described , except as subsequently described . distal element 3210 of device 3000 has a distal portion with a square cross - section , a central lumen 3240 , a sharpened distal edge therebetween , and a proximal lumen 3242 . as best seen in fig6 , inner hub 3302 has no features for torque transmission , being instead configured to provide a means for transmitting proximal spring force from spring 3340 positioned between outer hub 3202 and inner hub 3302 to inner rod element 3310 . referring to fig5 , distal element 3210 may move axially within element 3208 distance 3510 . in its unconstrained state , distal end 3314 of inner rod element 3310 is displaced distance 3520 from the proximal end of elements 3210 and 3212 . referring now to fig6 through 63 , which depict device 3000 with corresponding elements of a percussive handpiece , thereby forming a system of the instant invention , drive element 3410 of the handpiece is in its retracted position in preparation for release causing drive element 3410 to travel distally at high velocity so as to cause distal end 3314 of inner element 3310 to impact the proximal end of element 3210 and element 3212 thereby impart percussive energy thereto . proximal force provided by spring 3340 on hub 3302 and therethrough to inner rod member 3310 maintains contact between the proximal end of member 3310 and drive element 3410 of the handpiece . fig6 through 66 depict the elements of fig6 through 63 except as depicted in fig6 through 66 drive element 3410 of the handpiece is at the distal extent of its travel , having imparted percussive energy to rod element 3310 and therethrough to distal element 3210 thereby causing distal element 3210 to travel distally distance 3560 . thereafter drive element 3410 is retracted proximally in the handpiece , spring 3340 maintaining contact between the proximal end of inner rod element 3310 and the distal end of drive element 3410 . when drive element 3410 has reached its proximal limit of travel , device 3000 and elements of the handpiece are as depicted in fig6 through 63 . cycling of the handpiece and device 3000 mounted thereto as herein described results in the repetitive transfer of percussive energy to distal element 3210 so as to allow penetration of element 3210 into a bony surface , or the driving of an implant into a prepared socket as previously herein described . the cycling frequency is preferably between one and ten hertz , and more preferably between one and five hertz . in a preferred embodiment the handpiece cycle rate is controlled by the surgeon by means of a proportional control for activation , the cycle rate at full displacement of the control being the device maximum rate . at slight levels of displacement of the activation control the speed is minimal so as to allow a high level of control of the penetration of the distal element 3210 . distal element 3210 of device 3000 is configured for the forming of square holes in a bony surface , the holes being formed in the following manner . a guidewire ( a small diameter rod ) is placed at the desired location . using a cannulated drill having a diameter equal to lumen 3240 of element 3210 , a hole is drilled to a predetermined depth . thereafter , device 3000 with is associated percussive handpiece is introduced to the site such that the guidewire enters cannulation 3242 of distal element 3210 thereby aligning element 3210 with the drilled hole . the distal sharpened end of element 3210 is then brought into contact with the bony surface and the handpiece activated so as to percussively drive element into the bone so as to create a square hole for the placement therein of a graft . distal element 3210 is configured to form a square socket by the removal of material . in an alternate embodiment depicted in fig6 , cannulated distal element 4210 is configured to produce a square socket by dilation of the bone adjacent to the previously drilled round hole . that is , instead of removing bone to create the square profile of the socket , bone is compacted to form the corners , the distal end of element 4210 being rounded so as to compact bone rather than sharpened as in element 3210 for the removal of bone . in all other aspects , the embodiment is identical to device 3000 . the ability to form a rectangular or square socket or tunnel is useful for surgeons who use a bone - patellar tendon - bone construct for acl repair . currently the graft has trapezoidal bone plugs at its ends when harvested and these bones must be made round to fit into standard round tunnels . eliminating this rounding step by using square or rectangular tunnels in the repair allows significant savings in procedure time . as noted previously , the present invention is directed to a surgical assembly having powered driver components that serve to control and automate the application of “ percussive force ” to the distal end component ( s ) of the assembly . by automating the percussive force , the present invention not only avoids the present need in the art for a “ third hand ” but further allows for precisely metered and controlled application of percussive force , thereby minimizing the risk of patient trauma and maximizing device efficiency . although described in detail with respect to arthroscopic applications , it will be readily apparent to the skilled artisan that the utility of the present invention extends to other minimally invasive endoscopic interventions , particularly with respect to orthopedic procedures such as compound fracture repair and bone grafting . 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 . the invention has been illustrated by reference to specific examples and preferred embodiments . however , it should be understood that the invention is intended not to be limited by the foregoing description , but to be defined by the appended claims and their equivalents .

in the context of bone surgery and in particular arthroscopic surgery , there is frequently a need for the application of “ percussive force ” to the distal end component of a surgical device , i . e ., repetitive percutient or striking force analogous to that of a hammer driving a nail . disclosed herein are mechanisms and methods for automating and / or controlling the application of such a percussive force so as to avoid the present need in the art for a “ third hand ”. the present invention addresses the significant and long felt need by providing a powered percussive driver device that may be controlled directly by the primary surgeon .

in rf electrical ablation procedures , as noted earlier , irrigating the area of the ablation site reduces tissue charring , thrombus formation , and adhesion between the ablation electrode and the tissue . methods and devices for irrigation to date have required that the electrode itself be perforated so that irrigation fluid can pass out of the catheter through the perforations into the treatment area . a perforated electrode of this type and methods for producing the perforations are described , for example , in u . s . patent application ser . no . 12 / 173 , 150 , filed jul . 15 , 2008 , which is assigned to the assignee of the present patent application and whose disclosure is incorporated herein by reference . creating the perforations is time - consuming and costly , however , and may weaken the electrode structure . embodiments of the present invention that are described hereinbelow provide a simple , inexpensive method for producing ring electrodes with irrigation . an invasive probe , such as a catheter , is produced with multiple perforations through its outer wall in the area in which a ring electrode is to be placed . the perforations communicate with a lumen inside the probe , which conveys irrigation fluid to the perforations . a conductive coil electrode , typically having the form and resilience of a helical spring , is fitted over and fixed to the probe at the desired electrode location . this coil electrode is connected to one or more wires running through the probe , which may be used , for example , to provide rf electrical energy to the coil for ablation therapy . although the placement of the coil electrode will typically cover some of the perforations in the wall of the probe , other perforations , in the gaps between the turns of the coil , remain uncovered . during operation , these open perforations provide irrigation throughout the treatment area . the design described above and shown in the figures that follow is easy and inexpensive to manufacture . it provides the benefits achieved by a perforated , irrigated electrode , while avoiding the difficulty and costs of actually creating the perforations in the electrode . this sort of electrode structure can be used in creating multiple ring electrodes along the length of a catheter or other structure , such as lasso . 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 portion 32 of the catheter contacts the endocardium in an area that is to be treated . the distal portion of the catheter is perforated to enable 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 portion 32 of catheter 28 at an ablation site , and ensuring that an electrode on the distal portion ( as shown below ) 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 the electrode . 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 portion . 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 electrode and the tissue without overloading the heart with irrigation fluid . a temperature sensor ( not shown in the figures ) in distal portion 32 may provide feedback to console 42 for use in controlling the rf energy dosage and / or irrigation volume . fig2 is a schematic side view of a portion of an insertion tube 50 of catheter 28 , in accordance with an embodiment of the present invention . the figure shows the distal portion of the insertion tube at a stage of manufacturing before assembly of an electrode onto distal portion 32 . tube 50 typically comprises a suitable biocompatible plastic , such as polyurethane , which is typically about 2 . 3 mm in diameter , with a wall thickness of about 0 . 15 mm . these dimensions , however , are given solely by way of illustration , and larger or smaller dimensions may be used depending on application requirements . the outer surface of the distal portion of tube 50 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 ). the perforations may be formed in tube 50 by any suitable method known in the art , such as pre - molding of the perforations at the time of fabrication of the tube , or punching or drilling ( by laser or mechanical means ) the perforations into the tube after extrusion . distal portion 32 contains an interior reservoir 56 , which is fed with irrigation fluid by a lumen 58 inside tube 50 . perforations 52 extend between reservoir 56 and the outer surface of tube 50 . in the embodiment shown in the figures , reservoir 56 has an inner surface 54 , which may be formed , for example , by a fitting a tube of smaller diameter inside tube 50 . alternatively , the reservoir may occupy the entire interior space at the distal tip of tube 50 , which may then be closed off by a plug ( not shown ) proximal to the distal tip , through which lumen 58 feeds . alternative reservoir configurations will be apparent to those skilled in the art and are considered to be within the scope of the present invention . typically , tube 50 has at least eight perforations , which are less than 0 . 5 mm in diameter , in order to distribute the irrigation over the area of distal portion 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 portion , with diameters no greater than 0 . 2 mm , and possibly as small as about 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 . fig3 is a schematic side view of a coil electrode 60 , in accordance with an embodiment of the present invention . this electrode is fitted over tube 50 , as shown in the figures that follow . electrode 60 typically comprises a resilient , biocompatible conductive material , such as gold , platinum or iridium wire , or an alloy of such metals . the coil electrode may comprise a wire , which is wound into a helical coil , as shown in the figure , resembling a coil spring . alternatively , the coil electrode may be made from a tube , which is cut out along a spiral pattern to create a helical shape , using laser cutting , for example . the coil electrode has an inner diameter equal to or slightly smaller than the outer diameter of tube 50 , so that the coil will fit snugly over the tube . reference is now made to fig4 and 5 , which schematically show distal portion 32 of catheter 28 , made by fitting coil electrode 60 over tube 50 , in accordance with an embodiment of the present invention . fig4 is a side view , while fig5 is a cross - sectional view taken along the line marked v - v in fig4 . electrode 60 is slid to the desired location on tube 50 , and is then glued or otherwise fastened in place . one or more wires 62 inside tube 50 penetrate through the outer surface of the tube ( possibly through one of perforations 52 ) and are soldered or otherwise bonded to electrode 60 . any suitable technique that is known in the art for electrical coupling to ring electrodes may similarly be used for this purpose . wires 62 run through to the proximal end of catheter 28 , where they connect via cable 38 to rf energy generator 44 ( fig1 ). as can be seen in fig4 and 5 , when electrode 60 is fastened over tube 50 , it covers some of the perforations ( marked 52 b in fig5 ). a sufficient number of the perforations ( marked 52 a ) remain open , however , to provide adequate irrigation of the area contacted by the electrode . this arrangement is advantageous in that it obviates the need for high positional precision in forming perforations 52 in tube 50 and in placing electrode 60 on the tube . during the ablation procedure , lumen 58 ( fig2 ) conveys fluid from irrigation pump 48 ( fig1 ) to reservoir 56 . the fluid exits tube 50 through perforations 52 a to the surrounding tissue while electrode 60 delivers the rf energy in order to ablate the tissue . fig6 is a schematic side view of a lasso catheter with coil electrodes 76 , in accordance with an embodiment of the present invention . the lasso catheter insertion tube is formed to define a shaft 72 with a distal portion 74 having a roughly circular lasso shape . this sort of lasso shape can be used , for example , in ablating myocardial tissue along a circular path around the ostia of the pulmonary veins in treatment of atrial fibrillation . in order to ablate multiple locations simultaneously along the desired path , electrodes 76 are distributed around the circumference of distal portion 74 . each electrode is slid into place , fastened , and connected electrically to wires inside catheter 70 in the manner described above . distal portion 74 may also have perforations ( not shown in this figure ) for the purpose of irrigation , as in catheter 28 . multiple coil electrodes may likewise be distributed along the length of catheters of other types , as well as on other sorts of tubular probes . 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 diagnostic and therapeutic procedures , particularly procedures 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 . as another example , coil electrodes of the type described above may also be used without irrigation on catheters and tubular probes of other types . 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 .

an invasive probe includes an insertion tube containing a lumen for providing an irrigation fluid and comprising a distal portion having a plurality of perforations therethrough providing fluid communication between the lumen and an outer surface of the insertion tube . at least one helical electrode is fitted over the distal portion of the insertion tube .

the detailed description set forth below in connection with the appended drawings is intended as a description of presently preferred embodiments of the invention and does not represent the only forms in which the present invention may be constructed and / or utilized . the description sets forth the functions and the sequence of steps for constructing and operating the invention in connection with the illustrated embodiments . generally , the present invention concerns a composite structural figure having at least one inflated balloon and at least one chenille stem attached to the balloon . chenille stems and inflated balloons are commingled in such a manner that allows for attachment and substitution with each other to form composite structures . it should be understood that the size and extent of inflation may vary depending on the use , function , and intended appearance of the composite structure . further , it should be understood that the term “ inflated ” applies to all extents of inflation . the composite structure may be shaped and designed to form a wide variety of structures resembling animals , fanciful creatures , hats , flowers , fruit , trees , planes , bicycles , cars , airplanes , helicopters , or other vehicles , among others . the composite structure achieves this by utilizing balloons of various shapes , sizes , and colors for use as a body for the structure , and utilizes chenille stems of various shapes , sizes and colors that are attached to the balloons as enhancements to enhance the entertainment value of the structures , as well as the variety , durability , and to create structural features that may not be as artistically viable using only balloons . these enhancements may include features such as arms , legs , hands , feet , wings , bodies , faces , skeletons , wheels , or flower stems , among others . this composite structure so constructed may be used as a toy or entertainment object for play , educational use , as an arts and craft activity , decoration , or distributed at parties , graduations , anniversaries , club meetings , carnivals , fairs , weddings , baby and wedding showers , and trade shows , among other venues . the balloon may vary in color , shape , size , and material depending on the structure to be made . the color , shape , size and material are critical when determining the impression and construction desired . further , the amount of inflation of the balloon may vary , depending on the structure to be made . the term chenille stem relates to a wire body that is somewhat flexible and formed by twisted wires on which fibers such as chenille are interwoven and held together by the twisted plies of the wire . the fibers may vary in size depending on the desired effective diameter of the chenille stem . the chenille stem may vary in color , effective diameter , length , and texture depending on the structure to be made . the color , effective diameter , length , and texture are critical when determining the impression and construction desired . fig1 a , 1 b , 1 c and 1 d show multiple views of one embodiment of the composite structure . the composite structure has a balloon body , best shown in fig1 a - 1b as a blossom shaped body 13 . balloons such as the geo blossom balloon manufactured by pioneer balloon company are commercially available to achieve this shape of balloon body . the blossom shaped body 13 is constructed as a bag made of thin latex , or other light material that is generally gas impermeable including but not limited to mylar , or metallic coated film . the blossom shaped body 13 defines an aperture 12 through the central axis of the blossom shaped body 13 . the blossom shaped body 13 may be inflated during construction of the composite structure by the supply of an inflation fluid such as air , lighter - than - air gas such as helium or hydrogen , water or other liquid , or a combination of gasses , a combination of liquids , or liquids and gasses . this inflation fluid is introduced through a neck portion 11 of the blossom shaped body 13 . the introduction of the inflation fluid may be performed manually by the user using air forced from the lungs , or by the aid of a pump , pressurized canister , water faucet or other similar device capable of moving a fluid with substantial pressure so as to inflate the balloon body . the neck portion 11 is constructed and arranged as a section of the balloon body with a substantially narrowed diameter and defining an aperture providing fluid communication between an inside of the balloon and the atmosphere . the neck portion thus creates a small channel for the inlet and outlet of inflation fluid to the balloon body . the neck portion 11 is constructed and arranged such that it creates a channel extending from the balloon body that may be sealed , preventing escape of the inflation fluid by tying - off creating a knot , or balloon knot , fusing the neck portion 11 closed , or other sealing method capable of preventing a rapid escape of inflation fluid . a facial portion 16 of the balloon body is located on an outer surface of the blossom shaped body 13 . facial features may be imprinted on this facial portion 16 . facial features imprinted on the facial portion 16 may include features such as hair , eyes , pupils , nose , mouth , eyebrows , and ears , among others . the facial portion 16 may have facial features imprinted on it manually by marker , pen , paint or other writing implement , or the features may be imprinted by being printed , screened , or sprayed onto the facial portion 16 . the facial portion 16 may be imprinted either before inflation , or after . a chenille stem 14 is inserted through the aperture 12 formed by the blossom shaped body 13 . preferably , the chenille stem 14 may be bent near the center of its length to create a central bend . this central bend may allow the chenille stem to be in the shape of an arc . preferably the chenille stem 14 is sized and bent such that it fits snugly within the aperture 12 and can maintain its position against minor forces such as gravity because of the frictional forces between the chenille stem 14 and the walls of the blossom shaped body 13 . this bending and positioning within aperture 12 allows the chenille stem 14 to rotate about an axis running through the aperture 12 of the blossom shaped body 13 . proper bending allows the chenille stem 14 to be rotatable and also to maintain its position once rotated . this central bending may be achieved by manual manipulation of the chenille stem 14 by a user , automated bending by machine , or the chenille stem 14 may be pre - formed during manufacture . in other embodiments , the chenille stem may be held in position using adhesives such as glue or tape . the chenille stem 14 may be further bent at its ends to form features such as hands 15 . this bending involves folding the ends of the chenille stem 14 inward in the same direction as the central bend . the hands 15 may be formed by manual manipulation by the user , automated bending by machine , or the chenille stem may be pre - formed during manufacture . in a further embodiment , the hands may be configured to hold an item ( not shown ), or to attach the composite structure to another item ( not shown ). the item held could be a wide variety of things , including other composite structures , and is limited only by the size of the hands 15 and the limitations of the chenille stem 14 used . a string 17 may be attached to the composite structure . the string may be attached to any part of the composite structure , such as the blossom shaped body 13 itself , through the aperture 12 of the blossom shaped body 13 , to the neck portion 11 , to the chenille stem 14 , or to the hands 15 . referring now to fig2 a and 2b , another embodiment of the present invention is shown . the composite structure may have a balloon body shown in fig2 a - 2b as a spherical body 21 . it should be understood that the spherical body 21 may be substantially spherical , including shapes such as approximately spherical , generally round , or teardrop shaped without straying from the scope of the present invention . the spherical body 21 is constructed as a bag made of thin latex , or other light material including but not limited to mylar , metallic coated film , or other thin , generally gas impermeable material . the spherical body 21 may be inflated during construction of the composite structure by the supply of an inflation fluid such as air , lighter - than - air gas such as helium or hydrogen , water or other liquid , or a combination of gasses , a combination liquids , or liquids and gasses . this inflation fluid is introduced through a neck portion 11 of the spherical body 21 . the introduction of the inflation fluid may be performed manually by the user using air forced from the lungs , or by the aid of a pump , pressurized canister , water faucet , or other similar device capable of moving a fluid with substantial pressure so as to inflate the balloon body . the neck portion 11 is constructed and arranged as a section of the balloon body with a substantially narrowed diameter that defines an aperture providing fluid communication between an inside of the balloon body and the atmosphere . the neck portion thus creates a small channel for the inlet and outlet of inflation fluid to the balloon body . the neck portion 11 is constructed and arranged that creates a channel extending from the balloon body such that it may be sealed , preventing escape of the inflation fluid by tying - off creating a knot , or balloon knot , fusing the neck portion 11 closed , or other sealing method capable of preventing a rapid escape of inflation fluid . a facial portion 16 of the balloon body is located on an outer surface of the spherical body 21 . facial features may be imprinted on this facial portion 16 . facial features imprinted on the facial portion 16 may include features such as hair , eyes , pupils , nose , mouth , eyebrows , and ears , among others . the facial portion 16 may have facial features imprinted on it manually by marker , pen , paint or other writing implement , or the features may be imprinted by being printed , screened , or sprayed onto the facial portion 16 . the facial portion 16 may be imprinted either before inflation , or after . a chenille stem 14 may be wrapped around a circumference of the spherical body 21 . in the embodiment shown in fig2 a - 2b , the chenille stem 14 is shown wrapped around the greatest circumference of the spherical body 21 . the length of the chenille stem 14 should be greater than the greatest circumference of the spherical body 21 to allow the chenille stem 14 to be secured to the spherical body 21 . the chenille stem 14 is secured to the spherical body 21 by twisting two end portions of the chenille stem 14 about each other , forming a knot 23 . the chenille stem 14 is thus held in place by the knot 23 and the friction caused by the outward pressure of the spherical body 21 against the chenille stem 14 . the knot 23 may be formed by manual manipulation by the user , automated twisting by machine , the chenille stem 14 may be twisted to form a knot 23 during manufacture , or the chenille stem 14 may have a pre - formed region act as a knot 23 , formed during manufacture . in alternate embodiments , the chenille stem 14 may be held in position using adhesives such as tape or glue . extending portions of the chenille stem 14 remaining after the formation of the knot 23 may be shaped to form features adding to the realism and effect of the composite structure . features may include ears , horns , hair , a crown , a hat , or the like . fig2 a - 2b show ears 24 , by way of example . these ears 24 may be formed by bending extending end portions of the chenille stem 14 by into substantially triangular or semi - circular shapes . each end of the chenille stem 14 may then be attached to the length of the chenille stem at a connection point 22 . this attachment may be done by wrapping or hooking the end of the chenille stem 14 to a length of the chenille stem 14 that is positioned along the spherical body 21 . thus providing a connection point 22 . attaching each end of the chenille stem 14 to the connection point 22 ensures that the ears 24 or other features remain in the proper shape and position . the ears 24 may be formed and secured by manual manipulation by the user , automated bending by machine , or the ears 24 may be pre - formed during manufacture of the chenille stem 14 . a string 17 may be attached to the composite structure . the string may be attached to any part of the composite structure , such as the spherical body 21 itself , to the neck portion 11 , to the chenille stem 14 , to the knot 23 , connection point 22 or to the ears 24 . referring now to fig3 a and 3b , another embodiment of the present invention is shown . the composite structure may have a balloon body , shown in fig3 a - 3b as a cylindrical body 30 . the cylindrical body of the embodiment shown comprises a head portion 32 , a body portion 33 and a tail portion 34 . the head portion 32 is formed by twisting part of the body portion 33 repeatedly , forming a generally circular head portion 32 separated from body portion 33 by a twisted portion 36 , the twisted portion 36 being a narrow section of twisted balloon material . the tail portion 34 is formed during manufacture of the balloon body by substantially reducing the diameter of the cylindrical body 30 . cylindrical balloons similar to the balloon body shown in fig3 a - 3b are manufactured by pioneer balloon company and by tilly balloons , and are often marketed as “ bee bodies .” it should be understood that the cylindrical body 30 may be of a substantially cylindrical shape such as approximately cylindrical , may have varying diameters along its length , or may be teardrop shaped , without straying from the scope of the present invention . the cylindrical body 30 consists of a bag made of thin latex , or other light material including but not limited to mylar , metallic coated film , or other thin , generally gas impermeable material . the cylindrical body 30 may be inflated during construction of the composite structure by the supply of an inflation fluid such as air , lighter - than - air gas such as helium or hydrogen , water or other liquid , or a combination of gasses , a combination of liquids , or liquids and gasses . this inflation fluid is introduced through a neck portion 11 of the cylindrical body 30 . the introduction of the inflation fluid may be performed manually by the user using air forced from the lungs , or by the aid of a pump , pressurized canister , water faucet , or other similar device capable of moving a fluid with substantial pressure so as to inflate the balloon body . the neck portion 11 is constructed and arranged as a section of the balloon body with a substantially narrowed diameter and defines an aperture providing fluid communication between an inside of the balloon and the atmosphere . the neck portion thus creates a small channel for the inlet and outlet of inflation fluid to the balloon body . the neck portion 11 is constructed and arranged such that it creates a channel extending from the balloon body that may be sealed , preventing escape of the inflation fluid by tying - off creating a knot or balloon knot , fusing the neck portion 11 closed , or other sealing method capable of preventing a rapid escape of inflation fluid . a facial portion 16 of the balloon body is located on an outer surface of the cylindrical body 30 . facial features may be imprinted on this facial portion 16 . facial features included on the facial portion 16 may include features such as hair , eyes , pupils , nose , mouth , eyebrows , and ears , among others . the facial portion 16 may have facial features imprinted on it manually by marker , pen , paint , or other writing implement , or the features may be imprinted by being printed , screened , or sprayed onto the facial portion of the balloon body . the facial portion 16 may be imprinted either before inflation , or after . a chenille stem 14 may be wrapped around the cylindrical body 30 . in the embodiment shown in fig3 a - 3b , the chenille stem 14 is wrapped around a region between the body portion 33 and the head portion 32 of the cylindrical body 30 , where the diameter of the cylindrical body 30 is reduced because of the twisting employed to form the head portion 32 . the chenille stem 14 is secured to the cylindrical body 30 by twisting two portions of the chenille stem 14 about each other , forming a knot 31 . fig3 b shows this knot 31 as a bow knot , however any twisting of the chenille stem 14 that maintains the chenille stem 14 position will suffice . the chenille stem 14 is thus held in place by the knot 31 and the friction caused by the outward pressure of the cylindrical body 30 against the chenille stem 14 . the knot 31 may be formed by manual manipulation by the user , automated twisting by machine , the chenille stem 14 may be twisted to form a knot 31 during manufacture , or the stem may have a pre - formed region to serve as a knot 31 . in other embodiments , the chenille stem 14 may be held in position using adhesives such as glue or tape . while forming the knot 31 , the chenille stem 14 may be formed to resemble enhancements , including features such as wings , legs , or arms , among others , as the user may desire , to increase the realism and entertainment value of the composite structure . these enhancements may also be formed before or after the knot 31 is formed . the embodiment shown in fig3 a and 3b comprises wings 35 formed by bending the chenille stem into a loop while creating the knot 31 . the wings 35 may be created , for example , while creating the knot 31 by using long portions of the chenille stem 14 to create the knot 31 , allowing for a substantial length of chenille stem 14 to remain free , i . e . not knotted . the substantial length of chenille stem 14 may then be bent as desired to form the wings 35 , or other features , as the user may desire . the wings 35 may be formed by manual manipulation by the user , automated bending by machine , or the chenille stem 14 may be bent to form the wings 35 during manufacture . a string 17 may be attached to the composite structure . the string may be attached to any part of the composite structure , such as portions of the cylindrical body 30 , namely the head portion 32 , the body portion 33 or the tail portion 34 , to the neck portion 11 , to the chenille stem 14 , to the knot 31 , or to the wings 35 . one embodiment of the present invention may involve the chenille stem being shaped as a skeleton , and the balloon bodies being shaped as an appendage ( not shown ). these appendages may include features such as eyes , nose , mouth , ears , head , flower , limbs , and the like . in this embodiment the balloon bodies may have facial portions that may be imprinted with facial features . one embodiment of the present invention involves a kit for constructing the composite structure providing the elements necessary to assemble the composite structure . the kit form of the present invention provides elements of the composite structure , and allows a user to assemble the composite structure themselves . the kit may be particularly useful for activities such as arts and craft gatherings . the kit may comprise at least one balloon body , and at least one chenille stem . in one embodiment , the kit may further comprise a marker , pen , paint or other marking implement for drawing features onto the face portion of the balloon body . in another embodiment , the kit may include a number of balloon bodies and chenille stems for complex composite structures . in another embodiment , the chenille stems may be pre - formed . in yet another embodiment the kit may include pre - made composite structures , in either deflated or inflated form . further , the kit may include an instruction manual providing instructions and information about the use of the kit . in still another embodiment , the kit may include a balloon pump for inflation of the balloon body or bodies . in yet another embodiment , the kit may include scissors for cutting and sizing the chenille stems . while several variations of the present invention have been illustrated by way of example in preferred or particular embodiments , it is apparent that further embodiments could be developed within the spirit and scope of the present invention , or the inventive concept thereof . however , it is to be expressly understood that such modifications and adaptations are within the spirit and scope of the present invention , and are inclusive , but not limited to the following appended claims as set forth .

a composite structure based from an inflated balloon and a chenille stem . the composite structure has the chenille stem attached to the inflated balloon to create enhancements to replicate real - world or fantasy items . a method for assembling the composite structure . a kit for assembling the composite structure .

the present invention provides kappa opioid antagonists that bind to kappa opioid receptors with high affinity and / or specificity . compounds of the present invention are those represented by the formula ( i ): r is c 1 - 8 alkyl , c 1 - 8 haloalkyl , c 3 - 8 alkenyl , c 3 - 8 alkynyl or ch 2 - aryl substituted by one or more groups y 1 ; y 1 is h , oh , br , cl , f , cn , cf 3 , no 2 , n 3 , or 8 , co 2 r 9 , c 1 - 6 alkyl , nr 10 r 11 , nhcor 12 , nhco 2 r 12 , conr 13 r 14 , or ch 2 ( ch 2 ) n y 2 ; y 2 is h , cf 3 , co 2 r 9 , c 1 - 6 alkyl , nr 10 r 11 , nhcor 12 , nhco 2 r 12 , conr 13 r 14 , ch 2 oh , ch 2 or 8 , or coch 2 r 9 ; y 3 is h , oh , br , cl , f , cn , cf 3 , no 2 , n 3 , or 8 , co 2 r 9 , c 1 - 6 alkyl , nr 10 r 11 , nhcor 12 , nhco 2 r 12 , conr 13 r 14 , or ch 2 ( ch 2 ) n y 2 ; r 2 is h , c 1 - 8 alkyl , c 3 - 8 alkenyl , c 3 - 8 alkynyl or ch 2 - aryl substituted by one or more groups y 1 ; r 3 is h , c 1 - 8 alkyl , c 3 - 8 alkenyl , c 3 - 8 alkynyl or ch 2 - aryl substituted by one or more groups y 1 , wherein r 2 and r 3 may be bonded together to form a c 2 - 8 alkyl group ; r 4 is hydrogen , c 1 - 8 alkyl , co 2 c 1 - 8 alkylaryl substituted by one or more groups y 1 , ch 2 - aryl substituted by one or more groups y 1 or co 2 c 1 - 8 alkyl ; z is n , o or s , wherein when z is o or s , there is no r 5 ; r 5 is h , c 1 - 8 alkyl , c 3 - 8 alkenyl , c 3 - 8 alkynyl , ch 2 co 2 c 1 - 8 alkyl , co 2 c 1 - 8 alkyl or ch 2 - aryl substituted by one or more groups y 1 ; r 6 is a group selected from the group consisting of structures ( a )-( p ): q is nr 7 , ch 2 , o , s , so , or so 2 ; x 1 is hydrogen , c 1 - 8 alkyl , c 3 - 8 alkenyl , or c 3 - 8 alkynyl ; x 2 is hydrogen , c 1 - 8 alkyl , c 3 - 8 alkenyl , or c 3 - 8 alkynyl ; or x 1 and x 2 together form ═ o , ═ s , or ═ nh ; each r 7 is , independently , h , c 1 - 8 alkyl , ch 2 - aryl substituted by one or more substituents y 1 , nr 10 r 11 , nhcor 12 , nhco 2 r 13 , conr 14 r 15 , ch 2 ( ch 2 ) n y 2 , or c (═ nh ) nr 16 r 17 ; each of r 8 , r 9 , r 10 , r 11 , r 12 , r 13 , r 14 , r 15 , r 16 and r 17 is , independently , h , c 1 - 8 alkyl , ch 2 - aryl substituted by one or more substituents h , oh , br , cl , f , cn , cf 3 , no 2 , n 3 , c 1 - 6 alkyl , or ch 2 ( ch 2 ) n y 2 ′; y 2 ′ is h , cf 3 , or c 1 - 6 alkyl ; r 18 is hydrogen , c 1 - 8 alkyl , c 2 - 8 alkenyl , c 3 - 8 alkynyl , or ch 2 - aryl substituted by one or more groups y 1 ; r is c 1 - 8 alkyl or c 1 - 8 haloalkyl , phenyl substituted by one or more groups y 1 or ch 2 - phenyl substituted by one or more groups y 1 ; r 1 is c 1 - 3 alkyl ; y 3 is h or c 1 - 6 alkyl ; r 2 is h or c 1 - 8 alkyl , r 3 is h or c 1 - 8 alkyl , or r 2 and r 3 are bonded together to form a c 2 - 8 alkyl group r 4 is h or c 1 - 8 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); and r 18 is h or c 1 - 8 alkyl , r is c 1 - 4 alkyl or c 1 - 4 haloalkyl ; r 1 is c 1 - 3 alkyl ; y 3 is h or c 1 - 4 alkyl ; r 2 is h or c 1 - 4 alkyl , r 3 is h or c 1 - 4 alkyl ; or r 2 and r 3 are bonded together to form a c 2 - 8 alkyl group r 4 is h or c 1 - 6 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); and r 18 is h or c 1 - 4 alkyl , r is c 1 - 2 alkyl or c 1 - 2 haloalkyl ; r 1 is c 1 - 2 alkyl ; y 3 is h or c 1 - 2 alkyl ; r 2 is h or c 1 - 2 alkyl , r 3 is h or c 1 - 2 alkyl , or r 2 and r 3 are bonded together to form a c 2 - 8 alkyl group ; r 4 is hydrogen or c 1 - 6 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); and r 18 is h or c 1 - 2 alkyl , r is methyl or trifluoromethyl ; r 1 is methyl ; y 3 is h or methyl ; r 2 is h or methyl , r 3 is h or methyl ; r 4 is h or c 1 - 6 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); and r 18 is h or methyl , r is methyl or trifluoromethyl ; r 1 is methyl ; y 3 is h ; r 2 is methyl , r 3 is h ; r 4 is h or c 1 - 4 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); r 18 is h or c 1 - 2 alkyl , q is nr 7 ; r 7 is h or c 1 - 8 alkyl ; y 1 is h , oh or or 8 ; r 8 is c 1 - 8 alkyl ; and n is 0 , 1 or 2 , r is methyl or trifluoromethyl ; r 1 is methyl ; y 3 is h ; r 2 is methyl , r 3 is h ; r 4 is hydrogen or c 1 - 4 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); r 18 is h or methyl , q is nr 7 ; r 7 is h or c 1 - 4 alkyl ; y 1 is h , oh or or 8 ; r 8 is c 1 - 4 alkyl ; and n is 0 or 1 , r is methyl or trifluoromethyl ; r 1 is methyl ; y 3 is h ; r 2 is methyl , r 3 is h ; r 4 is h or c 1 - 4 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); r 18 is h or methyl , q is nr 7 ; r 7 is h or c 1 - 2 alkyl ; y 1 is h , oh or or 8 ; r 8 is c 1 - 2 alkyl ; and n is 0 or 1 , r is methyl ; r 1 is methyl ; y 3 is h ; r 2 is methyl , r 3 is h ; r 4 is h or c 1 - 4 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); r 18 is h or methyl , q is nr s ; r 7 is h or methyl ; y 1 is oh or or 8 ; r 8 is methyl ; and n is 0 or 1 , r is trifluoromethyl ; r 1 is methyl ; y 3 is h ; r 2 is methyl , r 3 is h ; r 4 is h or c 1 - 4 alkyl ; z is n ; x 1 and x 2 together form ═ o ; r 6 is represented by the formula ( a ), ( b ) or ( c ); r 18 is h or methyl , q is nrs ; r 7 is h or methyl ; y 1 is oh or or 8 ; r 8 is methyl ; and n is 0 or 1 , in another preferred embodiment of the present invention , the kappa opioid receptor antagonist is represented by formula 8d , 8f , 8h , 8k , 8l , 8n or 8p shown in table 1 . the present invention includes any and all combination of the different structural groups defined above , including those combinations not specifically set forth above . in particular , the present invention includes the combination of each r group with any is c 1 - 8 alkyl , c 1 - 8 haloalkyl , c 3 - 8 alkenyl , c 3 - 8 alkynyl , aryl substituted by one or more groups y 1 or ch 2 - aryl substituted by one or more groups y 1 as used throughout this disclosure , the terms “ alkyl group ” or “ alkyl radical ” encompass all structural isomers thereof , such as linear , branched and cyclic alkyl groups and moieties . unless stated otherwise , all alkyl groups described herein may have 1 to 8 carbon atoms , inclusive of all specific values and subranges therebetween , such as 2 , 3 , 4 , 5 , 6 , or 7 carbon atoms . as used throughout this disclosure , the terms “ haloalkyl group ” or “ haloalkyl radical ” encompass all structural isomers thereof , such as linear , branched and cyclic groups and moieties . unless stated otherwise , all haloalkyl groups described herein may have 1 to 8 carbon atoms , inclusive of all specific values and subranges therebetween , such as 2 , 3 , 4 , 5 , 6 , or 7 carbon atoms . a c 1 - 2 haloalkyl group is particularly preferred . at least one hydrogen atom is replaced by a halogen atom , i . e ., fluorine , chlorine , bromine or iodine . in one embodiment , all of the hydrogen atoms are replaced with halogen atoms . fluorine is preferred . perfluoroalkyl groups are particularly preferred . examples of haloalkyl groups include trifluoromethyl (— cf 3 ) and perfluoroethyl (— cf 2 cf 3 ). the alkenyl group or alkynyl group may have one or more double or triple bonds , respectively . as will be readily appreciated , when an alkenyl or alkynyl group is bonded to a heteroatom a double or triple bond is not formed with the carbon atom bonded directly to the heteroatom . unless stated otherwise , all alkenyl and alkynyl groups described herein may have 3 to 8 carbon atoms , inclusive of all specific values and subranges therebetween , such as 4 , 5 , 6 , or 7 carbon atoms . preferred examples include — ch 2 ch ═ ch 2 and — ch 2 cch . the aryl group is a hydrocarbon aryl group , such as a phenyl , naphthyl , phenanthryl , anthracenyl group , which may have one or more c 1 - 4 alkyl group substituents . the compounds of the present invention are opiates which are preferably antagonists that are selective for the kappa receptor . the κ / μ selectivity may be at least 2 : 1 , but is preferably higher , e . g ., at least 5 : 1 , 10 : 1 , 25 : 1 , 50 : 1 , 100 : 1 , 200 : 1 or even 500 : 1 . the κ / δ selectivity may be at least 2 : 1 , but is preferably higher , e . g ., at least 5 : 1 , 10 : 1 , 25 : 1 , 50 : 1 , 100 : 1 , 200 : 1 , 250 : 1 , 500 : 1 , 1000 : 1 , 10 , 000 : 1 , 15 , 000 : 1 , 20 , 000 : 1 , 25 , 000 : 1 or even 30 , 000 : 1 . these ranges include all specific ranges and subranges therebetween as well as all combinations of κ / μ and κ / δ selectivity . the compounds of the present invention may be in the form of a pharmaceutically acceptable salt via protonation of the amines with a suitable acid . the acid may be an inorganic acid or an organic acid . suitable acids include , for example , hydrochloric , hydroiodic , hydrobromic , sulfuric , phosphoric , citric , acetic , fumaric , tartaric , and formic acids . the receptor selectivities discussed above are determined based on the binding affinities at the receptors indicated or their selectivity in opioid functional assays . the compounds of the present invention may be used to bind opioid receptors . such binding may be accomplished by contacting the receptor with an effective amount of the inventive compound . of course , such contacting is preferably conducted in an aqueous medium , preferably at physiologically relevant ionic strength , ph , etc . the inventive compounds may also be used to treat patients having disease states which are ameliorated by binding opioid receptors or in any treatment wherein temporary suppression of the kappa opioid receptor system is desired . such diseases states include opiate addiction ( such as heroin addiction ), cocaine , nicotine , or ethanol addiction . the compounds of the present invention may also be used as cytostatic agents , as antimigraine agents , as immunomodulators , as immunosuppressives , as antiarthritic agents , as antiallergic agents , as virucides , to treat diarrhea , as antipsychotics , as antischizophrenics , as antidepressants , as uropathic agents , as antitussives , as antiaddictive agents , as anti - smoking agents , to treat alcoholism , as hypotensive agents , to treat and / or prevent paralysis resulting from traumatic ischemia , general neuroprotection against ischemic trauma , as adjuncts to nerve growth factor treatment of hyperalgesia and nerve grafts , as anti - diuretics , as stimulants , as anti - convulsants , or to treat obesity . additionally , the present compounds can be used in the treatment of parkinson &# 39 ; s disease as an adjunct to l - dopa for treatment of dyskinesia associated with the l - dopa treatment . the compounds of the present invention are particularly useful for treating addiction , such as addiction to cocaine , alcohol , methamphetamine , nicotine , heroine , and other drugs of abuse . with respect to nicotine , the compounds of the present invention are also useful in treating nicotine withdrawal effects . the compounds may be administered in an effective amount by any of the conventional techniques well - established in the medical field . for example , the compounds may be administered orally , intraveneously , or intramuscularly . when so administered , the inventive compounds may be combined with any of the well - known pharmaceutical carriers and additives that are customarily used in such pharmaceutical compositions . for a discussion of dosing forms , carriers , additives , pharmacodynamics , etc ., see kirk - othmer encyclopedia of chemical technology , fourth edition , vol . 18 , 1996 , pp . 480 - 590 , incorporated herein by reference . the patient is preferably a mammal , with human patients especially preferred . effective amounts are readily determined by those of ordinary skill in the art . studies by the present inventors show no toxicity and no lethality for the present compounds at amounts up to 300 mg / kg in mice . the compounds of the present invention can be administered as a single dosage per day , or as multiple dosages per day . when administered as multiple dosages , the dosages can be equal doses or doses of varying amount , based upon the time between the doses ( i . e . when there will be a longer time between doses , such as overnight while sleeping , the dose administered will be higher to allow the compound to be present in the bloodstream of the patient for the longer period of time at effective levels ). preferably , the compound and compositions containing the compound are administered as a single dose or from 2 - 4 equal doses per day . suitable compositions containing the present compounds further comprise a physiologically acceptable carrier , such as water or conventional pharmaceutical solid carriers , and if desired , one or more buffers and other excipients . having generally described this invention , a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified . the structure of 3 was modified to introduce methyl groups at five different sites of the molecule ( see table 1 for exemplary structures ): at the phenol moieties ( r a , r ), on the linker of the phenylpiperidine to the tetrahydroisoquinoline carboxamide fragments ( r c ), at the position alpha to the carboxamide moiety ( r 18 ), and at the isoquinoline nitrogen ( r 7 ). analogues 8a - c were synthesized as previously reported . 14 , 23 the synthesis of the new analogues 8d - p is shown in scheme 1 ( fig2 ). coupling of the appropriate 1 , 2 , 3 , 4 - tetrahydroisoquinoline carboxylic acids 6a - e with 7a - d using benzotriazole - 1 - yloxy - tris ( dimethylamino ) phosphonium hexafluorophosphate ( bop ) in tetrahydrofuran ( thf ) or o -( benzotriazol - 1 - yl )- n , n , n ′, n ′- tetramethyluronium hexafluorophosphate ( hbtu ) in acetonitrile ( followed by removal of the boc - protecting group with trifluoroacetic acid in methylene chloride when 6a and 6c were used ) yielded 8d - p . the tetrahydroisoquinoline carboxylic acids 6a - d needed for the synthesis of 8e , 8g , 8h , 8i , 8l , 8m , 8n , and 8o were prepared following the transformations outlined in scheme 2 ( fig3 ). d - alanine ( 9 ) was converted to the sodium salt using sodium hydroxide in ethanol , followed by conversion to the chiral oxazolidinone 10 by condensation with benzaldehyde under azeotropic distillation conditions and benzoylation using benzoyl chloride . 25 alkylation of 10 with 4 - methoxybenzyl bromide using lithium hexamethyldisilazide as the base at − 78 ° c . proceeded with high diastereomeric selectivity to give the p - methoxybenzylated intermediate 11 . 26 acid hydrolysis of the chiral intermediate 11 gave the amino acid 12 . formation of the tetrahydroisoquinoline ring system was achieved via the pictet - spengler reaction . this was carried out by bromination of 12 to give 13 to protect the ortho positions of the methoxy group followed by treatment with hydrobromic acid and formaldehyde at 80 ° c . to give 14 . compound 14 was converted to 6a by treatment with concentrated hydrobromic acid to demethylate the 7 - methoxy to a phenol , followed by catalytic debromination using palladium on carbon under hydrogen , and finally treatment with di - tert - butyl dicarbonate in dimethylformamide containing triethylamine to give 6a . the n - methyl analogue 6b was obtained by treating 6a with trifluoroacetic acid to give the free amine followed by reductive methylation using raney nickel catalyst , hydrogen , and formaldehyde in methanol . compounds 6c and 6d were obtained from 14 by protection as the tert - butoxycarbonyl ester using di - tert - butyl dicarbonate and then debromination using palladium on carbon as catalyst under hydrogen to give 6c . removal of the boc - protecting group from 6c using hydrochloric acid followed by reductive methylation using the same conditions as for 6b gave the n - methyl analogue 6d . compound 7b was synthesized by coupling n - boc - l - valine with ( 3r , 4r )- 4 -( 3 - methoxyphenyl )- 3 , 4 - dimethylpiperidine ( 16a ) 27 using bop in tetrahydrofuran followed by reduction with diborane in tetrahydrofuran ( scheme 3 ; fig4 ). coupling of 16b and 16a with n - boc - l - isoleucine using hbtu in acetonitrile followed by reduction with diborane gave 7c and 7d , respectively . compound 7a was synthesized as previously reported . 28 compounds 1 , 3 , and 8a - p were first evaluated at 10 μm for intrinsic activity in the [ 35 s ] gtpγs binding assay at all three opioid receptors . as none of the compounds displayed measurable intrinsic activity at this concentration , they and the reference compound 1 were evaluated for functional antagonism and selectivity at the opioid receptors . these data were obtained by monitoring the ability of test compounds to inhibit stimulated [ 35 s ] gtpγs binding produced by the selective agonists damgo ( μ ), dpdpe ( δ ), or u69 , 593 ( κ ) using cloned human opioid receptors expressed in cho cells . 29 agonist dose response curves were run in the presence or absence of a single concentration of test compound . test compound assay concentrations ranged from 1 - 5000 nm , depending on their activity . the k e values were calculated using the formula : k e =[ l ]/ dr − 1 , where [ l ] is the concentration of test compound and dr is the ratio of agonist ec 50 value in the presence or absence of test compound , respectively . at least two different concentrations of test compound were used to calculate the 1c , and the concentrations were chosen such that the agonist ec 50 exhibited at least a four - fold shift to the right and there was a clear upper asymptote to the agonist + compound concentration response curve . the k e values along with those for the reference compound 1 are shown in table 1 . the calculated log p , tpsa , and log bb values for compounds 1 , 3 , and 8a - p are given in table 2 . the log bb values were calculated using equation 6 ( the clark equation ) given in reference 24 . topological polar surface areas ( tpsa ) and log p values were calculated using chemaxon &# 39 ; s instant jchem ® version 5 . 03 software . even though 3 ( k e = 0 . 02 nm ) was more potent as a κ - opioid receptor antagonist than any of the methylated analogues studied , many of the analogs were potent and selective κ antagonists . all of the monomethylated analogues 8a - 8e , the dimethylated analogues 8f - 8j , and the trimethylated analogues 8m retained subnanomolar potency at the κ - opioid receptor . all of the monomethylated compounds 8a - 8e , the dimethylated compounds 8h and 8k , and the trimethylated compound 8n retained greater than 100 - fold κ selectivity relative to the μ and δ receptors . the two most potent analogues were 8a ( r 3 ═ ch 3 ) and 8e ( r 4 ═ ch 3 ), both with k e values of 0 . 03 nm at the ic - opioid receptor . both compounds had 100 - fold or greater selectivity for the κ receptor relative to the μ receptor . the κ selectivity for 8a and 8e relative to the δ receptor was 800 and 28 , 500 , respectively . the n - methyl compound 8c ( r 5 ═ ch 3 ) with a k e value of 0 . 16 nm at the κ - opioid receptor and 1313 - and 3070 - fold selectivity for the κ receptor relative to the μ and δ receptors was the most κ selective analogue of this new series . compound 8b ( r 2 ═ ch 3 ) with a k e value of 0 . 06 nm was 3 times less potent than 3 , and with μ / κ and μ / δ ratios of 857 and 1970 , it was also highly κ selective . compound 8d , with a methyl substituted at the 3 - hydroxyl in the phenylpiperidine fragment , had only a two - fold decrease in potency for the ic receptor ( k e = 0 . 037 nm ) relative to 3 . methylation of the alkyl side chain on the linker between the phenylpiperidine and tetrahydroisoquinoline carboxamide fragments ( r 3 ) produced compounds 8a , 8f , 8i , 8j , and 8m that had increased potency at μ receptors compared to 3 . this effect was most notable in the monomethyl substituted compound 8a , which had an eight - fold increase in potency at μ receptors compared to 3 . these observations mirror those seen in previous studies where large substituents at this position increased μ receptor potency . 28 n - methylation at the tetrahydroisoquinoline nitrogen to give the n - methyl 3 analogue 8c resulted in a reduction in potency at all receptor subtypes . at κ receptors , this modification consistently gave decreases in potency for all analogues 8j , 8k , 8o , and 8p . nevertheless , analogues 8c and 8j with k e values of 0 . 16 and 0 . 11 nm , respectively , were still highly potent κ antagonists . in general it was observed that introduction of multiple methyl groups into the structure of 3 was detrimental for potency and selectivity at ic receptors . compounds 81 and 8j with k e values of 0 . 11 nm each at the κ receptor were the two most potent analogues with multiple methyl groups . the effect was more noticeable for compounds with three methyl substitutions . the most potent analogue containing three methyl groups was 8n , which had a 1c value of 0 . 52 nm at the κ receptor . the calculated log p , tpsa , and log bb values for 1 , 3 , and 8a - p are given in table 2 . 24 in contrast to standard compound 1 ( calculated log bb =− 1 . 42 ), the calculated log bb for 3 and 8a - p (− 0 . 07 to − 0 . 55 ) are above the threshold proposed by clark to indicate low blood brain barrier penetration . the calculated log bb values 24 show that all 16 methylated analogues would be expected to show enhanced brain penetration relative to 3 . in the case of 8b for instance , monomethylation shifts the calculated log bb value positively by 0 . 22 log units ( calculated log bbs for 3 and 8b are − 0 . 55 and − 0 . 33 , respectively ). this change in the relative concentration of drugs implies an approximately 66 % increase in the concentration of the drug in the brain . in summary , 16 analogues of 3 with methyl substituents at five different positions on the 3 structure were synthesized . eleven of the analogues had sub - nanomolar κ values at the κ opioid receptor . the monomethylated analogues 8a , 8b , 8d , and 8e with k e values of 0 . 03 to 0 . 06 nm were the most potent compounds . even though the efficacy at the opioid receptor is not as good as that for 3 , the calculated log bb values suggest that these analogues may have activity comparable to that of 3 in vivo . 1 h nmr spectra were determined on a bruker 300 spectrometer using tetramethylsilane as an internal standard . mass spectral data were obtained using a finnegan lcq electrospray mass spectrometer in positive ion mode at atmospheric pressure . medium - pressure flash column chromatography was done on a combiflash companion system using teledyne isco prepacked silica gel columns or using em science silica gel 60 å ( 230 - 400 mesh ). all reactions were followed by thin - layer chromatography using whatman silica gel 60 tlc plates and were visualized by uv . optical rotations were measured on an auto pol iii polarimeter . all solvents were reagent grade . hcl in dry diethyl ether was purchased from aldrich chemical co . and used while fresh before discoloration . cma - 80 is a mixture of 80 % chloroform , 18 % methanol , and 2 % concentrated ammonium hydroxide . purity of compounds (& gt ; 95 %) was established by elemental analysis . elemental analyses were performed by atlantic microlab , inc ., atlanta , ga . care should be used when using bop in coupling reactions as it yields the carcinogenic byproduct hmpa . compound 10 25 ( 6 . 35 g , 0 . 023 mol ) in 50 ml of thf at − 78 ° c . was added over 20 min to a solution of lihmds in thf ( 25 ml of 1 m solution in thf ). after 10 min , 1 . 1 eq . of 4 - methoxybenzyl bromide ( 25 mmol , 5 ml ) was added in one portion . the mixture was stirred at − 78 ° c . for 3 h and then at room temperature overnight . saturated nh 4 cl solution was added , the thf was removed in vacuo , et 2 o ( 100 ml ) was added , and the phases were separated . the organic layer was washed with 50 ml of nahco 3 solution and brine . after drying ( na 2 so 4 ), filtration , and removal of the solvent , the residue was purified by chromatography using silica gel isco column with 9 % etoac in hexanes as eluent . concentration of the product fractions gave 7 . 4 g ( 82 %) of 11 as a white solid : mp 128 - 129 ° c . [ α ] 25 d =− 260 ( c 0 . 8 , meoh ). 1 h nmr ( cdcl 3 ) δ 7 . 27 ( 2h , d , j = 8 hz ), 7 . 19 - 7 . 14 ( 2h , m ), 7 . 09 - 7 . 05 ( 4h , m ), 6 . 94 ( d , 2h , j = 8 hz ), 6 . 76 - 6 . 72 ( m , 4h ), 5 . 68 ( s , 1h ), 3 . 88 ( d , 1h , j = 12 hz ), 3 . 86 ( s , 3h ), 3 . 27 ( d , 1h , j = 12 hz ), 2 . 14 ( s , 3h ). 13 c nmr 175 . 1 , 169 . 4 , 159 . 6 , 136 . 7 , 131 . 5 , 130 . 1 , 130 . 0 , 128 . 8 , 128 . 7 , 128 . 2 , 127 . 2 , 126 . 3 , 114 . 6 , 90 . 7 , 65 . 9 , 55 . 8 , 40 . 5 , 24 . 6 . esims : m / z 402 ( m + 1 , 100 ). compound ii ( 2 . 2 g , 0 . 0055 mol ) was suspended in 20 ml of concentrated hcl solution . after nitrogen flush , the mixture was heated under reflux for 3 h . after filtration and removal of the hcl solution , the white precipitate was dried . 1 h nmr ( cd 3 od ) δ 7 . 24 ( d , 2h , j = 6 hz ), 6 . 91 ( d , 2h , j = 6 hz ), 3 . 77 ( 3h , s ), 3 . 26 ( d , 1h , j = 14 hz ), 3 . 13 ( d , 1h , j = 14 hz ), 1 . 66 ( s , 3h ). 13 c nmr 173 . 8 , 161 . 3 , 132 . 9 , 115 . 9 , 62 . 4 , 56 . 4 , 43 . 5 , 23 . 2 , ms ( esi ) 210 ( m + 1 ). the product was used in the next step without purification . to a solution of compound 12 from above in distilled water ( 20 ml ), 12 m hcl ( 4 ml ) was added . the reaction mixture was cooled to 5 ° c ., and bromine ( 2 . 1 ml , 41 mmol ) was injected into the stirred solution . after 15 min , ni gas was passed through the reaction mixture until the product precipitated . apcims : m / z 366 ( m + 1 , 100 ). the product was used in the next step without purification . compound 13 from above ( assumed to be 4 . 8 mmol ) was added to trifluoroacetic acid ( 5 ml ). hbr ( 33 % in acetic acid , 0 . 9 ml , 4 . 8 mmol ) was added dropwise to the reaction mixture under a nitrogen atmosphere . after the addition of the acid , formaldehyde ( 8 . 64 mmol , 260 mg , 0 . 7 ml ) was added dropwise and the mixture stirred at 70 - 80 ° c . for 17 h . the reaction mixture was cooled , dried , and concentrated . apcims : m / z 378 ( m + 1 ). the product was used in the next step without purification . the crude compound 14 reported above ( assumed to be 4 . 8 mmol ) was dissolved in dmf ( 7 ml ) and water ( 2 ml ). triethylamine ( 1 . 01 g , 0 . 01 mol ) was added , followed by di - tert - butyl dicarbonate ( 1 . 57 g , 0 . 007 mol ). the reaction mixture was stirred at room temperature for 4 h and then concentrated to dryness . the resulting residue was treated with water ( 30 ml ) and etoac ( 30 ml ). khso 4 ( 2 g ) was added to the mixture ( ph = 2 ), and the organic layer was separated , dried , and concentrated . the product was purified by chromatography on silica gel ( isco column ), using 35 % etoac in hexanes as eluent to afford 500 mg of 15 ( 22 % from 13 ) as a syrup . 1 h nmr ( cd 3 od ) δ 7 . 55 ( s , 1h ), 4 . 84 ( d , 1h , j = 16 hz ), 4 . 54 ( d , 1h , j = 16 hz ), 3 . 85 ( s , 3h ), 3 . 19 ( d , 1h , j = 16 hz ), 2 . 92 ( d , 1h , j = 16 hz ), 1 . 47 ( s , 9h ), 1 . 42 ( s , 3h ). 1 c nmr 177 . 7 , 154 . 7 , 138 . 1 , 135 . 4 , 132 . 9 , 118 . 6 , 117 . 9 , 62 . 5 , 62 . 0 , 46 . 1 , 41 . 7 , 29 . 1 , 28 . 3 , 23 . 9 . esims : m / z 478 ( m + 1 ). a suspension of 14 ( 5 . 00 g , 0 . 012 mol ) in 75 ml of 48 % aqueous hbr was heated to reflux for 5 h . the solution was then evaporated to dryness under reduced pressure and dissolved in 30 ml of meoh and 7 . 00 ml of et 3 n ( 0 . 05 mol ). this solution was added to 300 mg of 10 % pd on carbon and shaken for 12 h in a parr hydrogenator under 60 psig hi . the suspension was filtered and the solvents removed under reduced pressure to leave a solid product ( containing the product and triethylammonium salts ) with a mass of 9 . 77 g . this solid was dissolved in 15 ml of h 2 o , 40 ml of dmf , and 4 . 78 ml ( 34 . 29 mmol ) of et 3 n . into this solution , di - tert - butyl dicarbonate ( 2 . 1 ml , 22 . 26 mmol ) was introduced and the mixture stirred for 10 h . the solution was reduced to 1 / 10 of its volume under reduced pressure and partitioned between 30 ml of h 2 o and 30 ml of etoac . the water layer was extracted with etoac ( 3 × 15 ml ). the pooled organic extracts were washed once each with 10 ml of h 2 o , 10 ml of brine , dried over mgso 4 , filtered , and concentrated to dryness to yield 3 . 42 g of 6a as a foam that was pure by nmr . 1 h nmr ( cdcl 3 ) δ 7 . 17 ( d , 1h , j = 8 . 1 hz ), 6 . 73 ( m , 2h ), 4 . 60 - 4 . 41 ( 2d , 2h ), 3 . 12 ( d , 1h , j = 14 . 7 hz ), 2 . 78 ( d , 1h , j = 14 . 7 hz ), 1 . 56 - 1 . 24 ( 2s , 12h ). esims : m / z 207 ( m + 1 - boc ). the boc - protected isoquinoline 6a ( 534 mg , 1 . 74 mmol ) was dissolved in 5 ml of a 1 : 1 mixture of cf 3 co 2 h / ch 2 cl 2 and stirred overnight . the solvents were removed under reduced pressure and the residue suspended in 2 ml of water . the ph of the solution was adjusted to 7 by addition of saturated nahco 3 . to this solution was added 300 mg of raney ni slurry in meoh using a spatula along with 1 ml of a 37 % solution of formaldehyde in water ( 13 . 4 mmol ), and the resulting suspension was stirred under 1 atm of h 2 overnight . the suspension was filtered , and the solvents were removed under reduced pressure to yield a residue that was subjected to silica gel flash - column chromatography . elution with chcl 3 / meoh / nh 4 oh ( 60 : 30 : 10 ) afforded 384 mg of the ammonium salt of 6b after removal of solvents . the triethylammonium salt of 6b was prepared by addition of 5 ml of et 3 n to a solution of the compound in 2 ml of meoh , followed by removal of the volatiles : mp & gt ; 220 ° c . 1 h nmr ( cd 3 od ) δ 7 . 07 ( d , 1h , j = 8 hz ), 7 . 77 ( d , 1h ), 6 . 58 ( s , 1h ), 4 . 43 ( bd , 1h ), 4 . 31 ( bd , 1h ), 3 . 37 ( d , 1h ), 3 . 20 ( m , 9h ), 2 . 95 ( d , 1h , j = 14 . 7 hz ), 1 . 52 ( s , 3h ), 1 . 25 ( t , 9h ), 2 . 88 ( m , 1h ), 2 . 75 ( m , 1h ). esims : m / z 222 ( m + 1 , 100 ). triethylamine ( 3 mmol , 0 . 42 ml ) and 10 % pd / c ( 20 mg ) were added to 15 ( 337 mg , 1 . 05 mmol ) in meoh ( 5 ml ). this mixture was shaken for 90 min under 40 psig of h 2 in a parr apparatus . the mixture was then filtered and concentrated under reduced pressure to give 6c in quantitative yield . an analytical sample was prepared by recrystallization from etoac - hexanes : mp 191 ° c . dec . 1 h nmr ( cd 3 od ) δ 7 . 10 ( d , 1h , j = 8 hz ), 6 . 82 ( m , 3h ), 4 . 69 ( d , 1h ), 4 . 40 ( d , 1h ), 3 . 18 ( d , 1h , j = 14 . 7 hz ), 2 . 79 ( d , 1h , j = 14 . 7 hz ), 1 . 46 ( s , 9h ), 1 . 39 ( s , 3h ). esims : m / z 322 ( m + 1 , 100 ). at 0 ° c ., 6c ( 266 mg , 1 . 13 mmol ) was dissolved in 5 ml of thf and 2 ml of 12 m hcl . after this solution was stirred for 4 h , the solvents were removed under reduced pressure . the residue was dissolved in 5 ml of meoh . into this solution were added 0 . 12 ml of et 3 n , 0 . 5 ml of 37 % formaldehyde in h 2 o , and 0 . 3 ml of raney ni slurry in meoh . the mixture was stirred overnight under an atmosphere of hi , filtered , and the solvents removed under reduced pressure to yield a residue that contained the title compound and et 3 n . hcl . this residue was used without further purification . 1 h nmr ( cd 3 od ) δ 7 . 13 ( d , 1h ), 6 . 88 ( d , 1h ), 6 . 75 ( s , 1h ), 4 . 57 ( d , 1h ), 4 . 32 ( d , 1h ) 3 . 77 ( s , 3h ), 3 . 41 ( d , 1h , j = 14 . 7 hz ), 3 . 21 ( q , 6h ), 2 . 99 ( d , 1h ), 2 . 90 ( s , 3h ), 1 . 53 ( s , 3h ), 1 . 31 ( t , 9h ). esims : m / z 322 ( m + 1 , 100 ). compound 6r 30 ( 1 . 087 g , 0 . 0034 mol ) was suspended in 15 ml of ch 2 cl 2 , and the mixture was cooled to 0 ° c . into this solution was added 7 ml of cf 3 cooh , and the mixture was stirred for 6 h . the solvents were removed under reduced pressure , and the residue was suspended in 100 ml of meoh and 5 ml of formalin . into this suspension was added 1 g of a slurry of raney ni in meoh using a spatula . the mixture was stirred under an atmosphere of h 2 for 5 h and was filtered through celite . to the filtered solution was added 10 ml of a 2 m solution of hcl in ethanol . the solvents were removed under reduced pressure , and the residue was recrystallized from meoh to give 879 mg ( 64 %) of 6e . hcl as a white powder : mp & gt ; 220 ° c . 1 h nmr ( d 6 - dmso ) δ 9 . 59 ( s , 1h ), 7 . 09 ( d , 1h , j = 8 . 4 hz ), 6 . 73 ( m , 1h ), 6 . 59 ( s , 1h ), 4 . 53 ( b , 1h ), 4 . 38 ( b , 2h ), 3 . 31 ( dd , 1h , j = 5 . 7 hz ), 3 . 16 - 3 . 07 ( m , 1h ), 2 . 91 ( s , 3h ). esims : m / z 208 ( m + 1 , 100 ). to a heterogeneous solution of ( 3r , 4r )- 4 -( 3 - methoxyphenyl )- 3 , 4 - dimethylpiperidine 27 ( 41 . 1 g , 0 . 161 mol ), n - boc - l - valine ( 34 . 9 g , 0 . 161 mol ), bop reagent ( 71 . 0 g , 0 . 161 mol ) in thf ( 450 ml ) was added triethylamine ( 51 . 9 g , 0 . 513 mol ) in thf ( 50 ml ). the reaction mixture became homogeneous within 5 min after addition of et 3 n . the reaction was stirred for 4 h at room temperature than added to ether ( 500 ml )/ h 2 o ( 300 ml ). the organic layer was separated , washed with saturated nahco 3 then brine , and separated . the extracts were dried ( na 2 so 4 ) and concentrated in vacuo to afford an off - white solid . this material was purified by silica gel column chromatography , eluting with 70 % hexanes in etoac to yield 63 . 6 g ( 94 %) of a white amorphous solid . diborane ( 260 ml , 1 . 0 m in thf , 0 . 260 mol ) was added to the material described above ( 54 . 6 g , 0 . 130 mol ) in thf ( 350 ml ). the reaction mixture was stirred under n2 at reflux for 2 h . the slightly heterogeneous reaction mixture was cooled to room temperature , and 6 n hcl was added ( initially cautiously ). after stirring at reflux for 2 h , the mixture was concentrated in vacuo and diluted with water . the reaction mixture was made basic with solid na 2 co 3 and extracted with ch 2 cl 2 . the organic layer was separated , dried ( na 2 so 4 ), and concentrated in vacuo to afford 44 g ( 100 %) of a thick oil . 1 h nmr ( cdcl 3 ) δ 7 . 21 ( t , 1h ), 6 . 88 ( d , 1h , j = 8 . 1 hz ), 6 . 83 ( s , 1h ), 6 . 71 ( d , 1h ), 3 . 81 ( s , 3h ), 2 . 77 ( m , 1h ), 2 . 63 - 2 . 13 ( m , 8h ), 2 . 10 ( bm , 1h ), 2 . 00 ( m , 1h ), 1 . 60 ( m , 1h ), 1 . 41 ( s , 3h ), 0 . 91 ( m , 7h ), 0 . 76 ( d , 3h , j = 7 . 2 hz ). esims : m / z 305 ( m + h + , 100 ). anal . ( c 19 h 32 n 2 o ) c , h , n . 3 -[( 3r , 4r )- 3 , 4 - dimethylpiperidin - 4 - yl ] phenol ( 2 . 42 g , 11 . 79 mmol ) and l - boc - ile ( 2 . 73 g , 11 . 79 mmol ) were stirred in 30 ml of ch 3 cn and the solution cooled to 0 ° c . into this solution , hbtu ( 4 . 47 g , 11 . 79 mmol ) was added followed by et 3 n ( 3 . 3 ml , 23 . 57 mmol ). the solution was stirred for 2 h and was then partitioned between 60 ml of etoac and 20 ml of h 2 o . the organic layer was washed with saturated nahco 3 ( 10 ml × 3 ) and brine ( 10 ml ). the solvent was dried over na 2 so 4 , filtered , and removed under reduced pressure . flash column chromatography on silica gel eluting with a solvent gradient ( 80 % hexanes in etoac to 66 % hexanes in etoac ) gave fractions that contained 3 . 39 g of pure amide . the amide ( 3 . 37 g , 8 . 33 mmol ) was dissolved in 20 ml of dry thf , and 16 . 67 ml of a 1 m solution of bh 3 in ti - if was added . the solution was heated at reflux for 3 h , cooled to ambient temperature , and carefully added to 3 ml of h 2 o . then 7 ml of conc . hcl was added . the mixture was heated at reflux for 2 h , and the volume of the reaction was reduced to one - third under reduced pressure . the remaining mixture was made basic by addition of solid nahco 3 and extracted thoroughly with a 4 : 1 mixture of ch 2 cl 2 / thf . the pooled extracts were washed once with 20 ml of h 2 o , dried over mgso 4 , filtered , and concentrated to give 2 . 50 g ( 70 %) of a clear oil that slowly crystallized . an analytical sample was prepared by recrystallization from etoac : mp 150 - 153 ° c . 1 h nmr ( cdcl 3 ) δ 7 . 13 ( t , 1h ), 6 . 80 ( m , 1h ), 6 . 71 ( s , 1h ), 6 . 64 ( d , 1h ), 2 . 82 - 2 . 78 ( m , 3h ), 2 . 74 - 2 . 52 ( m , 4h ), 2 . 42 - 2 . 26 ( m , 6h ), 1 . 97 ( m , 1h ), 1 . 54 ( m , 2h ), 1 . 49 - 1 . 38 ( m , 1h ), 1 . 31 ( s , 3h ), 1 . 27 - 1 . 19 ( m , 1h ), 0 . 89 ( t , 6h ), 0 . 77 ( d , 3h , j = 6 . 9 hz ).). esims : m / z 305 ( m + h + , 100 ). anal . ( c 19 h 32 n 2 o ) c , h , n . ( 3r , 4r )- 4 -( 3 - methoxyphenyl )- 3 , 4 - dimethylpiperidine 27 ( 533 mg , 2 . 43 mmol ) and boc - l - ile ( 562 mg , 2 . 43 mmol ) were stirred in 20 ml of ch 3 cn , and the solution was cooled to 0 ° c . into this solution was added hbtu ( 922 mg , 2 . 43 mmol ) followed by et 3 n ( 0 . 7 ml , 4 . 87 mmol ). the solution was stirred for 2 h and was then partitioned between 30 ml of etoac and 10 ml of h 2 o . the organic layer was washed with saturated nahco 3 ( 7 ml × 3 ) and brine ( 5 ml ) solutions . the solvent was dried over na 2 so 4 , filtered , and removed under reduced pressure . flash column chromatography on silica gel eluting with 83 % hexanes in etoac gave fractions that after removal of solvent yielded 680 mg of pure amide . the amide ( 675 mg , 1 . 56 mmol ) was dissolved in 20 ml of dry thf and 3 . 12 ml of a 1 m solution of bh 3 in thf was added . the solution was heated at reflux for 3 h , cooled to room temperature , and then 1 ml of h 2 o was added carefully followed by 3 ml of conc . hcl . the mixture was heated at reflux for 2 h , and the volume of the reaction was reduced to one - third under reduced pressure . the remaining mixture was made basic by addition of nahco 3 and extracted thoroughly with ch 2 cl 2 . the pooled extracts were washed once with 10 ml of h 2 o , dried over mgso 4 , filtered , and the solvents removed to give 540 mg ( 70 %) of a clear oil . 1 h nmr ( cd 3 od ) δ 7 . 20 ( t , 1h , arh ), 6 . 89 ( m , 1h , arh ), 6 . 82 ( s , 1h , arh ), 6 . 72 ( m , 1h , arh ), 3 . 77 ( s , 3h , ch 3 oar ), 2 . 88 - 2 . 25 ( m , 9h ), 2 . 03 ( m , 1h ), 2 . 57 - 2 . 40 ( m , 3h ), 1 . 30 ( d , 3h , ch 3 , j = 6 . 6 hz ). ), 1 . 28 - 1 . 10 ( m , 1h ), 0 . 96 - 0 . 89 ( m , 7h ), 1 . 60 - 1 . 70 ( dd , 3h , ch 3 ). eims : m / z 319 ( m + h + , 100 ). anal . ( c 20 h 34 n 2 o ) c , h , n . a phenylpiperidine 7 ( 1 eq .) was dissolved along with a tetrahydroisoquinoline 6 ( 1 . 05 eq .) in 10 ml of dry thf and cooled to 0 ° c . into this flask was introduced bop ( 1 . 05 eq .) dissolved in 5 ml of dry thf . immediately afterwards et 3 n ( 1 . 05 eq .) was added , and the solution was warmed to room temperature and allowed to stir for 3 h . the solution was added to 30 ml of saturated nahco 3 . the resulting mixture was extracted 3 × with 10 ml of etoac . the pooled organic solvents were washed once with 5 ml of water and dried over mgso 4 . the mixture was then separated by flash chromatography on silica gel . for the reactions employing boc - protected tetrahydroisoquinolines , the crude coupling mixture was dissolved in 10 ml of a 20 % cf 3 co 2 h solution in ch 2 cl 2 and stirred overnight . the solvents were removed and the crude product stirred in 10 ml of saturated nahco 3 and 10 ml of etoac . the layers were separated , and the aqueous layer was extracted 2 × with 5 ml of etoac . the pooled etoac extracts were washed once with 3 ml of brine , dried over na 2 so 4 , filtered , and concentrated under reduced pressure to yield a crude residue . when needed , the impure compound was purified by preparative thick layer chromatography . the dihydrochloride salts were formed by dissolving the freebase in 5 ml of etoh followed by addition of 5 ml of 2 m hcl in etoh and evaporation of the solution under reduced pressure . a phenylpiperidine 7 ( 1 eq .) was dissolved along with a tetrahydroisoquinoline 6 ( 1 . 05 eq .) in 15 ml of a 50 % solution of thf in ch 3 cn and cooled to 0 ° c . into this flask was introduced hbtu ( 1 . 05 eq .) dissolved in 10 ml of ch 3 cn . immediately afterwards et 3 n ( 1 . 05 eq .) was added , and the solution was warmed to room temperature and allowed to stir for 3 h . to the reaction solution was added 30 ml of saturated nahco 3 . the resulting mixture was extracted three times with 10 ml of etoac . the pooled organic solvents were washed once with 5 ml of water and dried over mgso 4 . the mixture was then separated by chromatography . for the reactions employing boc - protected tetrahydroisoquinolines , the crude coupling mixture was dissolved in 10 ml of a 20 % cf 3 co 2 h solution in ch 2 cl 2 and stirred overnight . the solvents were removed and the crude product stirred in 10 ml of saturated nahco 3 and 10 ml of etoac . the layers were separated , and the aqueous layer was extracted 2 × with 5 ml etoac . the pooled etoac extracts were washed once with 3 ml of brine , dried over na 2 so 4 , filtered , and concentrated under reduced pressure to yield a crude residue . when needed , the impure compound was purified by preparative thick layer chromatography . the dihydrochloride salts were formed by dissolving the freebase in 5 ml of etoh followed by addition of 5 ml of 2 m hcl in etoh and evaporation of the solvents under reduced pressure . general procedure ( a ) was employed using 100 mg ( 0 . 328 mmol ) of 7b and 112 mg ( 0 . 382 mmol ) of 6f to afford 65 mg ( 35 %) of the freebase . 1 h nmr ( cd 3 od ) δ 7 . 26 ( t , 1h , j = 8 . 1 hz ), 7 . 00 ( d , 1h , j = 8 . 1 hz ), 6 . 91 ( d , 1h , j = 8 . 1 hz ), 6 . 86 - 6 . 75 ( m , 2h ), 6 . 63 ( s , 1h ), 4 . 30 - 4 . 37 ( m , 3h ), 3 . 50 ( m , 2h ), 3 . 15 - 3 . 11 ( m , 1h ), 2 . 80 - 2 . 71 ( m , 1h ), 2 . 45 ( m , 1h ), 1 . 93 - 1 . 87 ( m , 1h ), 1 . 49 ( s , 3h ), 1 . 29 - 1 . 13 ( m , 1h ), 1 . 07 ( 2d , 6h ), 0 . 85 ( d , 3h ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 69 ° ( c 0 . 35 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 31 ( t , 1h , j = 9 hz ), 7 . 12 ( d , 1h , j = 9 hz ), 6 . 95 ( d , 1h ), 6 . 86 - 6 . 73 ( m , 3h ), 6 . 63 ( s , 1h ), 4 . 40 ( d , 1h ), 4 . 34 ( d , 1h ), 4 . 27 ( m , 2h ), 3 . 81 ( s , 3h ), 3 . 63 ( d , 1h ), 3 . 60 - 3 . 24 ( m , 6h ), 3 . 20 ( d , 1h ), 2 . 63 ( dt , 1h ), 2 . 43 ( m , 1h ), 1 . 95 ( m , 1h ), 1 . 48 ( s , 3h ), 1 . 03 - 0 . 87 ( m , 3h ), 0 . 83 ( d , 3h , j = 9 hz ), 0 . 80 - 0 . 68 ( m , 6h ). esims : m / z 480 ( m + 1 , 50 ). anal . ( c 29 h 43 cl 2 n 3 o 3 . 2h 2 o ) c , h , n . general procedure ( b ) was employed using 100 mg ( 0 . 344 mmol ) of 7a and 111 mg ( 0 . 361 mmol ) of 6a to afford 65 mg ( 35 %) of the freebase after separation by preparative tlc eluting with 1 : 1 cma - 80 / ch 2 cl 2 . 1 h nmr ( cd 3 od ) δ 7 . 09 ( t , 1h , j = 8 . 4 hz ), 6 . 87 ( d , 1h , j = 8 . 4 hz ), 6 . 70 ( m , 2h ), 6 . 55 ( m , 2h ), 6 . 47 ( s , 1h ), 4 . 02 ( d , 1h ), 3 . 77 ( m , 2h ), 3 . 16 ( d , 1h ), 2 . 74 - 2 . 33 ( m , 7h ), 2 . 14 ( dt , 1h ), 1 . 89 - 1 . 75 ( m , 2h ), 1 . 47 ( d , 1h ), 1 . 38 ( d , 3h ), 1 . 26 - 1 . 17 ( m , 7h ), 0 . 82 ( t , 6h ), 0 . 58 ( d , 3h ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 47 . 2 ° ( c 1 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 18 ( m , 2h ), 6 . 75 ( m , 3h ), 6 . 62 ( m , 1h ), 4 . 42 ( d , 1h ), 4 . 27 ( d , 1h ), 4 . 25 ( m , 1h ), 3 . 67 - 3 . 30 ( m , 6h ), 3 . 18 ( d , 1h ), 2 . 63 ( dt , 1h ), 2 . 39 ( m , 1h ), 1 . 90 ( d , 1h ), 1 . 85 - 1 . 60 ( m , 1h ), 1 . 79 ( s , 3h ), 0 . 85 ( d , 3h , j = 9 hz ), 0 . 68 ( 2d , 6h ). esims : m / z 480 ( m + 1 , 50 ). anal . ( c 29 h 41 cl 2 n 3 o 3 . 2h 2 o ) c , h , n . general procedure ( a ) was employed using 120 mg ( 0 . 377 mmol ) of 7d and 116 mg ( 0 . 396 mmol ) of 6f to afford 50 mg ( 27 %) of the freebase after separation by preparative tlc eluting with 1 : 1 cma - 80 / et 2 o , nmr ( cd 3 od ) δ 7 . 19 ( t , 1h ), 6 . 87 - 6 . 81 ( m , 2h ), 6 . 80 ( s , 1h ), 6 . 69 ( ds , 1h ), 6 . 58 ( ds , 1h ), 6 . 47 ( s , 1h ), 4 . 06 ( m , 1h ), 3 . 77 ( dd , 2h ), 3 . 75 ( s , 3h ), 3 . 50 ( dd , 1h ), 2 . 82 ( dd , 1h ), 2 . 78 - 2 . 70 ( m , 2h ), 2 . 65 - 2 . 39 ( m , 5h ), 2 . 27 ( dt , 1h ), 1 . 99 ( m , 1h ), 1 . 70 - 1 . 50 ( m , 4h ), 1 . 40 ( m , 5h ), 1 . 22 - 1 . 03 ( m , 2h ), 0 . 8 ( m , 9h ), 0 . 69 ( d , 3h ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 95 . 9 ° ( c 0 . 71 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 30 ( t , 1h , j = 9 hz ), 7 . 12 ( d , 1h , j = 9 hz ), 6 . 91 ( d , 1h , j = 9 hz ), 6 . 89 - 6 . 73 ( m , 2h ), 6 . 62 ( s , 1h ), 4 . 40 - 4 . 20 ( m , 3h ), 3 . 89 ( d , 1h ), 3 . 81 ( s , 3h ), 3 . 67 - 3 . 23 ( m , 7h ), 3 . 12 ( m , 1h ), 2 . 82 ( dt , 1h ), 2 . 45 ( m , 1h ), 1 . 92 ( d , 1h ), 1 . 70 ( m , 1h ), 1 . 55 ( m , 1h ), 1 . 50 ( s , 3h ), 1 . 42 ( m , 1h ), 1 . 31 ( m , 1h ), 1 . 20 ( m , 1h ), 1 . 10 - 0 . 89 ( m , 9h ). esims : m / z 494 ( m + 1 , 80 ). anal . ( c 30 h 45 cl 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( b ) was employed using 172 mg ( 0 . 593 mmol ) of 7a and 200 mg ( 0 . 622 mmol ) of 6c to afford 250 mg of the freebase after isolation ( 68 % yield ): mp 210 - 212 ° c . 1 h nmr ( cd 3 od ) δ 7 . 09 ( t , 1h , j = 8 . 1 hz ), 6 . 73 - 6 . 57 ( m , 2h ), 4 . 13 ( d , 1h ), 3 . 95 - 3 . 87 ( m , 2h ), 3 . 64 ( s , 3h ), 3 . 25 ( d , 2h ), 2 . 68 ( m , 1h ), 2 . 65 - 2 . 50 ( m , 2h ), 2 . 40 ( m , 4h ), 2 . 18 ( dt , 1h ), 1 . 82 ( m , 2h ), 1 . 52 ( d , 1h ), 1 . 37 ( s , 3h ), 1 . 24 ( s , 3h ), 0 . 85 ( 2d ), 0 . 47 ( d , 3h ). the hydrochloride salt synthesized by the general procedure had mp 210 - 212 ° c . dec . [ α ] d 25 + 15 ° ( c 1 . 2 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 17 - 6 . 74 ( m , 5h ), 6 . 61 ( m , 1h ), 4 . 44 ( d , 1h ), 4 . 25 ( d , 1h ), 4 . 23 ( m , 1h ), 3 . 79 ( s , 3h ), 3 . 65 - 3 . 29 ( m , 6h ), 3 . 17 ( d , 1h ), 2 . 63 ( dt , 1h ), 2 . 40 ( m , 1h ), 1 . 91 ( d , 1h ), 1 . 84 - 1 . 59 ( m , 1h ), 1 . 79 ( s , 3h ), 0 . 84 ( d , 3h , j = 9 hz ), 0 . 67 ( 2d , 6h ). esims : m / z 494 ( m + 1 , 100 ). anal . ( c 30 h 45 cl 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( b ) was employed using 100 mg ( 0 . 328 mmol ) of 7b and 120 mg ( 0 . 390 mmol ) of 6a to afford 27 mg ( 17 %) of the freebase after separation by preparative tlc eluting with 75 : 1 etoac / et 3 n . 1 h nmr ( cd 3 od ) δ 7 . 17 ( t , 1h ), 6 . 79 - 6 . 90 ( m , 2h ), 6 . 70 ( m , 1h ), 6 . 56 ( m , 1h ), 6 . 48 ( s , 1h ), 4 . 00 ( d , 1h ), 3 . 87 ( m , 2h ), 3 . 78 ( s , 3h ), 3 . 17 ( d , 1h ), 2 . 72 - 2 . 28 ( m , 7h ), 2 . 15 ( dt , 1h ), 1 . 89 ( m , 1h ), 1 . 79 ( sextet , 1h ), 1 . 50 ( d , 1h ), 1 . 38 - 1 . 20 ( m , 7h ), 1 . 10 - 0 . 77 ( m , 7h ), 0 . 56 ( d , 3h ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 49 . 8 ° ( c 0 . 45 , meoh ). 1 h nmr ( cd 3 od ) 7 . 30 ( t , 1h , j = 9 hz ), 7 . 13 ( d , 1h , j = 9 hz ), 6 . 94 ( d , 1h , j = 9 hz ), 6 . 85 - 6 . 74 ( m , 3h ), 6 . 63 ( s , 1h ), 4 . 41 ( d , 1h ), 4 . 35 ( d , 1h ), 4 . 27 ( m , 1h ), 3 . 81 ( s , 3h ), 3 . 63 ( d , 1h ), 3 . 60 - 3 . 25 ( m , 6h ), 3 . 20 ( d , 1h ), 2 . 63 ( dt , 1h ), 2 . 45 ( m , 1h ), 1 . 95 ( m , 1h ), 1 . 78 ( s , 3h ), 1 . 48 ( s , 3h ), 1 . 05 - 0 . 89 ( m , 3h ), 0 . 83 ( d , 3h , j = 9 hz ), 0 . 80 - 0 . 68 ( m , 6h ). esims : m / z 494 ( m + 1 , 80 ). anal . ( c 30 h 45 cl 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( a ) was employed using 104 mg of 7d ( 0 . 341 mmol ) and 110 mg ( 0 . 358 mmol ) of 6a to afford 29 mg of the freebase after separation by preparative tlc eluting with 1 : 1 cma - 80 / ch 2 cl 2 ( 17 % yield ). 1 h nmr ( cd 3 od ) δ 7 . 19 ( t , 1h ), 6 . 79 ( d , 1h , j = 8 . 1 hz ), 6 . 77 - 6 . 66 ( m , 2h ), 6 . 58 ( m , 2h ), 6 . 48 ( s , 1h ), 4 . 09 ( q , 1h ), 4 . 02 - 3 . 95 ( d , 1h ), 3 . 93 - 3 . 8 ( m , 2h ), 3 . 15 ( d , 2h ), 2 . 70 - 2 . 50 ( m , 3h ), 2 . 49 - 2 . 32 ( m , 3h ), 2 . 15 ( dt , 1h ), 1 . 88 ( m , 1h ), 1 . 62 - 1 . 3 ( m , 11h ), 0 . 91 - 0 . 79 ( m , 9h ), 0 . 58 ( d , 3h , ch 3 ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 42 . 2 ° ( c 0 . 51 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 20 ( t , 1h , j = 9 hz ), 7 . 13 ( d , 1h , j = 9 hz ), 6 . 80 - 6 . 75 ( m , 2h ), 6 . 69 - 6 . 64 ( m , 2h ), 4 . 41 ( d , 1h ), 4 . 30 ( d , 1h ), 4 . 28 ( m , 1h ), 3 . 64 - 3 . 32 ( m , 7h ), 3 . 17 ( d , 1h ), 2 . 63 ( dt , 1h ), 2 . 40 ( m , 1h ), 1 . 92 ( d , 1h ), 1 . 76 ( s , 3h ), 1 . 47 ( m , 4h ), 1 . 20 ( m , 2h ), 0 . 92 - 0 . 71 ( m , 9h ). esims : m / z 494 ( m + 1 , 80 ). anal . ( c 30 h 45 cl 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( a ) was employed using 130 mg ( 0 . 427 mmol ) of 7c and 109 mg ( 0 . 448 mmol ) of 6e to afford 55 mg ( 25 %) of the freebase after separation by preparative tlc eluting with 2 : 1 cma - 80 / ch 2 cl 2 . 1 h nmr ( cd 3 od ) δ 7 . 19 ( t , 1h , j = 8 . 1 hz ), 6 . 90 ( d , 1h , j = 8 . 1 hz ), 6 . 73 ( m , 2h ), 6 . 59 ( m , 2h ), 6 . 51 ( s , 1h ), 4 . 09 ( q , 1h ), 3 . 98 ( m , 1h ), 3 . 84 ( d , 1h ), 3 . 50 ( d , 1h ), 3 . 13 ( t , 1h ), 2 . 99 ( m , 1h ), 2 . 88 ( m , 1h ), 2 . 75 ( m , 1h ), 2 . 55 ( m , 2h ), 2 . 45 ( s , 3h ), 2 . 37 ( m , 2h ), 2 . 23 ( m , 1h ) 1 . 94 ( m , 2h ), 1 . 63 ( m , 1h ), 1 . 50 ( m , 2h ), 1 . 62 - 1 . 3 ( m , 11h ), 0 . 80 - 1 . 0 ( m , 9h ), 0 . 7 ( d , 3h , ch 3 ). the hydrochloride salt synthesized by the general procedure had mp 180 ° c . dec . [ α ] d 25 + 84 . 3 ° ( c 0 . 6 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 19 - 7 . 11 ( m , 2h ), 6 . 89 - 6 . 65 ( m , 4h ), 4 . 50 ( m , 2h ), 4 . 32 ( m , 1h ), 3 . 73 ( d , 1h ), 3 . 55 - 3 . 16 ( m , 8h ), 3 . 08 ( s , 3h ), 2 . 78 ( dt , 1h ), 2 . 39 ( m , 1h ), 1 . 86 ( d , 1h , j = 15 hz ), 1 . 68 ( m , 1h ), 1 . 51 - 1 . 40 ( m , 4h ), 1 . 21 ( m , 2h ), 1 . 02 ( d , 3h , j = 6 hz ), 0 . 97 - 0 . 80 ( m , 6h ). esims : m / z 494 ( m + 1 , 100 ). anal . ( c 30 h 45 o 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( a ) was employed using 120 mg ( 0 . 394 mmol ) of 7b 86 mg ( 0 . 414 mmol ) of 6e to afford 67 mg ( 35 %) of the freebase after separation by preparative tlc eluting with 2 : 1 : 1 cma - 80 / etoac / hexanes . 1 h nmr ( cd 3 od ) δ 7 . 20 ( t , 1h , j = 8 . 1 hz ), 6 . 91 ( d , 1h , j = 8 . 1 hz ), 6 . 86 ( d , 1h , j = 8 . 1 hz ), 6 . 81 ( s , 1h ), 6 . 71 ( dd , 1h ), 6 . 59 ( dd , 1h ), 6 . 51 ( d , 1h ), 4 . 09 ( q , 1h ), 3 . 92 ( m , 1h ), 3 . 84 ( dd , 1h ), 3 . 77 ( s , 1h ), 3 . 50 ( d , 1h ), 3 . 13 ( dd , 1h ), 3 . 05 ( dd , 1h ), 2 . 96 ( dd , 1h ), 2 . 73 ( m , 1h ), 2 . 53 ( dd , 1h ), 2 . 50 - 2 . 40 ( m , 4h ), 2 . 40 - 2 . 37 ( m , 2h ), 2 . 22 ( dt , 1h ) 1 . 98 ( m , 2h ), 1 . 84 ( m , 1h ), 1 . 57 ( t , 1h ), 1 . 33 ( m , 5h ), 0 . 94 - 0 . 84 ( m , 8h ), 0 . 84 - 075 ( dd , 1h ), 0 . 73 - 0 . 68 ( m , 3h ). the hydrochloride salt synthesized by the general procedure had mp 210 - 215 ° c . dec . [ α ] d 25 + 75 . 7 ° ( c 1 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 29 ( t , 1h , j = 9 hz ), 7 . 12 ( d , 1h , j = 9 hz ), 6 . 91 ( d , 1h ), 6 . 87 - 6 . 61 ( m , 3h ), 4 . 48 ( d , 1h ), 4 . 35 ( d , 1h ), 4 . 30 ( m , 1h ), 3 . 81 ( s , 3h ), 3 . 78 ( d , 1h ), 3 . 63 - 3 . 15 ( m , 6h ), 3 . 09 ( s , 3h ), 3 . 07 ( m , 1h ), 2 . 80 ( dt , 1h ), 2 . 45 ( m , 1h ), 1 . 91 ( m , 2h ), 1 . 49 ( s , 3h ), 1 . 08 - 0 . 90 ( m , 7h ), 0 . 86 ( d , 3h , j = 9 hz ). esims : m / z 494 ( m + 1 , 100 ). anal . ( c 30 h 45 cl 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( a ) was employed using 126 mg ( 0 . 414 mmol ) of 7b 140 mg ( 0 . 435 mmol ) of 6c to afford 51 mg ( 23 %) of the freebase after separation by preparative tlc eluting with 2 : 1 chcl 3 / cma - 80 . 1 h nmr ( cd 3 od ) δ 7 . 39 - 7 . 19 ( m , 2h ), 7 . 92 - 6 . 78 ( m , 5h ), 4 . 5 - 4 . 32 ( q , 2h ), 4 . 25 ( m , 1h ), 3 . 70 ( d , 6h ), 3 . 6 - 3 . 30 ( m ), 3 . 20 ( d , 1h ), 2 . 67 ( dt , 1h ), 2 . 45 ( m , 1h ), 1 . 92 ( bd , 1h ), 1 . 78 ( s , 3h ), 1 . 75 - 1 . 60 ( m , 1h ), 1 . 47 ( s , 3h ), 0 . 86 ( d , 3h ), 0 . 70 ( t , 6h ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 49 . 8 ° ( c 1 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 30 ( t , 1h ), 7 . 26 ( d , 1h , j = 6 hz ), 6 . 92 - 6 . 80 ( m , 2h ), 6 . 84 - 6 . 80 ( m , 2h ), 4 . 48 ( d , 1h ), 4 . 36 ( d , 1h ), 4 . 38 ( m , 1h ), 3 . 81 ( s , 3h ), 3 . 79 ( s , 3h ), 3 . 58 ( d , 1h ), 3 . 44 - 3 . 25 ( m , 6h ), 3 . 23 ( d , 1h ), 2 . 64 ( dt , 1h ), 2 . 46 ( m , 1h ), 1 . 95 ( d , 1h ), 1 . 78 ( s , 3h ), 1 . 80 ( m , 1h ), 0 . 83 ( d , 3h , j = 7 . 5 hz ), 0 . 79 ( m , 6h ). esims : m / z 508 ( m + 1 , 100 ). anal . ( c 31 h 47 cl 2 n 3 o 3 h 2 o ) c , h , n . general procedure ( b ) was employed using 65 mg ( 0 . 213 mmol ) of 7c and 46 mg ( 0 . 224 mmol ) of 6c to afford 25 mg ( 25 %) of the freebase after separation by preparative tlc eluting with 1 : 1 cma - 80 / ch 2 cl 2 . 1 h nmr ( cdcl 3 ) δ 7 . 41 ( d , 1h ), 7 . 12 ( t , 1h ), 6 . 96 ( d , 1h ), 6 . 82 - 6 . 52 ( m , 5h ), 4 . 18 - 3 . 77 ( m , 4h ), 3 . 73 ( s , 3h ), 3 . 11 ( d , 1h ), 2 . 82 - 2 . 57 ( m , 4h ), 2 . 48 - 2 . 28 ( m , 4h ), 2 . 17 - 2 . 02 ( m , 2h ), 1 . 91 - 1 . 54 ( m , 3h ), 1 . 55 - 1 . 22 ( m , 9h ), 0 . 98 - 083 ( m , 6h ), 0 . 48 ( d , 3h ). 1 . 47 ( d , 1h ), 1 . 38 ( d , 3h ), 1 . 26 - 1 . 17 ( m , 7h ), 0 . 82 ( t , 6h ), 0 . 58 ( d , 3h ). the hydrochloride salt synthesized by the general procedure had mp & gt ; 220 ° c . dec . [ α ] d 25 + 44 . 7 ° ( c 0 . 45 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 24 ( d , 1h , j = 9 hz ), 7 . 18 ( t , 1h , j = 9 hz ), 6 . 92 ( m , 1h ), 6 . 80 ( s , 1h ), 6 . 76 ( m , 1h ), 6 . 68 ( m , 1h ), 4 . 48 ( d , 1h ), 4 . 38 ( d , 1h ), 4 . 30 ( m , 1h ), 3 . 79 ( s , 3h ), 3 . 70 ( d , 1h , j = 15 . 9 hz ), 3 . 60 - 3 . 31 ( m , 5h ), 3 . 20 ( d , 1h , j = 15 . 9 hz ), 2 . 67 ( dt , 1h ), 2 . 40 ( m , 1h ), 1 . 91 ( d , 1h ), 1 . 79 ( s , 3h ), 1 . 46 ( bs , 4h ), 1 . 13 ( m , 1h ), 0 . 85 ( d , 3h ), 0 . 80 - 0 . 69 ( m , 6h ). esims : m / z 508 ( m + 1 , 100 ). anal . ( c 31 h 47 cl 2 n 3 o 3 . 2h 2 o ) c , h , n . general procedure ( a ) was employed using 145 mg ( 0 . 455 mmol ) of 7d and 146 mg ( 0 . 478 mmol ) of 6a to afford 60 mg ( 26 %) of the freebase after separation by preparative tlc eluting with 3 : 1 chcl 3 / cma - 80 . 1 h nmr ( cd 3 od ) δ 7 . 18 ( t , 1h , j = 8 . 1 hz ), 6 . 88 ( d , 1h , j = 8 . 1 hz ), 6 . 82 ( d , 1h ), 6 . 78 ( t , 1h ), 6 . 89 ( dd , 1h , j 2 = 5 . 7 hz , j = 2 . 1 hz ), 6 . 53 ( dd , 1h j 2 = 5 . 7 hz , j = 2 . 1 hz ), 6 . 46 ( d , 1h , j = 2 . 4 hz ), 3 . 96 ( d , 1h ), 3 . 92 ( m , 1h ), 3 . 76 ( s , 3h ), 3 . 30 ( m , 1h ), 3 . 15 ( d , 1h , j = 15 . 9 hz ), 2 . 69 ( m , 1h ), 2 . 64 ( d , 1h ), 2 . 54 ( b , 1h ), 2 . 47 - 2 . 36 ( m , 5h ), 2 . 17 ( dt , 1h ), 1 . 91 ( m , 1h ), 1 . 52 - 1 . 35 ( m , 5h ), 1 . 32 ( s , 3h ), 1 . 26 ( m , 4h ), 1 . 15 ( d , 1h ), 1 . 06 - 0 . 9 ( m , 2h ), 0 . 86 ( t , 3h , j = 7 . 2 hz ), 0 . 81 ( d , 3h , j = 6 . 9 hz ), 0 . 57 ( d , 3h , j = 6 . 9 hz ). the hydrochloride salt synthesized by the general procedure had mp 210 ° c . dec . [ α ] d 25 + 39 . 7 ° ( c 0 . 41 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 27 ( t , 1h , j = 9 hz ), 7 . 11 ( d , 1h , j = 9 hz ), 6 . 90 - 6 . 70 ( m , 3h ), 6 . 61 ( s , 1h ), 4 . 38 ( d , 1h ), 4 . 29 ( m , 1h ), 3 . 65 ( d , 1h ), 3 . 60 - 3 . 25 ( m , 5h ), 3 . 15 ( d , 1h ), 2 . 64 ( dt , 1h ), 2 . 42 ( m , 1h ), 1 . 92 ( d , 1h ), 1 . 76 ( s , 3h ), 1 . 46 ( bs , 4h ), 1 . 12 ( m , 1h ), 0 . 82 ( d , 3h , j = 9 hz ), 0 . 78 - 0 . 71 ( m , 6h ). esims : m / z 508 ( m + 1 , 100 ). anal . ( c 31 h 47 cl 2 n 3 o 3 . 2h 2 o ) c , h , n . general procedure ( a ) was employed using 104 mg ( 0 . 358 mmol ) of 7a and 88 mg ( 0 . 376 mmol ) of 6d to afford 80 mg ( 44 %) of the freebase after separation by preparative tlc eluting with 3 : 1 chcl 3 / cma - 80 . 1 h nmr ( cd 3 od ) δ 7 . 07 ( t , 1h ), 6 . 93 ( d , 1h ), 6 . 73 - 6 . 52 ( m , 5h ), 4 . 86 ( s , 3h ), 4 . 07 ( d , 1h , j = 16 . 5 hz ), 3 . 89 ( m , 1h ), 3 . 80 ( d , 1h , j = 16 . 5 hz ), 3 . 67 ( s , 3h ), 3 . 14 ( d , 1h , j = 16 . 5 hz ), 2 . 72 ( m , 1h ), 2 . 62 - 2 . 57 ( m , 2h ), 2 . 50 - 2 . 37 ( m , 5h ), 2 . 31 ( dd , 1h ), 2 . 18 ( dt , 1h ), 1 . 90 ( m , 1h ), 1 . 89 - 1 . 75 ( m , 1h ), 1 . 51 ( bd , 1h ), 1 . 37 - 1 . 25 ( m , 7h ), 1 . 01 - 0 . 84 ( m , 8h ), 0 . 54 ( d , 3h , j = 6 . 9 hz ). the hydrochloride salt synthesized by the general procedure had mp 199 ° c . dec . [ α ] d 25 + 50 . 2 ° ( c 0 . 55 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 29 ( d , 1h , j = 9 hz ), 7 . 18 ( t , 1h , j = 9 hz ), 6 . 95 ( d , 1h , j = 9 hz ), 6 . 83 - 6 . 68 ( m , 2h ), 6 . 67 ( d , 1h ), 4 . 70 - 4 . 48 ( bm , 2h ), 4 . 33 ( bm , 1h ), 3 . 80 ( s , 3h ), 3 . 67 - 3 . 30 ( m , 7h ), 2 . 99 ( s , 1h ), 2 . 68 ( dt , 1h ), 2 . 42 ( m , 1h ), 1 . 92 ( d , 1h ), 1 . 48 ( s , 3h ), 0 . 99 - 0 . 50 ( s , 9h ). esims : m / z 508 ( m + 1 , 100 ). anal . ( c 31 h 47 cl 2 n 3 o 3 . 2h 2 o ) c , h , n . general procedure ( a ) was employed using 100 mg ( 0 . 328 mmol ) of 7d and 71 mg ( 0 . 345 mmol ) of 6e to afford 40 mg ( 34 %) of the freebase after separation by preparative tlc eluting with 1 : 1 cma - 80 / et 2 o . 1 h nmr ( cd 3 od ) δ 7 . 19 ( t , 1h , j = 7 . 8 hz ), 6 . 92 - 6 . 84 ( m , 2h ), 6 . 82 ( s , 1h ), 6 . 71 ( d , 1h ), 6 . 59 ( m , 1h ), 6 . 21 ( m , 1h ), 4 . 09 ( q , 1h ), 3 . 98 ( m , 1h ), 3 . 87 ( m , 1h ), 3 . 77 ( s , 3h ), 3 . 49 ( d , 1h , j = 15 hz ), 3 . 14 - 2 . 82 ( m , 4h ), 2 . 79 - 2 . 60 ( m , 2h ), 2 . 60 - 2 . 28 ( m , 9h ), 2 . 23 ( dt , 1h ) 1 . 97 ( m , 1h ), 1 . 68 - 1 . 35 ( m , 4h ), 1 . 29 ( d , 3h ), 1 . 23 ( t , 3h ), 0 . 93 ( t , 5h ), 0 . 90 - 0 . 77 ( m , 2h ), 0 . 70 ( t , 3h ). the hydrochloride salt , synthesized by the general procedure , had mp 180 ° c . dec . [ α ] d 25 + 66 . 2 ° ( c 0 . 5 , meoh ). 1 h nmr ( cd 3 od ) δ 7 . 29 ( t , 1h , j = 9 hz ), 7 . 13 ( d , 1h , j = 9 hz ), 6 . 93 - 6 . 78 ( m , 3h ), 6 . 67 ( d , 1h ), 6 . 85 - 6 . 74 ( m , 3h ), 6 . 67 ( d , 1h ), 4 . 48 - 4 . 28 ( m , 3h ), 3 . 81 ( s , 3h ), 3 . 63 ( d , 1h ), 3 . 60 - 3 . 25 ( m , 6h ), 3 . 09 - 3 . 01 ( m , 4h ), 2 . 78 ( dt , 1h ), 2 . 46 ( m , 1h ), 1 . 92 ( m , 1h ), 1 . 78 ( s , 3h ), 1 . 48 ( bs , 4h ), 1 . 1 - 0 . 8 ( m , 10h ). esims : m / z 508 ( m + 1 , 100 ). anal . ( c 31 h 47 cl 2 n 3 o 3 . h 2 o ) c , h , n . abbreviations : gpcrs , g - protein - coupled receptors ; cdnas , complementary deoxyribonucleic acid ; sar , structure activity relationship ; [ 35 s ] gtpγs , sulfur - 35 guanosine - 5 ′- o -( 3 - thio ) triphosphate ; damgo , [ d - ala 2 , mephe 4 , gly - ol 5 ] enkephalin ; dpdpe , [ d - pen 2 , d - pen 5 ] enkephalin ; u69 , 593 , ( 5α , 7α , 8β )-(−)- n - methyl - n -[ 7 -( 1 - pyrrolidinyl )- 1 - oxaspiro [ 4 , 5 ] dec - 8 - yl ] benzeneacetamide ; cho , chinese hamster ovary ; gdp , guanosine diphosphate ; bop , benzotriazole - 1 - yloxy - tris ( dimethylamino ) phosphonium hexafluorophosphate ; hbtu , o -( benzotriazol - 1 - yl )- n , n , n ′, n ′- tetramethyluronium hexafluorophosphate ; tic , tetrahydroisoquinolinecarboxylic acid ; tpsa , topological polar surface area . obviously , numerous modifications and variations of the present invention are possible in light of the above teachings . it is therefore to be understood that within the scope of the appended claims , the invention may be practiced otherwise than as specifically described herein . 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( 21 ) bortolato , m . ; aru , g . n . ; frau , r . ; orru , m . ; fa , m . ; manunta , m . ; puddu , m . ; mereu , g . ; gessa , g . l . kappa opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats . biol . psychiatry 2005 , 57 , 1550 - 1558 . ( 22 ) carroll , f . i . ; thomas , j . b . ; dykstra , l . a . ; granger , a . l . ; allen , r . m . ; howard , j . l . ; pollard , g . t . ; aceto , m . d . ; harris , l . s . pharmacological properties of jdtic : a novel κ - opioid receptor antagonist . eur . j . pharmacol . 2004 , 501 , 111 - 119 . ( 23 ) cai , t . b . ; zou , z . ; thomas , j . b . ; brieaddy , l . ; navarro , h . a . ; carroll , f . i . synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist ( 3r )- 7 - hydroxy - n -(( 1s )- 1 -{[( 3r , 4r )- 4 -( 3 - hydroxyphenyl )- 3 , 4 - dimethyl - 1 - piperidinyl ] methyl }- 2 - methylpropyl )- 1 , 2 , 3 , 4 - tetrahydro - 3 - isoquinolinecarboxamide ( jdtic ). j . med . chem . 2008 , 51 , 1849 - 1860 . ( 24 ) clark , d . e . rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena . 2 . prediction of blood - brain barrier penetration . j . pharm . sci . 1999 , 88 , 815 - 821 . ( 25 ) hsiao , y . ; hegedus , l . s . synthesis of optically active imidazolines , azapenams , dioxocyclams , and bis - dioxocyclams . j . org . chem . 1997 , 62 , 3586 - 3591 . ( 26 ) ma , d . ; ma , z . ; kozikowski , a . p . ; pshenichkin , s . ; wroblewski , j . t . synthesis and biological evaluation of two analogues of ( s )- alpha - methyl - 3 - carboxyphenylalanine . bioorg . med . chem . lett . 1998 , 8 , 2447 - 2450 . ( 27 ) zimmerman , d . m . ; leander , j . d . ; cantrell , b . e . ; reel , j . k . ; snoddy , j . ; mendelsohn , l . g . ; johnson , b . g . ; mitch , c . h . structure - activity relationships of the trans - 3 , 4 - dimethyl - 4 -( 3 - hydroxyphenyl ) piperidine antagonists for μ and κ opioid receptors . j . med . chem . 1993 , 36 , 2833 - 2841 . ( 28 ) thomas , j . b . ; fall , m . j . ; cooper , j . b . ; rothman , r . b . ; mascarella , s . w . ; xu , h . ; partilla , j . s . ; dersch , c . m . ; mccullough , k . b . ; cantrell , b . e . ; zimmerman , d . m . ; carroll , f . i . identification of an opioid k receptor subtype - selective n - substituent for (+)-( 3r , 4r )- dimethyl - 4 -( 3 - hydroxyphenyl ) piperidine . j . med . chem . 1998 , 41 , 5188 - 5197 . ( 29 ) carroll , f . i . ; chaudhari , s . ; thomas , j . b . ; mascarella , s . w . ; gigstad , k . m . ; deschamps , j . ; navarro , h . a . n - substituted cis - 4 - a -( 3 - hydroxyphenyl )- 8a - methyloctahydroisoquinolines are opioid receptor pure antagonists . j . med . chem . 2005 , 48 , 8182 - 8193 . ( 30 ) liu , c . ; thomas , j . b . ; brieaddy , l . ; berrang , b . ; carroll , f . i . an improved synthesis of ( 3r )- 2 -( tert - butoxycarbonyl - d - 7 - hydroxy - 1 , 2 , 3 , 4 - tetrahydroisoquinoline - 3 - carboxylic acid . synthesis 2008 , 856 - 858 .

kappa opioid recep - tor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors , and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor , such as heroin or cocaine addictions .

fig1 shows an isometric view of the x - ray gantry apparatus of the invention . a vertical standard 10 is fixed via shock mounts indicated at 12 and 14 to a mounting structure 16 , which in the preferred embodiment may comprise the body of a van or other vehicle . in the preferred embodiment , standard 10 is fabricated in box section form of aluminum plates bolted together , but this is not critical to the invention as claimed . disposed on either side of the standard 10 are guide rods 20 on which a first carriage 22 moves vertically along the z - axis . the carriage 22 is supported on the guide rods 20 by conventional linear bearings . a drive unit 24 rotating a lead screw 24a located within the standard 10 is employed to drive the carriage 22 and the associated x - ray apparatus vertically with respect to standard 10 , that is , along the z - axis . a locking member 26 may be provided to lock the first carriage 22 in any desired vertical position , both during patient examinations and for security of the apparatus during travel . the locking device 26 may simply comprise a screw which is tightened by a lever 28 to bear against the face of the standard 10 . the shock mounts 12 , 14 can be chosen from a wide variety of commercially available units in accordance with the weight of the unit and its anticipated use in vehicles . a horizontal arm assembly 30 is mounted on the carriage 22 . the horizontal arm assembly comprises a splined shaft 192 ( shown in phantom in fig1 ; see fig5 ) which extends from a horizontal drive unit 32 into a second carriage indicated generally at 34 . the second carriage 34 is mounted to the splined shaft 192 by a linear ball bushing , such that the second carriage 34 is movable along the horizontal shaft 30 , that is , along the x - axis . the horizontal arm assembly 30 remains horizontal , such that no motor unit is required to drive the carriage 34 along the x - axis ; use of the splined shaft 192 provides low friction movement of the carriage 34 such that minimal effort is required to move the carriage 34 through its travel along the x - axis . the splined shaft 192 is rotatable about the x - axis by the motor unit 32 such that the second carriage 34 and the assembly it carries ( to be described below ) are likewise pivoted about the x - axis . the motor unit 32 may comprise an electric motor connected through a gear train or chain reduction unit to the splined shaft 192 , possibly by way of an intermediate rigid second shaft . in the preferred embodiment , an electric brake is provided on the shaft 192 , such that in the event of failure of the gear train or chain or otherwise the carriage assembly 34 is prevented from unrestrained pivoting . the electric brake may be arranged such that in the event of loss of power to the gantry of the invention , it is actuated to lock shaft 192 and the associated assembly against rotation . see fig5 . a locking member 40 is also provided , which comprises a screw extending through an arcuate slot 42a in a sector 42 . thus , when the screw is tightened , either to lock the apparatus for patient examination or for travel , the sector 42 bears against the first carriage 22 , restraining the second carriage assembly 34 from rotation about the x - axis . a further lock 50 may be provided to restrain the carriage assembly 34 from motion along the x - axis , again both in use and for travel . as indicated above , second carriage 34 is supported on the horizontal arm 30 by a linear ball bearing 190 ( shown in fig5 ) which allows it to move freely along the x - axis . the outer race of the linear ball bearing 190 is affixed to a block 52 comprising the principal element of second carriage 34 . a second outer race of a second linear ball bearing 154 is also fixed to block 52 , and the corresponding splined shaft 150 , extending along the y - axis , is an integral part of transverse arm 54 . see fig4 described below . in this case , the combination of the splined shaft 150 and the second linear ball bearing 154 within the block 52 permits motion of x - ray apparatus support plate 60 back and forth along the y direction . in the preferred embodiment , movement of the x - ray support plate 60 and the associate x - ray apparatus along the y - axis is controlled by a hand screw 64 operating a conventional lead screw arrangement . see fig4 . this motion is locked by a lock 70 which bears directly on the shaft 54 . rotation of the x - ray apparatus 76 , 78 about the y - axis is provided by rotating the support plate with respect to the splined shaft 150 ( see fig4 ) within arm 54 . in a currently preferred embodiment of the invention , a motor is provided for rotating the plate 60 and the associated x - ray apparatus 76 , 78 with respect to the shaft 54 . this assembly is detailed in connection with fig4 . however , it will be recognized by those of skill in the art that alternative arrangements would be possible , and these are believed to be within the scope of the invention where not specifically excluded by the claims hereof . rotation of the support plate 60 and the associated x - ray apparatus about the y - axis is locked by a further lock member 86 which is detailed below in connection with fig4 . as indicated above , the gantry assembly of the invention is particularly designed for supporting x - ray apparatus for detection of lead toxicity in patients using an x - ray fluorescence technique . this apparatus comprises a source of x - ray energy indicated generally at 76 and a detector indicated at 78 . see wielopolski et al , supra , for further details . however , the utility of the gantry of this invention is not limited to that particular application . note that to the extent the y - axis defined by the transverse arm 54 is varied upon rotation of arm 54 about the x - axis , the y - axis is no longer literally &# 34 ; orthogonal &# 34 ; to the z - axis . reference herein to the &# 34 ; y - axis &# 34 ; is generally meant to refer to the axis defined by arm 54 , unless the context indicates otherwise , whether or not this is at any particular time literally at 90 degrees to the z - axis defined by standard 10 . fig1 shows one embodiment of the caging arrangement which is suitable for supporting the support plate 60 of the apparatus of the invention during travel . the caging arrangement includes first and second caging arms , 80 and 82 respectively . in this embodiment , first caging arm 80 is mounted to the mounting structure 16 ( which as noted may be a vehicle ) by a shock mount or other vibration - damping arrangement . the other end of the caging arm 80 is releasably fixed to the support plate 60 by any manner of convenient , yet rigid locking means . the second caging arm 82 is mounted to the standard 10 , again by a shock mount , and its outer end is similarly releasably fixed to the support plate 60 . in this way support for the support plate 60 is provided in orthogonal directions , whereby it is rigidly fixed with respect to the vehicle during travel . a second embodiment of the caging arrangement which is presently preferred is shown in connection with fig2 . as noted , fig2 shows the presently preferred embodiment of the caging arrangement . in this case first and second caging arms 100 and 102 are attached to the mounting structure 16 ( which , again , may be the body of a vehicle ) by shock mounts 104 , 106 respectively . as indicated , the caging arm 100 , 102 are each hinged to the mounting structure 16 by hinges 100a and 102a , the axes of which are orthogonal to one another . the axis of the hinge 100a of the first caging arm 100 is vertical , such that in order to secure the gantry for transit , the arm 100 is swung outwardly from a position in which it is parallel to the mounting structure 16 to a position at right angles thereto . caging arm 100 is then rigidly fixed to the support plate 60 by locking assemblies 130 , which are discussed below . the axis of hinge 102a by which arm 102 is fixed to the vehicle is horizontal , such that the second caging arm 102 is swung downwardly from a vertical position to the horizontal in order to secure support plate 60 for travel . arm 102 is then similarly fixed to plate 60 by locking assemblies 130 . as indicated in fig2 in the caged or &# 34 ; home &# 34 ; position as secured for travel , the support plate 60 and the x - ray apparatus indicated generally at 78 are horizontal . in use , the support plate 60 and the x - ray apparatus are typically disposed in a vertical position as shown in fig1 . however , the invention is not so limited . therefore , when it is desired to arrange the apparatus of the invention for use , the caging arms 100 , 102 are detached from the support plate 60 , to which they are attached by the structure detailed in connection with fig3 and pivoted to positions against the mounting structure 16 , which again may be the wall of a vehicle . the support plate and x - ray apparatus are then moved into a desired position for use . as will be appreciated by those of skill in the art , the caging arrangement shown in fig2 employing two caging arms with orthogonal pivot axes directly restrains movement of the support plate 60 itself and the associated x - ray apparatus against motion in orthogonal directions . this provides the maximum possible protection of the x - ray apparatus against vibration damage during travel , and avoids reliance on the rigidity of the remaining elements of the gantry of the invention for this restraint during travel . more specifically , any freely pivoting hinge will allow some motion of the hinged member along the axis of the hinge pivot . by provision of the plural caging arms with orthogonal axes , each arm prevents motion of the support plate along the axis of the other caging arm . in this way , when secured , the support plate 60 together with the caging arms 100 and 102 make up a rigid unit fixed to the support member 16 by the shock mounts 104 , 106 . fig3 shows a cross - sectional view along the line 3 -- 3 of fig2 and details a typical locking assembly 130 by which arms 100 and 102 may be releasably fixed to the support plate 60 for travel . in this case , the support plate 60 comprises a side member 110 . the caging arm 100 comprises a main member 112 , which is stiffened by a second member 114 . the main member 112 is juxtaposed to the side member 110 when the caging arm 100 is fixed to the support plate for travel . a threaded locking bolt 116 extends through the main member 112 into a threaded hole in the member 110 , locking the two together . preferably , the bolt extends through a slot 120 in the member 112 permitting some variance of the relative position of the support plate 60 in the home or locked position . the bolt 116 may be retained in the slot 120 by a threaded washer 124 . the washer 124 fits within a counterslotted recess 126 in the face of the member 112 . the bolt 116 may be fitted with a bar 128 to ease its rotation by the medical technicians who operate the x - ray apparatus , to ensure that the apparatus will be properly caged prior to travel . one or more essentially equivalent locking assemblies 130 may be provided on both caging arms 100 , 102 , again to ensure that the support plate 60 and the associated x - ray apparatus are appropriately secured to the vehicle itself via shock mounts 104 , 106 in transit . the slot on the arm 102 may extend orthogonal to the arm 100 for ease of securing . the tight fitting of the screws and their pivot arrangement with respect to the support plate gives great security to the arrangement . in particular , the washers 126 confine the bolts 116 with respect to the arms 100 , 102 . thus , when plural bolts 116 are provided , as on the left side of the assembly of fig2 they must each be tightened or loosened progressively . this provides further security to the arrangement . preferably a microswitch 200 is mounted on a bracket 202 such that it is actuated when the bolt 116 is tightened home . the microswitch 202 is connected in circuit as indicated at 204 with an alarm 206 and the ignition of the associated vehicle , such that if the vehicle is moved when the support plate is not caged , the alarm is sounded . this allows the vehicle to be moved quickly , e . g ., in emergency situation but would prohibit long drives with the support plate not caged . fig4 shows a detail of the assembly of the transverse arm 54 and the support plate 60 and the x - ray apparatus 78 . fig4 is essentially a cross - section along the y -- y axis in fig1 ; however , some parts have been displaced from their positions in the preferred embodiment of the invention , for clarity of the view . in particular , the horizontal arm 30 is shown beneath the transverse arm 54 . as indicated above , the second carriage assembly 34 comprises a block member 52 which receives the horizontal arm 30 and also the transverse arm 54 . as indicated above , horizontal arm 30 is rotated by motor assembly 32 to rotate this entire assembly about the x - axis . as shown in detail in fig4 the transverse arm 54 comprises a second splined shaft 150 which is threaded to a hand screw 64 to move the support plate assembly 60 back and forth along the y - axis , as discussed above . this motion is facilitated by employment of the splined shaft 150 in connection with a second linear ball bushing assembly 154 received within the block 52 . mounted on the end of the splined shaft 150 is a bearing 156 , shown as a single ball bearing ; plural bearings can be used to reduce the specific loading if desired . to the outer race of this ball bearing is mounted a gear 158 , which is engaged with a pinion gear 160 driven by a motor 162 , which is fixed to shaft 54 . a plate . 164 is also fixed to the shaft 54 by screws 166 . the support plate 60 is mounted on gear 158 as shown , such that when the motor 162 is energized , the support plate 60 and the associated x - ray apparatus 78 are pivoted about the y - axis . a locking assembly 86 is provided to lock the support plate 60 against rotation , during patient examination and during movement of the device . this assembly 86 comprises a bolt 184 which extends through an arcuate slot in plate 164 and is threaded into a post 182 fixed to the support plate 60 . bolt 184 frictionally engages the stationary plate 164 against the post 182 when tightened by rotation of handle 180 . a cover plate 186 rotating with plate 60 may be provided to keep the patient &# 39 ; s hair , clothing , jewelry , etc . out of the gear assembly and to prevent entry of dust . a similar locking assembly 70 is provided to lock the motion of transverse arm 54 with respect to the second carriage 34 . the assembly shown in fig4 thus provides hand screw adjustment of the position of the support plate 60 along the y - axis and allows rotation of the support plate 60 with respect to shaft 54 , that is , rotation about the y - axis . as discussed above , it would also be possible to power the motion of the shaft 54 along the y - axis , but this would substantially complicate the actual construction of the device and is , therefore , not provided in the presently preferred embodiment of the invention . a counterweight 66 ( fig1 ) is provided opposite the x - ray apparatus 78 to limit the physical effort required to move this assembly along the y - axis . fig5 shows a view through a portion of the x - axis , illustrating the manner in which the second carriage 34 is assembled to the horizontal arm 30 . a linear splined member 192 runs within the horizontal arm 30 . block 34 rides on splined member 192 by way of recirculating linear ball bushing 190 . this allows very easy movement of the entire assembly carried by the second carriage 34 , including the support plate 60 , the x - ray apparatus 78 , the transverse arm 54 , and the counter weight 66 ( fig1 ), along the horizontal arm 30 . clamp 50 locks the second carriage assembly 34 at any desired position along the horizontal bar 30 . motor assembly 32 , comprising a motor 202 and a chain drive 204 , is connected to the splined member 192 to rotate the horizontal arm 30 , the second carriage 34 , and the associated apparatus . an electric brake 200 is provided to lock member 192 to first carriage 22 . the brake 200 may be arranged to lock the member 192 upon failure of the motor unit 32 by shearing a key , for example , in the chain drive 204 . this prevents the x - ray apparatus 78 from falling on the patient . lock 40 has the same function . the electric brake 200 may be arranged to lock member 192 to first carriage 22 upon loss of electrical power to the device . preferably the electric brake 200 is functionally connected to the ignition of the vehicle in which the gantry of the invention is employed , so that if the ignition is &# 34 ; on &# 34 ; the brake is locked . the other electrical controls of the gantry may similarly be disabled unless the ignition of the vehicle is &# 34 ; off &# 34 ;. preferably a patient chair is associated with the x - ray apparatus of the invention , and comprises a back , a seat , a cradle for receiving the patient &# 39 ; s leg , and a foot clamp for maintaining the foot and tibia in a fixed position during the examination . preferably the seat and back are tiltable and adjustable for height with respect to the cradle , and the overall assembly is also adjustable for height , thus providing substantially unlimited patient position adjustment for the convenience of the technicians operating the x - ray apparatus associated with the gantry of the invention . while a preferred embodiment of the invention has been described in detail , it will be appreciated by those of skill in the art that there are numerous alternatives and improvements thereto which can be made and which are intended to be encompassed within the scope of the invention . for example , it would be possible to drive the gantry of the invention through each of its three degrees of freedom in orthogonal directions , as well as through its two degrees of rotational freedom . similarly , there are additional features which can conveniently be added . in a preferred embodiment of the invention , each of the motions of the gantry which is powered is controlled by limit switches , such that the limit switches define the &# 34 ; home &# 34 ; ( i . e ., caged for transit ) and fully extended positions . exemplary limit switches 24b are shown in fig1 . accordingly , when it is desired to return the apparatus to its home position for transit the operator simply sets all the drive motors to move the device toward the home position . when the home position is reached , the limit switches cause the motors to stop , such that the device is automatically in its home position with respect to all powered dimensions of motion . this provides substantial operator convenience , and further aids in the long - term reliability of the gantry of the invention by simplification of the caging arrangement . many alternative arrangements of the drive devices as well as the support members and the like of the apparatus of the invention are considered to be within the skill of the art , given the disclosure of the invention provided above , as are the details of its construction , where not described specifically above . for example , in the above , the second carriage moves along the horizontal arm to provide movement along the x - axis . it would be equivalent to move the horizontal arm with respect to the first carriage . similarly , the transverse arm moves with respect to the second carriage to provide movement of the support plate along the y - axis . it would be equivalent to move the support plate with respect to the transverse arm . where the functional limitations of the following claims do not require otherwise , they are to be read as including these and like equivalents of the structure described . therefore , while a preferred embodiment of the invention has been described in detail , this is not to be considered a limitation on the invention but merely as exemplary thereof . instead , the invention is to be limited only by the following claims .

an improved gantry for an examination apparatus , such as an x - ray apparatus comprising a source of x - rays and a detector of fluoresced photons , is disclosed . the apparatus is particularly suitable for use in a vehicle such that the examination can be carried out at locations convenient to the patients . the apparatus comprises a vertical standard and first and second carriages . the first carriage is movable along the vertical standard and carries a horizontal arm . the horizontal arm carries the second carriage , which moves along the horizontal arm in a direction orthogonal to the axis of the standard . a transverse arm carrying the x - ray apparatus is carried by the second carriage and moves with respect thereto in a third direction orthogonal to the first and second directions , so that three directions of motion along orthogonal axes are thus provided . additionally , the second carriage is rotatable about the horizontal arm providing a first direction of rotation . the x - ray apparatus is mounted on a support plate which is pivotable with respect to the transverse arm , providing a second degree of rotation . caging arms are provided which extend from the frame of the vehicle directly to the support plate and are readily fixed thereto , to confine the support table and the associated x - ray apparatus in transit . the caging arms and the standard are shock mounted to the vehicle such that any vibration occurring during travel is damped out .

referring first to fig1 it can be seen that in a two - dimensional truefisp - type mr pulse sequence , the time integrals of the slice - select gradient , the phase - encoding gradient , and the read gradient are all zero at the center of each rf pulse . the same is true for a three - dimensional truefisp mr pulse sequence ( fig2 ). as a result , the magnetization of the sample remains in a steady - state while lines of mr data are being acquired . turning now to the first preferred embodiment as schematically illustrated in fig3 the magnetizations of the heart and blood contained therein are initially brought to steady - state by applying the same rf pulses that are later used during acquisition of mr data . the patient &# 39 ; s cardiac cycle is monitored and used to gate data acquisition prospectively ; acquisition of lines of mr data commences when an r - wave is detected . then , lines of mr data are acquired over e . g . 15 cardiac cycles . if for example each k - space matrix is chosen to have 165 lines , eleven lines ( a “ segment ”) might be acquired during each cardiac cycle so that each k - space matrix is filled after 15 cardiac cycles . in one possible implementation , lines 1 , 16 , 31 , 46 , 61 , 76 , 91 , 106 , 121 , 136 , 151 might be acquired during the first cardiac cycle . then , lines 2 , 17 , 32 , 47 , 62 , 76 , 91 , 107 , 122 , 136 , 152 might be acquired during the second cardiac cycle . lines 3 , 18 , 33 , 48 , 63 , 77 , 92 , 108 , 123 , 136 , 153 might be acquired during the third cardiac cycle , and this process would be continued until all 165 lines of mr data had been acquired to fill up the full k - space matrix for each image in the cine series . ( the order in which the lines of mr data are acquired need not be as stated . for example , it would also be possible to acquire lines 1 - 11 during the first cardiac cycle , lines 12 - 22 during the second cardiac cycle , and lines 23 - 33 during the third cardiac cycle , and so on . the order in which the lines of mr data are acquired is not part of the invention .) if it is assumed that 220 lines of mr data are acquired during each cardiac cycle , then at the end of a single breath hold sufficient data will have been acquired to fill up twenty 165 - line k - space matrices . accordingly , twenty mr images can be reconstructed to form a 20 - image cine loop , and the image loop displayed . echo - sharing and other data interpolation techniques can be used to arbitrarily increase the number of reconstructed images . in this first preferred embodiment , acquisition of lines of mr data will likely occur during only a fraction of each cardiac cycle . hence , there will be a period between the end of mr data acquisition in a current cardiac cycle and the beginning of mr data acquisition in the next cardiac cycle . during this period , rf pulses must be continued , to keep the magnetizations of the heart and blood in steady - state . if these pulses are not continued , the magnetizations of the heart and the blood will die out and will not be in steady - state at the beginning of the next cardiac cycle , when mr data acquisition begins once again . in accordance with the second preferred embodiment of the invention as is schematically illustrated in fig4 lines of mr data are acquired continuously during a single breath hold while the patient &# 39 ; s cardiac cycle is monitored . then , the acquired mr data are retrospectively gated , reconstructed into cine mr images , and displayed . a segmented truefisp mr pulse sequence was implemented on a 1 . 5t magnetom sonata ( siemens medical systems , iselin n . j .) with a high performance gradient system ( 40 mt / m amplitude , 200 t / m / sec slew rate ). echo - sharing was used to improve temporal resolution . the basic truefisp timing module used has tr = 4 . 0 ms and te = 2 . 0 ms . segmented truefisp pulse sequences with various numbers of lines per segment have been implemented . typical imaging parameters for an 11 line / segment segmented truefisp sequence are 165 × 256 pixels with dimensions of 1 . 5 mm × 1 . 25 mm × 6 mm slice thickness acquired over 15 heartbeats . the flip angle ( α ) is set to the maximum allowed by sar ( specific absorption rate ) limitations in each patient ; it is typically in the range of 50 ° to 70 °. the receiver bandwidth ( sampling rate ) was 780 hz / pixel . a cp 4 - channel phased array body coil was used . the above example is merely exemplary , and the various parameters can and should be varied in accordance with the patient &# 39 ; s condition and the intended use for the results of the mr study .

a segmented cine mr pulse sequence of the “ truefisp ”- type having a short repetition time tr is used to acquire mr data during a single breath hold . in the resulting cine images , the blood and the myocardium have distinctly different image contrasts .

reference numeral 10 generally identifies a bag or purse carried by a strap 12 having a length adjustable between a shorter length depicted in fig1 and a longer length depicted in fig4 . the bag 10 includes an outer shell or container 14 , and an inner liner 16 located within the container 14 and bounding an interior space 18 therewith . the container 14 may have any shape and , as shown , the shape of the container 14 is a parallelepiped having spaced - apart end walls 20 , 22 ; spaced - apart side walls 24 , 26 ; a bottom wall 28 ; and a top wall 30 openable and closeable by a zipper 32 . the container walls may be constructed of leather , vinyl , fabric , or any other flexible , non - rigid material commonly used in the art of making bags . the container walls are conventionally sewn or fused together . the liner 16 is preferably also made of flexible , non - rigid material such as cloth or plastic material and covers the interior surfaces of the end , side and bottom walls of the container . the liner 16 is preferably sewn in place . as best seen in fig2 and 5 , a pair of first fasteners or prongs 34 , 36 is mounted on wall portions of the container that are spaced apart of each other . the prongs 34 , 36 extend outwardly of the end walls 20 , 22 and have enlarged heads 38 , 40 . the strap 12 extends longitudinally between opposite strap ends 42 , 44 and has a succession of second fasteners or holes 46 , 48 , 50 , 52 spaced longitudinally along the strap . the holes 46 , 48 are spaced apart by a shorter distance as compared to the spacing between the holes 50 , 52 . if a user wishes to carry the bag with a shorter strap , as shown in fig1 then the holes 46 , 48 are selected to mate with the prongs 34 , 36 . otherwise , if the user wishes to use the longer strap of fig4 then the holes 50 , 52 are selected to mate with the prongs 34 , 36 . each head 38 , 40 is slightly larger in cross - section than a respective hole so that the head must be forced through the respective hole . the material surrounding each hole yields to permit entry of the head . the strap is made of yieldable material such as leather , vinyl and the like . once through , the hole freely receives the prong . the head insures that the strap will stay in place on the prong unless forcibly pulled in the opposite direction through the hole to make another adjustment . the aforementioned strap ends 42 , 44 are not left dangling from the prongs . instead , the strap ends 42 , 44 are inserted into openings 54 ( see fig3 ) into the interior space 18 between the container and the liner . fig2 depicts how the longer strap ends 42 , 44 extend along the end walls 20 , 22 and along the bottom wall 28 . fig5 depicts how the shorter strap ends 42 , 44 extend only partially along the end walls 20 , 22 . in either case , the strap ends are received in the interior space and concealed from view . in alternate embodiments , more than two pairs of holes can be provided along the strap for greater adjustment versatility . it will be understood that each of the elements described above , or two or more together , also may find a useful application in other types of constructions differing from the types described above . while the invention has been illustrated and described as embodied in a bag with adjustable carrying strap , it is not intended to be limited to the details shown , since various modifications and structural changes may be made without departing in any way from the spirit of the present invention . for example , the first and second fasteners can be replaced by hook and loop fasteners , or by magnetic fasteners . without further analysis , the foregoing will so fully reveal the gist of the present invention that others can , by applying current knowledge , readily adapt it for various applications without omitting features that , from the standpoint of prior art , fairly constitute essential characteristics of the generic or specific aspects of this invention and , therefore , such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims .

an adjustable length strap for a bag has strap ends received and concealed within an interior space for an aesthetic appearance in which dangling strap ends , buckles and bulky , folded strap portions are avoided .

the present invention is an innovative device for the amelioration of snoring , light and airborne disease vector transmission . the device is a shield , cleverly constructed of inflatable tubes to form an integral horizontal base and vertical shield . the base comprises an stretched oval tube , with long sides and short ends , as portrayed in fig1 . there is a long , narrow solid film filling the horizontal interior of the oval . the vertical surface is comprised of a hollow tube in the form of a semicircular arch . as in the base , the interior of the vertical arch formed by said hollow tube is filled by a solid film . the shield thus formed has no air spaces or gaps in the surface . said solid films may be opaque or transparent . the effect of the film and tube is that the base also forms a tray , with the solid film forming the base of the tray , and the oval tube forming a rim or lip . while this device is primarily intended for use in and on a bed , it will be apparent to the reader that it can also be used in other common sleeping areas , including but not limited to : tent , rv , boat , futon , automobile , campsite , air mattress , and the like . it can be used outdoors on the ground , preferably on a relatively level site . in the preferred embodiment of the invention , the device is constructed of plastic , preferable polyethylene or polyvinyl chloride , the latter widely know by the acronym pvc . the device is more preferably constructed entirely of pvc , of 0 . 2 - 1 mm thickness , more preferably about 0 . 4 mm in thickness . preferably this is of a high degree of purity , such that the resulting device can be made transparent . in the preferred embodiment , the tubes are a uniform 3 inches in diameter . the solid portion of the vertical wall is a plastic sheet in the form of a semicircle of diameter of approximately 10 inches . the vertical arch tube ends at the solid base , just inside the curve of the oval tube of said base . again in the preferred embodiment , the overall height of the shield at the apex of the arch is about 16 inches . the length of the shield along its long axis is preferably about 24 inches . when viewed on end , as displayed in fig3 the shape of the shield appears as an inverted “ t ”, with the preferred width of the short horizontal dimension about 9 inches , and the width of the longer vertical dimension about 3 inches , since the longer dimension is comprised of only 1 tube ( the arch ). preferably the invention is constructed very simply of two distinct and separate tubes , one forming the arch , and one forming the oval base , with solid film filling the interstices thus formed . preferably the tubes are sealed from each other and the environment . also preferably , each tube is fitted with one nozzle . often the user of this invention will prefer simply to fill the tubes with air . yet this arrangement allows the user of the invention to fill the vertical arch tube with one type of fluid , and the base oval tube with another . this allows for the base to be weighted , if desired , by the filling of the base tube with a dense liquid , while filling the vertical arch with air or other gas . preferably the fluid used to fill the device will be compatible with the material of construction of said device , in order to prevent leaks of said fluid . in the preferred embodiment , the shield is constructed entirely of transparent plastic , as described above . this leads to another feature of the invention . if the user so desires , one or both tubes may be filled with a colored fluid , thus imparting color to the device . since the tubes are sealed from each other , different fluids of differing colors may be used in the two tubes to produce a pleasing visual effect . in a useful alternative embodiment , the shield is constructed entirely of opaque or colored plastic . in this embodiment , the shield is useful as a light blocker , for instance to shield the sleeper from daylight , or from light sources at night . the preferred embodiment forms a tray in the base of the shield , between the two ends of the vertical arch . this tray is quite useful for storing handy small bedside articles , including but not limited to : remote controls , medicine bottles , baby bottles or pacifiers , and the like . a useful feature of the present invention is its unibody construction . unlike multi - component devices , the present invention has no pieces which are at risk of being lost or mislaid , which loss could render said multi - component devices useless . furthermore , the present invention is deflatable , allowing for convenient storage of the device when not in use . in a current embodiment , an actual model produced by the inventor deflates and folds to a 10 in × 10 in square , of only ½ in thickness . said thickness is limited primarily by the size of the nozzles attendant to the invention . larger nozzles allow faster and easier filling , at the expense of larger thickness of deflated shield . it will be apparent to the skilled reader that this description of the present invention , both in text and as shown in the accompanying drawings , should be interpreted as illustrative and not in a limiting sense to the invention herein contemplated .

the present invention comprises a lightweight , portable guard to separate two people sleeping in a common area . the invention serves to block a great deal of the noise attendant to snoring , and to shield to some degree the transmission of airborne spray emanating from the mouth of a sleeper , and optionally to shield light reaching the sleeper . the device is portable , inflatable with air or a similar innocuous fluid , and easily deflatable for compact storage after use .

in view of the limitations now present in the prior art , the present invention provides new and useful features and mechanisms for the incision of the coronary artery and myocardium . the present invention utilizes an alignment means to properly position a cutting means , a cutting means to perform cutting of the coronary artery and myocardium , a dilating means to expand the vessel and a perfusing means to supply blood to the distal portion of the vessel . the alignment means , cutting means , and perfusing means are contained in an endovascular catheter ( s ). preferably , the catheter is formed with a guidewire lumen which extends the = rough the length of the catheter and through which a guidewire may be run . the guidewire may be chosen from a variety of medical guidewire types well known in the art . when properly placed into position from the periphery , these embodiments , in coordination with one another , are used to reconfigure the blood vessel to a desired new geometry . once the reconfiguration is completed the catheter is then retracted and the entry wound sealed . referring to fig1 a , an occluded coronary artery is shown . the artery 16 is beneath the pericardium 14 . the artery 16 sits atop the epicardium 12 and the myocardium 10 . as can be seen , the lumen 20 is occluded by a stenosis 18 . referring to fig1 b , the same artery 16 is shown after coronary artery incision and dilation . the stenosis 24 has been expanded , leaving a larger lumen 20 . the myocardium 12 has been incised 23 . dilation may be performed by a traditional angioplasty balloon , with the attendant stoppage of perfusion noted . in such case , the balloon may be inflated by means well known in the art . an improvement ( called herein the “ expanding bands ” technique ) on the angioplasty balloon is the collapsible mechanical method shown in fig2 a and 2b . as shown in fig2 a , a catheter 28 may be guided to the coronary artery ( not shown ) by a guide wire 32 . such a guide wire 32 is of the type generally used for angioplasty procedures and is inserted through a guide wire lumen ( not shown ) formed in the catheter 28 . the catheter 28 is shown foreshortened , but may be of any suitable length , able to conveniently reach from the point of insertion to the stenosis to be treated . a portion of the outer circumference of the distal end 30 of the catheter 28 is made from a stiff flexible material , being an expander 36 . a compressor or 38 is attached by a cable or wire ( not shown ) to a controller 34 , proximal end 26 of the catheter 28 which , when pulled , causes the compressor 38 to move toward the proximal end of the catheter 28 . fig2 b shows a controller 34 moving in the direction shown 36 from the proximal end of the catheter 28 , and likewise the compressor 38 moving in the direction shown 34 , causing the expanders 36 move outward away from the central axis of the catheter 28 . one or more expanders 30 can beneficially be utilized . they need not surround the circumference of the catheter 28 , but rather can be utilized in conjunction with co - located cutting means . an advantage of the chef &# 39 ; s hat technique is that perfusion can continue in the interstices between the expanders when expanded . for example , fig3 a shows an example of a “ sliding retractable blade ” cutting means 38 . the cutting means comprises a blade of 40 controllable by a control wire 42 running through the catheter 28 to the proximal end 26 . in fig3 a , the blade 40 is shown retracted and attached to a controller 34 . when operated by the controller 34 , as shown in fig3 b blade 42 has extended to a depth 42 and has moved an incision length 44 . the operation of the sliding retractable knife means may be seen more clearly in fig4 a through 4d which show a cutaway view of a portion of the catheter 28 containing the sliding retractable blade 40 . in fig4 a , the blade 40 is shown fully retracted . an upper control slot 46 and a lower control slot 48 are shown on one side . in operation , there would be one upper and one lower control slot on each side of the catheter 28 . the blade 40 has an upper control pin 50 fitted into the upper control slot 46 , and likewise a lower control pin 52 fitted into the lower control slot 48 . as the blade 40 is pulled toward the proximal end of the catheter 28 upper control pin 50 forces the blade 42 rotate counterclockwise 54 . as seen in fig4 c , when upper control pin 50 has reached the highest point in upper control slot 46 , the blade 40 has fully extended . in fig4 d , the blade 40 is again fully retracted , forced by control pin 52 rotate clockwise 56 . as will be seen below , the cutting means , such as the sliding retractable blade , can beneficially be held in place during operation by the dilation means . in some implementations , the dilation means and cutting means may be co - located in the same longitudinal section of the catheter 28 . use of co - located cutting and dilation means , especially in instances where the dilation means allow continuing perfusion during the procedure , permits more positive control of the cutting means with respect to length and depth of cut . fig5 a shows a cutaway view of a “ scissors jack ” type cutting means . in this embodiment of the scissors jack , a stationary member 58 is held in position with the aid of braces 59 and 61 attached by swivel ( not shown ) to nuts 62 and 64 , respectively and similarly attached to stationary member 58 . a blade 60 is attached by swivels ( not shown ) to adjustable braces 67 and 68 which in turn are attached by swivels ( not shown ) to nuts 62 and 64 . adjustable braces 67 and 68 are constructed and attached so as to inhibit motion side to side ( that is , in and out of the page in fig5 a .) as shown in fig5 b , screw rod 63 has been turned by controller 34 , causing nuts 62 and 64 move away from one another , causing the blade 60 to extend from the side of the catheter 28 . this may be accomplished by having the distal end of the screw rod 63 oppositely threaded from the inner portion of the screw rod 65 , and likewise nuts 64 and 62 oppositely threaded . when nuts 62 and 64 are moved away from one another , it forces the blade 60 down by means of adjustable braces 67 and 68 . other implementations of a scissors jack to perform the same function and well - known in the art could be used beneficially . fig5 a and 5b show one embodiment of a dilating means used in conjunction with a scissors jack cutting means . it is not implied that this is the only dilating means described which may beneficially be used with the scissors jack cutting means . a balloon type dilation means 31 both in the unexpanded view in fig5 a and the expanded view in fig5 b . the balloon may cover all or a portion of the circumference of the catheter 28 except that portion wherein the cutting means extends beyond the circumference of the catheter 28 when co - located with the cutting means . the dilating means may be , as shown , co - located with the cutting means or placed elsewhere over the length of the catheter 28 and used sequentially with the cutting means by first dilating the stenosis and then performing the incision . it is beneficial , however , to co - locate the dilation means with the cutting means as it serves to hold the cutting means in position over the myocardium to be incised . fig5 c shows another embodiment of the scissors jack means wherein the side portions brace 58 is movable . either through a slot in the side of the catheter ( not shown ) or by replacing a portion of the side of the catheter with the member 58 , member 58 can hold the catheter in position against the wall of the artery ( not shown ). a cutaway view of transecting the catheter at the cutting means is shown in fig6 . the blade 60 is shown in retracted position . pushing members 69 , 70 and 71 comprise elements which are capable of protruding through the side of the catheter 28 . when retracted , they can form portions of the side of catheter 28 . fig6 b shows a portion of a catheter 28 with an extendable pushing member in the closed position . referring again to fig6 , an expanding side dilation means is shown with a scissors jack cutting means . pushing member 69 is supported and extendable by adjustable brace 73 , and pushing members 70 and 71 are supported and extendable by adjustable braces 72 and 74 respectively . the knife 60 is supported and extendable by adjustable brace 68 . fig7 is the same view , but with pushing members 69 , 70 and 71 shown in the extended position , with extendable braces 72 , 73 and 74 fully extended . likewise the knife 60 is shown extended , with extendable brace 68 fully extended . while shown with 3 pushing members , more or fewer pushing members may be used , and may be co - located with the cutting means or separate and used sequentially . when extended , pushing members 60 , 70 and 71 dilate the stenosis . this method of dilation supports simultaneous perfusion during dilation , which can continue during incision . referring to fig8 a , a cutaway view of a spiral knife cutting means is shown . a blade ( not shown ) is attached to a flexible but stiff membrane 75 , which is wound around a control rod ( not shown ) attached to a controller 34 at the proximal end of the catheter 28 . a guide 78 is provided to guide the blade and the stiff membrane 75 when in use . the material from which the stiff membrane 75 is made may be such as to have memory which causes it to straighten when not on around the control rod . fig8 b shows the same spiral knife cutting means with the blade 76 extended . controller 34 has been rotated in the direction 35 . fig8 c is a transected view perpendicular to the longitudinal axis of catheter 28 . the spiral of the flexible membrane 75 is wrapped around the hollow control rod 33 , through which guide wire 32 runs . just as easily , guide wire 32 could run outside and parallel to control rod 33 . an rf cutting wire means is shown in fig9 a , 9 b , 9 c and 9 d , shown in sequential steps of operation . an rf cutting wire is well known in the art , being basically a wire carrying an radio frequency signal the emission of which from the end region of the wire cuts the tissue . an rf cutting wire 86 is contained within a guide 92 , being a hollow tube . the end of the rf cutting wire 86 is shown retracted above in a cutaway view of a portion of the catheter 28 . a slot ( not shown ) within which they rf cutting wire 86 can extend and travel permits the rf cutting wire 86 when extended to protrude beyond the outer perimeter of the catheter 28 . a spacer 88 is placed between the proximal end of the guide 92 and a stop 90 attached to the proximal end of the rf cutting wire 84 . with the spacer 88 in place , the stop 90 pressing against the spacer 88 effectively prevents the rf cutting wire 86 from protruding beyond the outer perimeter of the catheter 28 . fig9 b shows the same rf cutting wire cutting means with the spacer 88 removed . the stop 90 has been moved proximate the proximal end of the guide tube 92 , thus allowing the stop 90 and rf cutting wire to move toward the distal and of the catheter the distance of the spacer 88 , plus enable in the rf cutting wire 86 to extend beyond the outer perimeter of the catheter 28 . referring to fig9 c , the guide 82 has been shifted away from the proximal end of the catheter 28 the distance of the desired cut . in fig9 d , the spacer 88 is then reinserted , thus moving the proximal end of the rf wire 84 and stop 90 a sufficient distance from the proximal end of the guide 92 to cause the rf wire 86 to withdraw inside the perimeter of the catheter 28 . a slot ( not shown ) in the bottom of the catheter exists to permit the rf wire to extend beyond the perimeter of the catheter 28 for purposes of performing the cut . the depth of the cut can be set by the size of the spacer 88 . a robotic movement and rotation device may be utilized to control the motion of the catheter 28 or rf cutting wire 86 or both . the stop , 90 can be in the form of an adjustable stop , allowing a variable depth of cut , and too , can be controlled robotically . previously recorded data from and intravascular ultrasound or other sensing means which contours the interior of the artery may be used to control the robotic movement and rotation device to cut a curve in the artery and myocardium , thus not limiting the cut to a straight line or a fixed depth . alignment of the cutting means is important . in order to create the new desired vessel geometry , the cutting means may need to cut through the vessel wall and in the case of a coronary artery , into the supporting myocardium . therefore , it is important to position the cutting means so it cuts into the myocardium and not into the pericardium , or said another way , into the heart instead of away from the heart . alignment can be accomplished by several means . as described by lary in u . s . pat . no . 5 , 713 , 913 “ device and method for transecting the coronary artery ,” a radiographic means could be used . however due to the resolution of the x - ray systems and the fact that the heart is beating there may be difficulty in assessing the proper alignment of the cutting means as described by lary . more effective means for positioning the cutting means in the orientation that would cut into the heart is desirable . the present invention embodies several means to address this issue . fig1 shows a schematic diagram of the overall concept embodied in each of the suggested means . a stylized chest 100 with a heart 102 therein contained has a coronary artery 104 superposed about the heart 102 . a catheter 106 has been inserted in the artery 104 . the internal part 108 of the positioning means is shown in the on the surface of the catheter 106 farthest from the heart 102 . the external part 110 of the positioning means is shown above the chest 100 . the internal part 108 of the positioning means may be placed at different orientations with respect to the heart 102 and catheter 106 , such as on the part of the catheter closest to the heart 102 , depending upon the positioning means utilized . in cases where the alignment means involves an internal sensor , the sensor signal may be conveyed externally by means of one or more wires running to and extending from the proximal end of the catheter . for example , one could use an x - ray sensor on the catheter and an x - ray blocker in known orientation and position with respect to the cutting means such that the sensor would indicate the optimal position of the catheter to cut into the heart based upon the position of the x - ray emitter commonly used in the catheter lab to perform cine . another means of alignment is to position a magnet on the catheter with one pole pointed in the proper orientation and the other end treated to optimize the field in conjunction with a magnetic sensor located outside the chest will allow proper positioning of the catheter and attached cutting means . alternatively , the magnetic field can be applied from outside the body , and a sensor such as a hall effect switch or fluxgate chip which is attached to one or more wires running the length of the catheter from the distal to the proximal end . shielding of the internal sensor may be used to inhibit triggering when the catheter is not in the optimal position . another means of alignment is to position an antenna on the catheter with one side collecting an emitted signal from outside the chest and the other treated in such a means as to indicate which side is facing the outside of the body , or away from the heart . again , shielding may be used to inhibit signal reception when the catheter is not in optimal position , another means of alignment is to position a transmitter on the catheter with one side emitting a signal and the other treated so as to block the signal , thus indicating to an external sensor which side is facing toward the outside of the body and therefore knowing that the cutting means is facing the heart . another means of alignment is to provide a light sensor on the catheter which can sense a light source that passes through the body from outside the body and therefore indicate the relationship between the sensor and emitter . knowing the relationship between the sensor and the cutting means enables positioning the cutting means . if the sensor is placed on the catheter away opposite the cutting means , a peak signal indicates the cutting means is placed toward the heart . the sensor can be shielding to inhibit light reception an all but the optimal position of the catheter , that is , when the cutting means is proximate the heart . another means comprises utilizing the natural electrical signals from the heart muscles contracting as the alignment method . it is well published that the heart muscles emit electrical signals on a regular basis and these signals are currently used to map the heart for ischemic sections , those with little or no signal . the present invention can utilize a directional receiver such that when the receiver was positioned to receive the maximum signal it would be facing normal to the heart and into the heart , enabling positioning the cutting means by knowing the positional relationship between the sensor and the cutting means . the details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below . other features and advantages of the invention will become apparent from the description , the drawings , and the claims . the invention has been described in terms of particular embodiments . other embodiments are within the scope of the following claims . for example , the steps of the invention can be performed in a different order and still achieve desirable results . modifications and substitutions by one of ordinary skill in the art are considered to be within the scope of the present invention , which is not to be limited except by the following claims .

the invention describes includes a device and method for dilating a coronary arterial stenosis and for creating a transection in the myocardium . the transection creates a new artery composed partially of the old artery and partially of the normal healing tissue and myocardium . several dilating means are described , as well as several cutting means and alignment means by which the cutting means may be located and properly oriented . in operation , the dilating means , cutting means and alignment means are advanced in the distal end of a catheter , which may be guided into position by a guidewire .

referring now to fig3 and 4 , an apparatus indicated generally at 40 , used for assembling and disassembling shell 12 and liner 14 of teat cup assembly 10 according to one embodiment of the invention is shown . the apparatus 40 includes a left cover plate 44 , a right cover plate 45 , front spacer panel 46 a , top spacer panel 46 b , back spacer panel 46 c , and bottom spacer panel 46 d ( see , fig6 ) located between , and spacing apart , the left cover plate 44 , the right cover plate 45 , and feet 47 supporting the center frame in an upright position . the center frame 42 encloses part of a mechanism ( to be described hereinafter ) that drives operation of the apparatus ( see fig6 ). a housing , generally indicated at 48 , encloses other operating components of the apparatus including a pulling mechanism , indicated generally at 50 , and a cutter mechanism , indicated generally at 52 ( shown in fig4 with the housing 48 removed ), both of which will be more fully described below . those of ordinary skill in the art will readily appreciate the construction and operation of teat cup assemblies 10 , previously described herein . accordingly , additional details of construction and operation of the teat cup assembly 10 will not be described herein . a teat cup assembly receiving fixture , generally indicated at 54 , projects upward through the top surface of the housing 48 . the teat cup assembly receiving fixture 54 is mounted on a platform 56 cantilevered from the left cover plate 44 and comprises a generally cylindrical receiving tube 58 open at an upper end 60 and having an internal rim 62 ( fig4 ) forming a small opening 64 at the lower end thereof . the small opening 64 extends through the platform 56 . the receiving fixture 54 is configured to receive and hold the shell 12 of the teat cup assembly 10 , with or without the liner 14 . the receiving tube 58 has a diameter slightly larger than the diameter of the shell 12 so that the shell 12 can be received into the tube 58 through the upper end 60 and rest on the internal rim 62 to hold the shell within the receiving fixture 54 . a fixture slot 65 in the receiving tube 58 is configured to accommodate the air tube 19 when the teat cup assembly 10 is inserted into the receiving fixture 54 . the platform 56 of the teat cup assembly receiving fixture 54 is fixed to the left cover plate 44 using suitable brackets and fasteners ( not shown ), although other means of fixing the platform 56 may be used without departing from the scope of the invention . the apparatus 40 has the described teat cup receiving fixture 54 and associated pulling mechanism 50 and cutter mechanism 52 on the left side of the center frame 42 , and a substantially identical second teat cup receiving fixture 54 ′ and associated pulling mechanism 50 ′ and cutter mechanism 52 ′ on the right side of the center frame 42 such that the apparatus can assemble or disassemble shells 12 and liners 14 of two teat cup assemblies 10 simultaneously ( see fig5 ). corresponding parts on the right side of the apparatus 40 ( as seen in fig5 and fig5 a ) are designated by the same reference numeral with the addition of a prime . any apparatus capable of assembling and / or disassembling one or more shells 12 and liners 14 does not depart from the scope of this invention by reason of the number of shells and liners handled at the same time . the cutter mechanism 52 ( shown on the left side of fig5 a ) comprises a cutter cylinder 66 having a rod 66 a ( broadly , “ a blade driving device ”) and a blade 67 mounted on the free end of the rod 66 a . the cutter cylinder 66 pushes the blade 67 toward the left cover plate 44 to cut the barrel section 20 of the liner 14 ( as shown in phantom in fig5 a ) when disassembling the teat cup assemblies 10 . on the left side of fig5 a , the liner 14 ( in phantom ) is shown with the pulling mechanism 50 fully rotated , the cutter rod 66 a of the cutter mechanism 52 fully extended , and the barrel section 20 severed . in the illustrated embodiment , the cutter cylinder 66 is a modified model nr091 . 5dxp manufactured by bimba available from john henry foster company of st . louis , mo . naturally , air cylinders are not the only type of driving device coming within the scope of the invention . driving devices could include any actuator which may apply adequate force to move the blade 67 toward the left cover plate 44 to cleave the liner 14 . the cutter cylinder 66 is mounted on a plate 66 b attached to and depending from a free end of the platform 56 . a catcher 68 is pivotally mounted on the left cover plate 44 and extends through the housing 48 via catcher slot 69 ( fig3 ). a finger 68 a projects laterally outwardly from the catcher 68 and can be positioned generally above the teat cup assembly receiving fixture 54 . the catcher 68 is configured to pivot between a first position ( shown in fig7 ) wherein the finger 68 a is positioned away from the open end of the receiving fixture 54 so that the teat cup assembly 10 may be freely inserted or removed from the receiving fixture 54 and a second position ( fig8 and 9 ) wherein the finger 68 a is adjacent to the top of the teat cup assembly 10 in the receiving fixture 54 during either the assembly or disassembly cycle . the catcher 68 is positioned above the teat cup assembly 10 so that when the liner 14 is cut in two , the upper barrel section 20 of the liner 14 is retained within the receiving fixture 54 . one skilled in the art will appreciate that other methods of preventing the liner 14 from springing from the receiving fixture 54 when cut can be used without departing from the scope of the invention . moreover , the catcher 68 could be eliminated in another embodiment of the invention ( not shown ). fig6 illustrates the apparatus 40 with the housing 48 and the left cover plate 44 removed for clarity . the pulling mechanism 50 comprises a rack 70 positioned within the center frame 42 . in the illustrated embodiment , the rack 70 is a model # 14½ ° pa 00540g 88165 24 ″ ra 16 × 2 rack available from motion industries of quincy , ill . opposite sides 71 , 72 of the rack 70 have teeth 74 along the length of the rack 70 . an air cylinder 76 ( broadly , a “ rack driving device ”) is connected to the rack 70 by a rod 78 having a magnaloy alignment coupler 77 and provides the driving force to move the rack 70 upward and downward . a guide block 75 receives and guides the rack 70 in its vertical movements . in the illustrated embodiment , the air cylinder 76 is a modified model 505dxp air cylinder manufactured by bimba available from john henry foster company of st . louis , mo . it will be appreciated that other actuators may be used without departing from the scope of the present invention . the pulling mechanism 50 further includes a pair of pinion gears 80 rotatably mounted on the left and right cover plates 44 , 45 . as shown , the pinion gears are each a model # 14½ ° pa 00540g 91118 51684 , available from motion industries of quincy , ill . each pinion gear 80 has teeth 82 around the outer circumferential surface thereof for engaging the teeth 74 of the rack 70 . movement of the rack 70 in either direction causes the pinion gears 80 to counterrotate . a shaft 84 extends from the rotational center of each of the pinion gears 80 . each shaft 84 is fixed for conjoint rotation with its respective pinion gear 80 , and is supported by a pillow block 85 . an arm 86 projects radially from an outward end of the shaft 84 and is attached to the shaft with a pin . other structures for connecting the arm 86 to the shaft 84 may be used without departing from the scope of the invention . as will be explained more fully below , rotation of each pinion gear 80 causes the arm 86 to pivot about an axis of rotation a of the gear 80 . the pulling mechanism 50 ′ on the right side of the center frame 42 has the same components as described for the pulling mechanism 50 . arms 86 ′ and arcuate shoes 92 ′ are mounted for conjoint rotation with respective ones of the same pinion gears 80 which mount the shafts 84 . thus , the air cylinder 76 simultaneously operates pulling mechanisms 50 and 50 ′. a shoe 92 , ( broadly , “ a gripping device ”) is fixed to a distal end of each of the arms 86 . the shoe 92 is configured to engage the lower section 30 of the liner 14 that extends below the opening 17 at the lower end 16 of the shell 12 . in one embodiment , the shoe 92 has a generally arcuate shape . the curve of the arc extends in a direction around the axis a . thus , when the shoes 92 are in opposed relation , the space between remains substantially constant . other shapes for a shoe ( not shown ), such as a series of straight segments forming a generally curved section and the like are contemplated . additionally , a shoe can be bulb - shaped or other suitable shape for engaging the liner 14 . the arcuate shoe 92 suitably has a length between about 2 and about 6 inches , and more suitably has a length between about 3 and about 5 inches . the shoe 92 desirably has an engagement surface 94 for contacting the liner 14 and is made of a suitable high friction material , such as fiber - cork pads available from mcmaster - carr supply company of chicago , ill . the engagement surface 94 is also resiliently deformable , providing cushioning to prevent damage to the liner 14 . operation of the apparatus 40 is controlled using a fluid circuit illustrated schematically in fig1 . the circuit includes an activating switch 100 capable of being connected to a supply of compressed air through line 102 . in the default position of the activating switch 100 , the pressurized air is directed to the air cylinder 76 and cutter cylinders 66 , 66 ′ via line 103 so that all cylinders are retracted . by depressing and holding down knob 100 a , air is redirected through line 104 to the air cylinder 76 to cause the main rod 78 to extend . air cylinder 76 has flow controls 106 associated with it that are selected to cause the rod 78 to extend ( and retract ) at a predetermined rate . at the same time , air is also directed to a cutter selector switch 108 , which as shown in fig1 is open so that air cannot pass toward the cutter cylinders 66 , 66 ′. the cutter selector switch 108 is set this way for installation of the liner 14 into the shell 12 . turning the cutter selector switch 108 to the closed position to activate the cutter mechanisms 52 , 52 ′ allows air from the activating switch 100 to pass through the cutter selector switch 108 through line 110 to delay switch 112 . air cannot pass through the delay switch 112 until it is tripped when the rod 78 of the air cylinder 76 reaches its full extension . in one embodiment , a trip control 112 a of the delay switch 112 is positioned so that one of the arms 86 engages the trip control 112 a at the bottom end of its motion ( i . e ., in the position shown in fig9 ). when the delay switch 112 is tripped , air is allowed to pass to the cutter cylinders 66 , 66 ′ through lines 114 and 116 for cutting the liner 14 to disassemble it from the shell 12 . after the knob 100 a is released , the fluid circuit returns to its start position with the rods 66 a , 66 a ′ and 78 of the air cylinders 66 , 66 ′, and 76 in a retracted position . other control arrangements , including those employing electronic controls may be used without departing from the scope of the present invention . referring now to fig7 – 9 , upward and downward movement of the rod 78 of the air cylinder 76 causes corresponding upward and downward movement of the rack 70 . the linear movement of the rack 70 is translated into rotational movement of the pinion gears 80 through engagement of the teeth 74 of the rack with the teeth 82 of the pinion gears . for example , as the rack 70 is moved downward , one pinion gear 80 ( i . e ., the left gear in fig7 ) rotates in a clockwise direction and the other pinion gear 80 ( i . e ., the right gear in fig7 ) rotates in a counterclockwise direction causing the shoes 92 to move toward each other and down . when the rack 70 is moved in the upward direction , the one pinion gear 80 rotates in the counterclockwise direction and the other pinion gear 80 rotates in the clockwise direction causing the shoes 92 to move upward and then away from each other . as seen in fig7 , the arcuate shoes 92 begin in an upward orientation such that a gap between the arcuate shoes 92 is wider than the lower section 30 of the liner 14 . the engagement gripping surfaces 94 of the shoes 92 are not opposed to each other . in this start position , the air cylinder 76 has fully retracted the rod 78 and raised the rack 70 to its upwardmost position . the catcher 68 is pivoted back so that the finger 68 a is not above the teat cup receiving fixture 54 . the teat cup assembly 10 is placed in the receiving fixture 54 . the lower section 30 of the liner 14 extends downward and is free to pass through the platform 56 and between the arcuate shoes 92 . downward movement of the rack 70 causes the pinion gears 80 to rotate about their axes of rotation . the shoes 92 move toward each other and the engagement gripping surfaces 94 engage the lower section 30 of the liner 14 and pinch the liner 14 there between as shown in fig8 . further downward movement of the rack 70 causes the shoes 92 to pivot to a generally downward orientation as shown in fig9 . the engagement gripping surfaces 94 of the shoes 92 frictionally engage the liner 14 and pull the liner 14 in a downward direction . the elastomeric nature of the liner material allows the liner 14 to stretch and elongate without breaking . to assemble a liner 14 with a shell 12 , rim 18 of the shell 12 is inserted into cuff 26 of the liner 14 . the shell 12 is then placed into the receiving fixture 54 so that the lower section 30 projects below the opening 17 in the bottom of the shell 12 , but the sealing ring 28 is located within the shell 12 above the opening 17 . this description will focus on the assembly of one liner 14 with one shell 12 by pulling mechanism 50 on one side of the apparatus 40 , it being understood that a second liner and shell ( not shown ) could be simultaneously assembled by the apparatus 40 by the pulling mechanism 50 ′ on the opposite side . thus , the shell 12 and liner 14 are unassembled and there is no sealed chamber within the shell 12 for the application of a pulsating vacuum needed to milk a cow . the cutter selector switch 108 is turned to the open position so that the cutter mechanisms 52 , 52 ′ are inactive . the knob 100 a of the activating switch 100 is depressed and held down to initiate extension of the rod 78 from the air cylinder 76 . the shoes 92 engage the liner 14 and pull it in a downward direction until the sealing ring 28 on the liner 14 snaps through the opening 17 in the lower end 16 of the shell 12 . the sealing ring 28 of the lower section 30 of the liner 14 bears around the opening 17 and seals the liner 14 with the shell 12 . the cuff 26 of the head section 22 of the liner 14 bears around the rim 18 and seals the liner 14 with the shell 12 . in this way , the sealed chamber between the shell 12 and liner 14 is formed . the knob 100 a is released , causing the air cylinder 76 to retract the rod 78 and return the shoes 92 to the start position releasing the liner 14 . the upper mark 27 on the head section 22 of the liner 14 is now aligned with the lower mark 29 on the lower section 30 of the liner 14 . the assembled teat cup assembly 10 can be removed from the receiving fixture 54 and used for milking . the apparatus 40 can also disassemble the shell 12 and liner 14 . when disassembling the teat cup assemblies 10 , the cutter selector switch 108 is turned to the closed position so that the cutter mechanism 52 will be active . the teat cup assembly 10 , with the liner 14 sealingly attached to the shell 12 , is dropped into the receiving fixture 54 . the lower section 30 of the liner 14 extends through and below the platform 56 . the knob 100 a of the activating switch 100 is pushed down and held , causing the shoes 92 to move from the raised position in fig7 together and downward . the shoes 92 engage the liner 14 as they move downward , and are shown in fig8 at a mid - stroke position somewhat after the initial engagement with the liner . the shoes 92 continue downward , pulling liner 14 in a downward direction to the position shown in fig9 . the downward pull continues until the sealing ring 28 is below the blade 67 of the cutter mechanism 52 ( fig9 ). one of the shoes 92 presses the trip control 112 a of the delay switch 112 , causing the cutter mechanism 52 to rapidly extend to cut the liner 14 ( see fig5 a ). after releasing the knob 100 a , the shoes 92 move to the upward position . the lower section 30 and part of the barrel section 20 of the liner 14 including the sealing ring 28 fall down permitting the remainder of the barrel section 20 and head section 22 of the liner 14 to be easily removed from the shell 12 . the finger 68 a catches the head section 22 and prevents the barrel section 20 and head section 22 of the liner 14 from flying from the shell 12 and receiving fixture 54 when the elastic tension is released upon cutting the liner 14 . the shell 12 can then be reassembled with a new liner 14 as described previously . fig7 shows the delay switch 112 not engaged , the shoes 92 retracted , the rack 70 in the up position , and the arm 86 positioned away from the receiving fixture 54 . fig9 shows the delay switch 112 engaged , the shoes 92 in the fully rotated position , the rack 70 in the down position , and the catcher 68 extended over the receiving fixture 54 . when introducing elements of the present invention or the preferred embodiment ( s ) thereof , the articles “ a ”, “ an ”, “ the ” and “ said ” are intended to mean that there are one or more of the elements . the terms “ comprising ”, “ including ” and “ having ” are intended to be inclusive and mean that there may be additional elements other than the listed elements . as various changes could be made in the above without departing from the scope of the invention , it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense .

an apparatus for installing and removing a teat cup liner from a shell has a fixture which holds and retains the shell in position . a pair of shoes is capable of moving to engage a portion of the liner projecting from the shell to pull the liner downwardly . in an installation mode , the liner is pulled so that a sealing ring on the liner moves through a restricted opening into a sealing relationship with the shell at one end . the resiliency of the liner also causes a seal to be formed at the other end of the shell . in a removal mode , the liner is stretched by movement of the shoes in the same way as installation . a cutter of the apparatus is then activated to sever an end portion of the liner , including the sealing ring from the remainder of the liner , releasing the liner from the shell .

while the present invention is susceptible of embodiment in various forms , there is shown in the drawings and will hereinafter be described presently preferred embodiments with the understanding that the present disclosure is to be considered an exemplification of the invention and is not intended to limit the invention to the specific embodiments illustrated . the reference numeral 1 designates generally a cross connector for attachment to a pair of laterally spaced apart rods 3 l , 3 r ( fig1 , 3 ) secured to a spine 5 and positioned on opposite sides 7 l , 7 r of the spine . the rods 3 may be held in place via screw mounts 9 secured to a vertebra 10 . such screw mounts 9 are well known in the art . the rods 3 extend longitudinally between various vertebrae 10 and may be attached to alternate vertebrae 10 a , 10 c on alternate sides 7 l , 7 r . two forms of mounting of the connector 1 are shown , one form where the connector 1 is mounted between the rods 3 l , 3 r adjacent screws 9 attached to one vertebra 10 and one form where the connector 1 is mounted between the rods 3 l , 3 r with one rod at that location being mounted to one vertebra while the other rod is free of mounting to that vertebra to assist in straightening the spine 5 . that is , a rod 3 bridges one or more vertebrae without attachment thereto . the connector 1 , as best seen in fig2 , 3 , includes a pair of hooks 12 . preferably , the hooks 12 have substantially the same configuration and include a shank 14 , a bight 16 , a leg 18 and a latch 20 defining a throat 22 therebetween and a mouth 24 defined by the latch 20 and the shank 14 . as configured for use , the throats 22 of the hooks 12 open generally toward one another . preferably the hooks 12 are made of a metal and their component parts are integral . one hook 12 is shown as having an attached flexible connector 26 such as a multi strand metal cable on the order of ⅛ inch in diameter or smaller . as shown , the connector 26 is secured to a shank 14 and in use extends to the other hook 12 of a pair of hooks for securement thereto to effect mounting of the hooks each to a respective rod 3 by having a rod 3 positioned in a respective throat 22 after moving through a respective mouth 24 . the hooks 12 and the connector 26 form a connector hook assembly with flexible link when assembled . in a preferred embodiment , the hooks 12 have a generally rectangular transverse cross sectional shape particularly in the shank 14 . the edges and corners of a hook 12 ( and other components of the connector 1 ) are preferably rounded . the latches 20 may also be provided with inclined surfaces 27 to facilitate mounting to a rod 3 . one of the shanks 14 of a pair of hooks 12 is configured to be associated with the flexible connector 26 to form an attached hook assembly . as shown , the shank 14 of one hook 12 is provided with a through passage 28 extending along a portion of the length of the shank 14 . the flexible connector 26 is inserted into the passage 28 and has a free end portion 29 extend beyond the shank 14 for gripping by a tool 30 adapted to induce tension in the flexible connector 26 to effect attachment of the hook assembly to the rods 3 . when the appropriate amount of tension is in the connector 26 , the connector 26 and the hooks 12 are secured together to make an assembly as with a fastener 31 as described below . this attachment fixes the maximum spacing between the hooks 12 during use . other means of attaching the free end portion 29 of the connector 26 may be utilized . a rigid connector 34 is associated with the hook assembly and is operable to fix the hooks 12 against moving toward and away from one another and for tensile loading , it is redundant to the flexible connector 26 . the connector 34 can resist both tensile and compression axial loading while the connector 26 can resist axial tensile loading . the connector 34 can be loaded in tension to resist hook separation or divergence and in compression to resist convergence toward one another . as shown , the connector 34 has opposite end portions 35 for connection to the shanks 14 of hooks 12 and a central rigid load bearing portion 36 extending between the hooks 12 . each of the end portions 35 includes a pair of longitudinally extending fingers 38 with a channel 39 therebetween . the shank 14 of a hook 12 is received in a respective channel 39 and is sandwiched between the fingers 38 . as shown , the finger 38 in the throat 22 is positioned between a rod 3 and a shank 14 to lock it against bending . the outer fingers 38 overlie a respective shank 14 and can be used to secure the connector 34 to the shanks 14 . as shown , a fastener 31 , such as a set screw or a hex head screw may be threadably engaged in holes 41 and received in recesses 42 in the shanks 14 . in the hook 12 with the passage 28 containing the connector 26 , the fastener 31 may be used to engage the connector 26 to secure it to the hook 12 . the connectors 34 can be provided in various lengths to accommodate different spacings between rods 3 . shoulders 40 are provided in the channels 39 to abut the ends 43 of the hooks 12 to help resist movement of one hook 12 toward the other hook 12 when the connector 1 is assembled and installed . the connector 34 is also provided with means to allow the flexible connector 26 to extend between the hooks 12 preferably in a generally straight line . in the illustrated embodiment , an open sided groove 44 is positioned on the side of the central portion 36 and opens into each of the channels 39 . this allows for the mounting of the connector 34 to the assembly of hooks 12 . the mouth 24 has an opening size less than the cross sectional dimension of the throat 22 and preferably less that the diameter of a rod 3 plus the thickness of a finger 38 to be received therein so the hook 12 can lock onto a rod 3 after mounting on a rod . the latch 20 and leg 18 are preferably resiliently deformable to form a resiliently deformable lock . the channels 39 and the hook shanks 14 are configured to resist rotational movement of the shanks 14 on the connector 34 . the present invention is better understood by a description of the use of the cross connector 1 . a patient has rods 3 mounted to a spine 5 in laterally spaced relationship on opposite sides 7 l , 7 r of the spine . the rods 3 may have been previously installed or installed as part of the current procedure . preferably , the procedure for installing the connector 1 is done percutaneously . openings are formed on opposite sides of the spine 5 and a cannula or the like is inserted into each of the openings to provide access to surgical site . after rod installation , the rigid connector 34 , the flexible connector 26 with hook 12 and the unattached hook 12 may be moved into place through an opening on one side under the skin to bridge the spine for attachment to the rods 3 . as shown , the connector 1 may be mounted adjacent two rod mount screws 9 on one vertebra as at 48 or where there is a screw 9 for one rod in a vertebra and not the other rod so tension in the flexible connector 26 can either move a portion of the spine laterally or retain it in a less curved condition . an opening in the skin of the patient is made to provide access to the spine 5 and the rods 3 when installed . a hook 12 with the attached connector 26 is positioned in the surgery site and the connector 26 has its free end portion 29 exposed for access . the hook 12 is placed on a rod 3 . the rigid connector 34 is then moved into place with an installation tool 49 and the flexible connector 26 is positioned in the groove 44 and the shank 14 of the inserted hook 12 is positioned in its respective channel 39 at which time , the fastener 31 may be installed to couple the connectors 26 , 34 together . the tool 49 has a handle 55 and a shank 56 connected thereto . an end portion 57 is configured to have a connector 34 removably mounted thereon as with a cable 63 and threaded fastener 61 . a foot 60 is removably mounted to the connector 34 and the cable 63 as with a fastener 61 . the foot 60 may be provided with a tapered lead - in section 65 . the free hook 12 has the connector 26 inserted through the passage 28 with the free end portion 29 being exposed for attachment to a tensioning tool 30 . such a tool can function like a pop rivet tool or a cable tie tightener . the tool 30 tensions the connector 26 and pulls the hooks 12 together . the connector 34 has its fingers 38 guided over the shanks 14 with the shanks each moving into a respective channel 39 if not already there . tensioning the connector 26 also urges the rods 3 to each move through a respective mouth deforming a respective latch 20 to move into a respective throat . the rods 3 may each already be positioned in a respective throat 22 and a finger 38 may move into the throat 22 to lock the rod 3 in a respective throat . when the appropriate tension is reached , the holes 41 are properly aligned each with a respective recess 42 and the shoulders 40 abut the ends 43 of the shanks 14 , the fasteners 31 may be installed and tightened to secure the connector 1 as an assembly and to retain tension in the connector 26 if desired . the free end portion 29 of connector 26 may cut off if desired . when installed , the connector 1 can maintain a spine &# 39 ; s lateral curvature and can also be used to reinforce the screw mounts 9 in a vertebra by limiting relative movement between the screw mounts . it is to be understood that while a certain form of the invention is illustrated , it is not to be limited to the specific form or arrangement herein described and shown . it will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification and any drawings / figures included herein . one skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned , as well as those inherent therein . the embodiments , methods , procedures and techniques described herein are presently representative of the preferred embodiments , are intended to be exemplary and are not intended as limitations on the scope . changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the appended claims . although the invention has been described in connection with specific preferred 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 which are obvious to those skilled in the art are intended to be within the scope of the following claims .

a surgical connector useful to link spine rods together . the connector may be used adjacent a pair of mounting screws in one vertebra to limit movement between the screws or may be used to apply a lateral force to a portion of the spine to change curvature . a method of performing spinal surgery is also provide to reinforce a patient &# 39 ; s spine .

refer now to fig1 of the drawings which illustrates a radial arm quick adjusting artery clamp 10 of the present invention . the clamp 10 is utilized in applying pressure to a puncture site of an artery . an artery is often penetrated in various medical and surgical procedures to facilitate insertion of a catheter for example . upon removal of the catheter , or preferably coincident with the removal , pressure is applied to the puncture site to control bleeding and to allow coagulation of the blood to seal the puncture site . the clamp 10 is particularly suited to clamping a puncture site of a femoral artery . the ease of adjustment , the independent locking of the vertical and lateral movements and the quick release mechanism providing rapid advancement and retraction of the pressure pad in addition to the fine adjusting mechanism controlling the pressure applied by the pressure pad are some of the novel and useful features of the present invention . referring also to fig2 a and 3 , the clamp 10 has a thin flat rectangular base 12 . a cylindrical column 14 extends normally from and is fixedly attached near one end of the base 12 by a fastener 16 as illustrated in fig2 . a carriage 20 is movably mounted on the column 14 , with the carriage 20 being moveable upwardly and downwardly on the column 14 as indicated by the directional arrow 130 and also being pivotally moveable in reference to the column 14 as indicated by the directional arrow 132 . the carriage 20 is movably mounted on the column 14 with the column 14 fitting in a bore 22 ( best seen in fig3 ) provided in the carriage 20 . as shown in fig3 a slit 24 is provided in one end of the carriage 20 that communicates with the bore 22 . the slit 24 provides a separation between end portion 26 and end portion 28 of the carriage 20 . a chamfered threaded bore 30 is provided in the end portion 26 of the carriage 20 that is a aligned with a bore 32 in the end portion 28 as shown . a lock screw 34 is threadably installed in the bore 30 with an end of the lock screw 34 extending through the bore 32 , the bore 32 being larger than the bore 30 permitting the lock screw 34 to be slidably received in the bore 32 . a washer 35 and lock knob 36 is threadably installed on the end of the lock screw 34 . clamping of the carriage 20 in a fixed position on the column 14 is achieved by tightening the knob 36 on the screw 34 which forces the end portions 26 and 28 toward each other causing bore 22 to reduce in size to affect clamping of the carriage 20 to the column 14 . the carriage 20 is arranged for the moveable mounting of a radial arm 40 . the arm 40 is mounted to the carriage 20 with the arm 40 extending in a parallel attitude with respect to the base 12 . the arm 40 , as seen in fig1 and 6 , has a channel portion 42 or u shape for mounting and guiding the arm 40 on the carriage 20 . an elongate slot 44 having a length substantially as illustrated in fig1 - 3 is provided in the channel portion 42 . a side 21 of the carriage 20 is sized to fit in the channel portion 42 of the arm 40 as shown in fig6 . a chamfered threaded bore 50 is provided in the carriage 20 that extends through side 21 for receiving a threaded lock bolt 52 . the lock bolt 52 is threadably installed in the bore 50 and is of sufficient length to extend through the slot 44 in channel portion 42 of the arm 40 when the arm 40 is mounted on the carriage 20 . a washer 53 and lock knob 54 is loosely threadably installed on the end of the lock bolt 52 to loosely engage the surface 46 of the channel portion 42 of the arm 40 to retain the arm 40 on the carriage 20 . with the lock knob loose , the arm 40 may be adjusted along the carriage 20 as indicated by directional arrow 134 to any position within its travel limits . the ends of the slot 44 engaging the lock bolt 52 define the travel limits . the arm 40 is frictionally clamped to the carriage 20 in an adjusted position by tightening the lock knob 54 . with reference to fig1 , 2a , and 3 an end 60 of the arm 40 is configured for a quick release adjusting mechanism , such as a feed nut 110 , and the mounting of a pressure pad carrier 68 . as shown the end 60 extends from and is greater in width than the channel portion 42 of the arm 40 and has a formed elongate slot 62 . the slot 62 is basically rectangular in section having an enlarged circular end or bore 64 . the enlarged circular end 64 has a diameter greater than the width of the slot 62 . the end 64 is sized to receive the threaded pressure pad carrier 68 with the carrier 68 being slidable in the end 64 . the carrier 68 comprises an elongate rod 70 having threads 72 formed thereon excepting for the ends 76 and 78 . the diameter of the threaded portion 72 of the carrier 68 is greater than the width of the slot 62 so that the carrier 68 is captive in the end 64 of the slot 62 . a knob 74 is fixedly attached to the end 76 of the rod 70 in a conventional manner such as by adhesive bonding . the opposite end 78 of the rod 70 is reduced in diameter as shown in fig4 and has a spherical end 80 . a groove 82 is formed adjacent the spherical end 80 . a groove 84 is provided in the threaded portion near end 78 for receiving a snap ring 86 . a pressure pad 90 is removably and rotatably mounted on the spherical end 80 of the carrier 68 . the pad 90 has a bore 92 sized to loosely receive the end 78 of the carrier 68 permitting the pad 90 to rotate on the end 78 . projections 94 are provided in the bore 92 that will enter the groove 82 when the pad 90 is installed on the end of the carrier 68 . the projections 92 will yieldably retain the pad on the carrier 68 . the pad 90 may thus be snapped on and snapped off the end 78 of the carrier 68 . referring again to fig2 and 2a , the sides 100 and 102 of the end 60 adjacent the slot 62 of the arm 40 have a through bore 104 for receiving a mounting shaft 106 . the shaft 106 bridges the slot 62 ( see fig3 ) and a feed nut 110 is pivotally mounted on the shaft with the feed nut being positioned in the slot 62 . as seen in fig2 and 2a , the nut 110 has a threaded portion 112 engageable and dis - engageable with the threads 72 of the carrier 68 . a lever 114 is formed on the feed nut 110 to facilitate pivoting the feed nut 110 on shaft 106 . the lever 114 is utilized to pivot the feed nut 110 out of engagement with the threads 72 on carrier 68 . as shown , the lever 114 extends below ( as viewed in the figures ) the end 60 of the arm 40 . a recess such as a bore 116 is provided in the end 66 of the slot 62 and a corresponding recess or bore 118 is provided in the feed nut 110 . the bores 116 and 118 are provided for receiving a biasing member such as the ends of a compression spring 120 . the spring 120 having its ends fitting in the bores 116 , 118 will urge the nut 110 to pivot on the shaft 106 and thus will urge nut 110 into engagement with the carrier 68 , that is the threads 112 of the nut 110 will be engaged with the threads 72 of the carrier rod 70 . the pad 90 mounted on the carrier 68 may be finely adjusted in relation to the arm 40 ( or to a puncture site in an artery ) when the nut 110 is in engagement with the carrier 68 . the fine adjustment to either advance the pad 90 toward the puncture site or to retract the pad 90 from the puncture site is accomplished by rotation of the knob 74 . the pad 90 mounted on the carrier 68 may be rapidly advanced toward or rapidly retracted from a puncture site by dis - engaging the feed nut 110 from the carrier 68 and simply sliding the carrier 68 in the bore 64 in the desired direction . the pivotal mounting arrangement of the feed nut 110 on the arm 40 also permits the rapid downward advance of the carrier 68 by urging the carrier downward ( as viewed in the figures ) such as by pushing down on the knob 74 . the force applied will cause the nut 110 to yieldably pivot out of positive engagement with carrier one thread form at a time . the feed nut 110 will be pivoting in a ratcheting manner into and out of engagement with the carrier as the carrier is forced downward . this arrangement is provided by the feed nut 110 being pivoted at a point above the threaded portion 112 whereby the spring 120 urges the nut 110 to pivot upwardly against the carrier 68 . thus an upwardly directed force on the carrier 68 will , in contra distinction , further tighten the nut on the carrier and prevent release . the clamp 10 is easily and rapidly adjusted . the independent locking or clamping of the carriage 20 to the column 14 and the independent locking or clamping of the arm 40 to the carriage 20 provides for adjustments to either without disturbing the adjustment made to the other . the releasable nut 110 provides for both rapid movement and finely controlled movement of the carrier 68 . with the nut dis - engaged the carrier 68 may be rapidly moved in the bore 64 which provides for rapid advancement or retraction of the pressure pad 90 toward and away from the puncture site such as made in a femoral artery . with the nut 110 engaged with the carrier 68 , the movement of the carrier 68 may be finely adjusted by rotating the carrier knob 74 . the fine adjustment of the movement of the carrier 68 is utilized to control the pressure applied to the puncture by the pad 90 . a typical setup and operational procedure for the clamp 10 includes elevating the carrier 68 to its upper position by pivotally disengaging the nut 110 from the carrier 68 and sliding the carrier 68 upward by grasping the knob 74 . the snap ring 86 installed in the groove 84 of the rod 70 limits the upward movement of the carrier 68 by engaging the underside of the end 60 of the arm 40 . the carriage 20 with the mounted arm 40 are elevated by loosening the locking knob 36 which unclamps the carriage from the column 14 . the assembly of the carriage 20 and arm 40 may thus be elevated and / or pivoted on the column 14 to a desired position . the lock knob 36 is tightened to hold the carriage and arm assembly in the adjusted position . the base 12 of the clamp 10 is slid under the patient strategic to the puncture site , generally as illustrated in fig3 the patient being designated by the dashed outline labeled p . the base 12 of the clamp 10 is supported on the item supporting the patient such as a table . the portion of the patient resting on the base 12 will hold the base of the clamp 10 in position . the locking knob 36 is loosened to allow the positioning of the carriage 20 ( with the arm 40 ) on the column , making vertical and pivotal adjustments as required . the locking knob 36 is tightened to secure the carriage 20 in the adjusted position on the column 14 . the position of the arm 40 may now be adjusted laterally by loosening the locking knob 54 . this allows the arm 40 to be adjusted on the carriage to its desired position . the pressure pad 90 may be rapidly advanced toward the puncture site by pivoting the nut 110 out of engagement with the carrier 68 . this allows the carrier 68 to be rapidly slid in the bore to advance the pressure pad 90 rapidly toward the puncture site . in the alternative , the carrier 68 may be rapidly advanced downward by applying a force to the knob 74 which will cause the feed nut 110 to yieldably dis - engage . when the pad 90 is near the puncture site or the pad 90 is in contact with the skin of the patient surrounding the puncture site , the nut 110 is allowed to pivot into engagement with the carrier 68 . the pressure pad 90 may now be finely adjusted to apply the desired pressure by rotation of the carrier 68 by using knob 74 . those skilled in the art will recognize that variations and modifications may be made without departing from the true spirit and scope of the invention . the invention is therefore not to be limited to the embodiments described and illustrated but is to be determined from the appended claims .

a adjustable clamping device for applying pressure to a puncture site of an artery . the clamping device has a radial arm movably supported on a column which extends from a base . a carrier movably mounted on the end of the arm supports a pressure pad . the radial arm extends in a parallel attitude over the base and may be adjusted vertically upwardly and downwardly in reference to the base and may also be pivoted in reference to the column . lateral movement of the arm facilitates positioning the pressure pad over the puncture site . a releasable feed mechanism on the arm controls movement of the carrier and thus the pressure pad . with the feed mechanism engaged , rotation of the carrier provides a controlled feeding of the carrier relative to the arm . with the feed mechanism disengaged , the carrier may be rapidly advanced or retracted . independent locking mechanisms are provided for clamping of the lateral movement of the arm separate from the vertical and pivotal movements .

fig1 a shows a schematic diagram illustrating a system 100 for implementing and mediating a reaction game . one or more users playing the reaction game may each have a personal electronic device 105 , which may be a smart phone , tablet , laptop computer , desktop computer , or another type of device that may enable the user to communicate with other users . in some embodiments , the device 105 may be a gaming console equipped with a camera and / or microphone , such as a playstation , xbox , wii , a later generation or derivative thereof , or another gaming console . the personal electronic device 105 may have a transceiver 113 to communicate with a communications server 180 that facilitates sessions of the reaction game . the personal electronic device 105 may further comprise a plurality of sensing elements that may enable the device 105 to collect sensor data potentially indicative of emotional information , surrounding objects , or other contextual information . in the embodiment shown in fig1 a , the device 105 may have a location sensor 114 , a camera 116 , a depth sensor 117 , a tactile input element 120 , and a microphone 140 . the device may further comprise a processor 112 that may receive the sensor data and , in some embodiments , have the sensor data transferred to entities external to the device 105 , as will be described further below . some sensor data such as a video stream from the camera 116 and an audio stream from the microphone 140 may be sent to the communications server 180 through the transceiver 113 and received by one or more users of other devices 105 ( e . g ., during a game session ). the processor 112 may operate based on instructions stored on a memory device 122 . while particular sensing elements are shown in the device 105 of fig1 a , it is to be understood that more , fewer , or different sensing elements may be implemented to enable determination of emotional information or other contextual information ( e . g ., to facilitate the response game ). for example , information from the location sensor 114 may be used to match players from the same country or other type of geographic region with one another . in some embodiments , one or more of the sensing elements may be implemented externally to the device 105 . the device 105 may further comprise output elements such as a display 118 and a speaker 119 for providing information and feedback to the user of the device 105 during the reaction game . the display 118 and / or the speaker 119 may additionally or alternatively be externally connected to the device 105 . in some embodiments , the display 118 may be closely integrated with the tactile input element 120 , which may be implemented as a touch screen sensor array . in other embodiments , the tactile input element 120 may be a discrete input element such as a keyboard and / or a mouse ( e . g ., when the device 105 is a desktop computer ). the device 105 may communicate over a connection 135 with a decision engine 110 that may receive the sensor data to determine or enable determination that a user has lost the reaction game or that a flagged object is present . in some embodiments , the decision engine 110 may be provided by a backend server , and the connection 135 may be implemented over the internet . when located on a backend server , the decision engine 110 may service many devices 105 in parallel . further , the decision engine 110 may service multiple devices 105 in a common game session , thereby centralizing and avoiding duplication of the processing required to determine winners and / or flagged objects . in general , sensor data may be sent from one or more devices 105 to the decision engine 110 over the connection 135 , and the decision engine 110 may provide outcome determinations , screen blackout instructions , and other control information back to the one or more devices 105 . in other embodiments , the connection 135 may be a direct wired or wireless connection , and the decision engine 110 may be collocated with the device 105 . in yet other embodiments , the decision engine 110 may be fully integrated into the device 105 , which may reduce the amount of data transmitted from the device 105 and may reduce the latency associated with providing outcome determinations and / or blackout instructions . the decision engine 110 may comprise a processor 130 operating on instructions provided by a memory device 132 . the processor 130 may enable the decision engine 110 to analyze , collect , and / or synthesize sensor data from the device 105 to determine when a user wins the game or when the sensor data includes flagged objects . the decision engine 110 may offload some of its processing to other specialized entities to help make these determinations . for example , the decision engine 110 may have an external interface 138 that enables the decision engine 110 to communicate with external hardware or services , such as an emotion detection engine 160 . the emotion detection engine 160 may analyze video streams from the camera 116 and / or audio streams from the microphone 140 on one or more game participants &# 39 ; user devices 105 to provide feedback about perceived emotions of the participants . these emotions may include happiness , excitement , boredom , fear , anger , and discomfort . video streams may comprise image frames having computer - recognizable facial expressions corresponding to such emotions . audio data may also be used to detect pitch or changes in pitch that may corroborate or supplement the emotional information derived from the video data . detected ambient noise may be used to provide further contextual clues . the emotion detection engine 160 may also provide a degree of confidence in the emotion information ( e . g ., determination that a user is feeling a known emotion ) that it provides to the decision engine 110 and / or the perceived extent to which the user feels a certain emotion . this additionally information allows the decision engine 110 to better determine when a game participant satisfies any of the loss criteria . in some embodiments , the emotion detection engine 160 may be fully integrated into the decision engine 110 , such that the external interface 138 is not required , at least for detecting emotions . in some embodiments , the external interface 138 may be an application programming interface ( api ) that enables the decision engine 110 to exchange information with the emotion detection engine 160 . the decision engine 110 may alternatively or additionally use the external interface 138 to communicate with a user behavioral safeguard subsystem 190 , which may analyze the sensor data to determine user violations ( e . g ., failures to follow the predefined rules and / or code of conduct of a game ). the user behavioral safeguard subsystem 190 may comprise a processor 136 , a transceiver 137 , a memory device 133 , and a flagged object database 134 . the transceiver 137 may receive sensor data such as video and / or audio streams associated with an ongoing reaction game . the processor 136 may , based on instructions stored on the memory device 133 , search the received sensor data to determine whether or not users are following rules associated with the game . if a rule is violated , the user behavioral safeguard subsystem 190 may initiate a safety protocol , as will be described further below . to assist with monitoring and violation detection , the user behavioral safeguard subsystem 190 may use the flagged object database 134 , which may store digital signatures or fingerprints of objects that may appear in the sensor data . the flagged object database 134 may be initially populated by a system administrator that preemptively flags objects that are inappropriate , forbidden by the rules of gameplay ( e . g ., a mask that could prevent detection of a participant &# 39 ; s emotions ), or otherwise worth tracking . in some embodiments , the flagged object database 134 may adapt over time as users and / or system administrators add and remove objects . additionally or alternatively , the user behavioral safeguard subsystem 190 may implement machine learning to recognize objects that are often present and associated video streams that have been reported as offensive or otherwise failing to comply with rules . that is , if certain objects have a strong correlation with content or behavior perceived to be objectionable , the user behavioral safeguard subsystem 190 may automatically flag those objects to prevent similarly objectionable content or behavior from being seen by users in future game sessions . one or more user behavioral safeguard subsystems 190 may synchronize their databases 134 with one another . in some embodiments , some or all of the objects in the flagged objects database 134 may be cached at a local database 124 of the device 105 . this may enable a more reactive system where a safety protocol may be implemented rapidly after the detection of a flagged object at either a transmitting device 105 that captures the flagged object through its sensors or at a receiving device 105 receiving video and / or audio data having the flagged object . in some embodiments , the user behavioral safeguard subsystem 190 may be fully integrated into a decision engine 110 or a device 105 . in some embodiments , a safety protocol may also be triggered when a user reports another user for a particular violation . the video stream and information contained in the manually - submitted report be used to further improve automated implementation of the safety protocol . the decision engine 110 may be in communication with other decision engines 110 and / or other devices 105 such that a large sample set representative of a plurality of users may be considered for machine learning processes . alternatively , a centralized database coordination processor ( not shown ) may send flagged objects to a plurality of user behavioral safeguard subsystems 190 on a periodic or discretionary basis and thereby synchronize the flagged object databases 134 of multiple user behavioral safeguard subsystems 190 . as discussed above , the camera 116 may provide video data that may be interpreted to detect emotions and / or flagged objects . the video data may be further analyzed to provide other types of contextual clues . for example , an image frame in the video data may be used to determine the number of people participating in a call from one device ( e . g ., the device 105 ). in some embodiments , a reaction game may only allow one person to be detected at each device , and thus the detection of multiple people may cause a party to receive a warning or automatically forfeit a game session . clocks and timers may also provide valuable data for analysis by the decision engine 110 . for example , if neither participant exhibits an emotion associated with a loss criterion that would conclude the session after a maximum time period allowable for a game session , the decision engine 110 may end the game session in a draw . in some embodiments , an account management server 182 may store details and maintain accounts for each participant or player of the mediated response game . the account management server 182 may be in communication with the communications server 180 that facilitates game sessions between or among the players &# 39 ; devices 105 . a player &# 39 ; s account may be credited when the player &# 39 ; s opponents are determined to have displayed emotional response or facial expression ( e . g ., smile ) or otherwise satisfied a loss criterion . the number of points ( e . g ., in - game tokens ) awarded may depend at least in part upon the duration of the game elapsed , and / or the degree of the facial expression and emotional response . for example , players may receive more points for shorter games and may thus be rewarded for provoking emotional responses or reactions more quickly . in some embodiments , players can spend their points to use in - game features such as humorous distractions ( e . g ., visual overlays or audio clips ) to be presented on the devices 105 of their opponents . in some embodiments , the decision engine 110 may generate confidence ratings when determining different contextual clues from the sensor data . as discussed above , the external services ( e . g ., the emotion detection engine 160 ) may also provide confidence ratings about the contextual clues that they provide . the decision engine 110 may determine that a game is over if the confidence rating and / or perceived extent with which a participant or player displays an emotional response is above a threshold established by a loss criterion . in embodiments where the decision engine 110 is fully integrated into the device 105 , the processor 130 may be the same as the processor 112 , such that a single processor receives sensor data , determines when a loss criterion is met , and alerts a user of the device 105 about the results . further , the memory device 132 may be the same as the memory device 122 and may provide instructions that enable the processor to perform the functions disclosed herein . in some embodiments , the user behavioral safeguard subsystem 190 may be integrated into the communications server , such that it may block potentially offensive content in transit and before it reaches a receiving device 105 intended to receive the potentially offensive content . in some embodiments , the user behavioral safeguard subsystem 190 may be integrated into a device 105 . in these embodiments , a single processor 112 and / or a single memory 122 may be used for both the device 105 and the user behavioral safeguard subsystem 170 . further , the flagged object database 134 may be the same as the flagged object database 124 and may store flagged objects detected from the sensors on the device 105 or on signals ( e . g ., video and / or audio streams ) from the communications server 180 . the decision engine 110 may thus be bypassed with respect to implementing the safety protocol but may still be used for emotion detection and determining when loss criteria are satisfied . fig1 b shows a schematic diagram illustrating communications between multiple devices 105 that may participate in a reaction game . a communications server 180 may enable a group of devices 105 - 1 through 105 - n to participate in mediated reaction games or otherwise communicate with one another as desired by the users of the devices 105 . the communications server 180 may be implemented as a cloud - based server 180 that may service a regional or even global client base through the internet . for example , the communications server 180 may provide videoconferencing - based games between the devices 105 , where the devices 105 may be similar or dissimilar to one another . for example , some devices 105 may be desktop computers or stationary gaming consoles and may engage in game sessions with other devices 105 that are tablets , laptop computers , mobile gaming consoles , or mobile phones . the account management server 182 may store information for the user accounts associated with each device 105 or the users of the devices 105 . the stored information may include a list of past games , friends , in - game currency ( e . g ., tokens ), a history of each user &# 39 ; s infractions ( e . g ., as stored whenever the safety protocol is initiated ), and other information . in some embodiments , a game session may have more than two users with devices 105 simultaneously participating . in such embodiments , one or more decision engines associated with the devices 105 may determine when a user of a device 105 displays an emotional response or reaction that satisfies a loss criterion . in some embodiments , whenever a participant or player displays such a response , they may lose the game session , but the game session may continue until a single participant remains ( e . g ., by not having triggered a loss criterion ) or a game timer expires . participants who have already lost within a game session may choose to spectate until the game session is completed or they may be prompted to disconnect and join another game session . in some embodiments , the devices 105 may connect to one another in a decentralized and peer - to - peer manner such that the communications server 180 is not used . fig2 shows a schematic diagram illustrating a presentation 200 of an introductory game screen associated with a mediated reaction game on a personal electronic device . the presentation 200 may have a feature button 210 , which can be used to navigate to other feature screens ; a tokens button 220 to check the player &# 39 ; s current token balance or purchase additional tokens using a real - world currency ; a first play button 230 to initiate a game with an existing friend ; and a second play button 240 to play a game against an opponent matched to the player . if the second play button 240 is selected , the matched opponent may not have a pre - existing relationship with the player and may thus be a stranger . given the uncertainty associated with stranger interactions , the disclosed user behavioral safeguards can lead to a more consistently pleasant gameplay experience . fig3 shows a schematic diagram illustrating a presentation 300 of game history associated with a mediated reaction game on a personal electronic device . the presentation may include a roster of entries 310 representative of game sessions in which a player previously participated . each entry may have the name of an opponent , an icon selected to be representative of the opponent , a date that the game session occurred , and the outcome of the game session . the presentation 300 may also include a search bar 320 , where a user may search through their own game history by opponent name , date , or other search criteria . the game history data may be stored at an account management server as described above . fig4 shows a schematic diagram illustrating a presentation 400 of a leaderboard associated with a mediated reaction game on a personal electronic device . the presentation 400 may include a graph or other display image 410 showing a particular player &# 39 ; s performance through their wins , losses , and ties . the presentation 400 may also include a cumulative score indicator 420 , a relative ranking 430 among the player &# 39 ; s friends , and leaderboard entries 440 of the scoring leaders and their corresponding scores . the presentation 400 may also include a first button 450 to limit the leaderboard entries 440 to be selected from only friends of the player and a second button 460 to see a complete leaderboard , with entries 440 selected from all players of the reaction game . fig5 shows a schematic diagram illustrating a presentation 500 of a friends list associated with a mediated reaction game on a personal electronic device . a player may add friends to their friends list by electing to “ follow ” them . each followed friend may have an entry 510 shown in the presentation 500 , where the entry 510 may include the friend &# 39 ; s name and icon as well as a button 512 to “ unfollow ” or remove the friend . in some embodiments , past opponents may be automatically added to the player &# 39 ; s friends list . the player may use a filter bar 520 to filter their friends list to more easily find particular individuals ( e . g ., using their account name as stored by an account management server ). if a player has not yet chosen to follow any friends within the game , the presentation 500 can have an instructional message for adding friends that serves as a placeholder . the presentation 500 may have a “ following ” button 530 to list friends that a player is presently following , as is depicted to be selected in fig5 to show the entries 510 . the presentation 500 may also have one or more social network ( s ) button 540 linking to the player &# 39 ; s social network , a contacts button 550 linking to the contacts within the player &# 39 ; s personal electronic device ( e . g ., a mobile phone contact list ), and a search button 560 to search for users within the reaction game community that the player has not yet followed . in general , the buttons 540 , 550 , and 560 may allow a player to follow and / or challenge others within or outside of the player &# 39 ; s networks . the challenged players who do not already have the game installed may receive a message ( e . g ., via email or text message ) having a link and instructions for downloading the game . fig6 shows a schematic diagram illustrating a presentation 600 on a personal electronic device during a session of a mediated reaction game . a user may challenge another user through an application installed on at least one of the users &# 39 ; devices . when the game session is established , participants may see and hear one another through the interfaces of their respective devices . a video stream of an opponent may be presented to the other participant in a primary window 610 , and a video stream of a participant may be presented to themselves in a secondary window 620 . in some embodiments , the primary window 610 showing the opponent may be more prominently displayed ( e . g ., centered and / or larger ) than the secondary window 620 showing the participant themselves . while fig6 shows the presentation 600 that is provided to one participant , a similar presentation may be presented to another participant ( or participants in a group conversation ). for example , each participant may see their opponent ( s ) in primary window ( s ) ( e . g ., the window 610 ) and may see themselves in a smaller window ( e . g ., the window 620 ). more windows may be presented if more users and devices are participating in the conversation . a timer 640 may indicate the progression of an ongoing game session . if the timer 640 expires , the game session may be declared a draw between the remaining players . a decision engine associated with one or more of the game participants &# 39 ; devices may monitor the video signals that are presented in the windows 610 and 620 as well as other sensors associated with the participants &# 39 ; devices . the decision engine may determine if and when a participant exhibits an emotional response ( e . g ., smiling ) to trigger a loss criterion . as described above with respect to fig1 a , the decision engine &# 39 ; s determination of winners and losers may be assisted by an emotion detection engine that also receives the video signals and provides real - time indications of detected emotions to the decision engine . when a participant provides such a response , all participants within a game session may be alerted that the participant who displayed the response has lost the game . if the game has more than two participants , it may continue until a single participant remains ( e . g ., by not exhibiting an emotional response ). during a game session , participants may attempt to incite one another into exhibiting an emotional response by using features built into the game . for example , participants may select visual overlays ( e . g ., digital stickers or animations ), audio clips , or other features from a selectable feature window 630 that may be presented to their opponents . other types of features include digital apparel and avatars that track movement of a participant . in some embodiments , these features may be purchased using in - game currency ( e . g ., tokens ), which may be earned by winning or simply participating in games . in some embodiments , in - game currency may be additionally or alternatively purchased using real - world currency . if a participant wants to use another feature that is not immediately presented in the selectable feature window 630 , the participant may make a gesture to receive the additional content . for example , the participant may use a tactile feedback element such as a touch screen or mouse to drag the window 630 sideways , which may prompt additional features to “ rotate ” into or otherwise appear in the selectable feature window 630 . if a participant does not want to use any features , they may perform yet another gesture ( e . g ., dragging the window 630 downward or selecting a “ hide features ” button ) to make the selectable feature window 630 disappear . after a feature such as a sticker is selected by one user and presented to another user , the other user receiving the feature may be presented with a set of selectable features that may be relevant as a direct or indirect response to the received feature . accordingly , the features presented in the selectable feature window 630 may help drive interaction between users . the set of selectable features in the selectable feature window 630 may be chosen for presentation to a participant based on a context perceived through video data analysis . for example , if a participant initiates a session from a particular location , the selectable feature window 630 of the participant and / or an opponent may provide features relating to the participant &# 39 ; s location . in some embodiments , the features suggested in the selectable feature window 630 may be random . in some embodiments , the users may also attempt to win by speaking ( e . g ., telling a joke ) to have their opponents display an emotional response . as described above , one or more user behavioral safeguard subsystems may also be active when a game is in progress . if a participant does not follow the rules of the game ( e . g ., showing one &# 39 ; s face ) or displays a flagged object that is recognized from their video stream , a user behavioral safeguard subsystem may initiate a safety protocol . the safety protocol may comprise disabling an offending video stream , censoring portions of the offending video stream , disconnecting the participants from one another , and / or other actions to promote safe and proper usage of a reaction game system . further , the disclosed principles may apply to many different types of communications beyond videoconferencing . in some embodiments , the disclosed principals may be applied audio conferencing sessions . in embodiments involving audio data , factors such as pitch , cadence , and other aspects of speech or background noise may be analyzed to discern emotions and other contextual information . some sensors , such as location sensors , may still be relevant and applicable across the different communications media . the types of features presented to a user may also vary based on the selected communications media . for example , if multiple users are competing with one another in an audio conferencing - based game , the users may be presented with sound clips or acoustic filters that may applied to the conversation . the features may , for example , be selectable from a dedicated auxiliary window or from a keypad . further , certain words may be flagged by a user behavioral safeguard subsystem to be filtered out of the conversation . a minor delay may be introduced to enable recognition and filtering of flagged words . fig7 shows a schematic diagram illustrating a presentation 700 that may occur on a personal electronic device after a safety protocol has been implemented . a participant may see the presentation 700 if they are within an instance of the reaction game and an opponent &# 39 ; s face is removed from or not within the captured video stream . in some embodiments , a timer 710 may accelerate and provide a limited time before the game session is ended . the user associated with the blocked feed may automatically forfeit the game and lose points . frequent violations or failures to play the game may result in a temporary or permanent ban from playing the game . in some embodiments , if a user behavioral safeguard subsystem detects a flagged object in the video stream of a participant , other participants within the game may see the presentation 700 , which blocks the video stream having potentially offensive , undesirable , or otherwise restricted content from reaching the participants . other safety protocols such as partially obscuring a video feed , muting an audio feed , and disconnecting a game session may also be implemented to respond to different types and severities of offenses . while fig7 shows the results of blocking video content in the context of a reaction game , similar techniques for automatically disabling or obscuring video feeds based on recognizing flagged objects may adapted for numerous other applications . for example , a frequent user of a streaming video service may create a list of preferences about objects they would not like to see within incoming streams . the service may use a flagged object database and video recognition technology to obscure portions of incoming video streams having those objects . in some embodiments , the objects may be selectively blurred or a video stream may be disabled altogether . such features may be immensely useful to individuals having phobias towards particular animals or other objects . similarly , certain brand logos and written text may also be selectively blocked within video streams ( e . g ., to avoid copyright or trademark infringement ). fig8 shows a flowchart illustrating an exemplary process 800 for participating in a mediated reaction game . the process 800 may be performed by a first device of a first participant playing the game . while the process 800 is described below as having a plurality of participants and devices , the mediated reaction game may also have a single participant within a session . with regard to embodiments where a plurality of participants play against one another , the first participant may directly challenge one or more other participant to begin the game , or the participants may be matched with one another prior to the process 800 . if the players are matched , the matching process may be performed by a communications server and may take age , gender , location , game history ( e . g ., win / loss ratio , number of games played ), and / or other factors into account . at an action 810 , the first device may transmit an image frame or portion of a video stream to a communications server that is facilitating a game session between the first device and at least a second device of a second player within the game . this may be an initial video stream portion or a subsequent video stream portion depending on whether or not the game recently began . the image frame or video stream portion may also be transmitted to and analyzed by a decision engine and / or supplementary engines and subsystems , which may each be internal or external to the first device , to determine if a loss criteria has been satisfied ( e . g ., a smile , eye - movement , other facial change , or detectable emotion ) and whether a safety protocol should be implemented . for example , a user behavioral safeguard subsystem may analyze the video streams or individual image frames from the first and second devices to determine whether or not they contain flagged objects or are missing objects required for the game ( e . g ., the first participant &# 39 ; s face ). in some embodiments , the first device may also transmit audio data and / or other information . at an action 820 , the first device may check whether or not it received an indication that a loss criterion has been satisfied ( e . g ., from a decision engine ). video streams or image frames from both ( or all ) participating devices may be analyzed ( e . g ., by an emotion detection engine ) to determine whether a player has smiled , moved , or shown emotion beyond a threshold level . in some embodiments , the threshold level may be optimized over many iterations of the game to balance responsiveness and difficulty with playability . in some embodiments , players may select a difficulty level before or after being matched with an opponent , and the threshold level for a particular game session may be adjusted based on the selected difficulty level . fig9 and the accompanying description below provide more detail into conducting the game itself and determining when the loss criteria is satisfied . if the first device receives an indication of a loss criterion , the process 800 may proceed to an action 830 . otherwise , the process 800 may proceed to an action 840 . in some embodiments , the process 800 may also proceed to the action 830 if a game timer expires and the game ends in a draw . at the action 830 , the first device may record and display the results of the game . in some embodiments having tokens , the winner may win a larger number of tokens from playing the game than the loser ( s ). furthermore , the number of tokens awarded may decrease as a function of the time required for a loss criterion to occur . this rewards players who are able to effectively provoke an emotional response or reaction in other players ( e . g ., through adept usage of available stickers and other features ). in some embodiments , the loser ( s ) of the game may not win any tokens or may lose tokens after losing the game . if the game ends in a draw , both or all tied players may receive an equal amount of tokens . an account management server in communication with the communications server may record the game and its results to both or all players &# 39 ; game histories . at the action 840 , the first device may check whether or not it has received an indication about a safety protocol from the user behavioral safeguard subsystem . fig1 and the accompanying description below provide more detail about safety protocols and , more generally , improving the overall safety of the game . if the first device and / or the user behavioral safeguard subsystem determine that the safety protocol is to be implemented , the process 800 may continue to an action 850 . if not , the process 800 may continue to an action 860 . at the action 850 , the first device may implement the safety protocol . this may entail blanking the video stream or image frames received from the second device and instead displaying a placeholder message , such the one as shown in fig7 . the safety protocol may vary depending on the nature of the triggering action . in some scenarios where the triggering action is minor , the safety protocol may entail merely blurring a portion of the video stream or muting the audio , and the process 800 may continue ( e . g ., to the action 860 ). in scenarios where the safety protocol allows the process 800 ( and associated game session ) to continue , a timer may be initiated such that the game session may be concluded early if the triggering action that instituted the safety protocol is not remedied in a sufficiently prompt manner ( e . g ., 5 , 10 , or 15 seconds ). conversely , in scenarios where the triggering action is major and / or a repeat violation , the safety protocol may entail substantially immediately disconnecting the users from one another and ending the game session . in some embodiments , the offending video stream may alternatively be caught and / or altered at a communications server or even the sending device , such that the potentially offensive content is prevented from reaching the first device . at the action 860 , the first device may receive and display an image frame or portion of a video stream of the second player to the first player . this may be an initial video stream portion or a subsequent video stream portion depending on whether or not the game recently began . if the first device is used to analyze this data for loss conditions and / or safety - related decisions , there may be a delay between receiving and displaying the data . the process may then proceed to the action 810 , where the next portion of the video stream or image frame from the first device is transmitted and / or analyzed . in some embodiments , the first device may also receive audio data and / or other information . the actions described in the process 800 may be performed by the first device in accordance with instructions stored on a nonvolatile , machine - readable medium . furthermore , the actions described in the process 800 may not necessarily take place in the presented order . for example , the first device may have a multi - threaded processor or multiple simultaneously running subsystems that continuously check for indications of the safety protocol and the loss criteria in a simultaneous manner and in parallel to receipt , presentation , and transmission of video streams . in some embodiments , more , fewer , or different actions may be implemented by devices participating in a reaction game . for example , in embodiments having a single participant playing the game ( e . g ., using a timer and / or against an artificial , computer - generated opponent ), the actions 840 and 850 relating to the safety protocol may be bypassed . fig9 shows a flowchart illustrating an exemplary process 900 for conducting a mediated reaction game . the process 900 may be performed by a decision engine that may be external to or integrated with a user &# 39 ; s personal electronic device . at an action 910 , the decision engine may receive sensor data from the devices of the player ( s ) involved in a game session . as described above with respect to fig1 a , this sensor data may be provided from a multitude of sensors associated with one or more devices within a game session , such as microphones , cameras , location sensors , and tactile input elements . in some embodiments , each device may have a dedicated decision engine that receives and processes the sensor inputs from that device . in some embodiments , the decision engine may be located at a backend server and / or integrated into the communications server supporting video transmission for the game session , and the decision engine may process sensor inputs ( e . g ., transmitted video streams ) from all devices involved in the game session . at an action 920 , the decision engine may process the sensor data to determine emotions of the player ( s ) within the game . in some embodiments , this processing may comprise the decision engine providing the sensor data to an emotion detection engine through an external interface . the emotion detection engine may return information about detected facial expressions and emotions , which may include confidence ratings and / or perceived intensity . at an action 930 , the decision engine may determine whether a loss criteria is satisfied or if the game has concluded for other reasons ( e . g ., timer expiry ). in some embodiments , the decision engine may compare the confidence ratings and / or perceived intensities of detected facial expressions against a list of prohibited facial expressions ( e . g ., a smile ) and corresponding threshold values to determine when a player loses . in some embodiments , the loss criteria may comprise a player flinching ( e . g ., rapidly moving their face or body ) beyond a threshold level , where the threshold level may be established prior to the game and / or by a selected difficulty level . other perceived indications of emotion or the players &# 39 ; mental states may be used as loss criteria to determine when a game should conclude . if the decision engine determines that a loss criterion has been satisfied or the game has otherwise concluded , the process 900 may proceed to an action 940 . otherwise , the process 900 may return to the action 910 , where the decision engine may receive new sensor data ( e . g ., for the next instant or period of time ). at the action 940 , the decision engine may provide a notification to the one or more devices involved in the game that the game has concluded and also which player ( s ) won , lost , or tied with one another . when the decision engine is provided by a backend server located remotely from the devices , the game results may be transmitted over the internet . if the decision engine is integrated into a device , the action 940 may simply involve presentation of the results on that device and / or transmission of the results to the device ( s ) of the other participant ( s ). as discussed above , a session of a mediated reaction game may involve a single player . in some embodiments , various features may be automatically provided at the player &# 39 ; s device during a single - player game session to elicit a response from the player . the player may achieve victory if they do not exhibit a response within and throughout a period of time established by a game timer . in some embodiments , the player may be matched with a computer opponent that is displayed on the player &# 39 ; s device and programed to react to actions taken by the player , so as to simulate gameplay with another human being . the actions described in the process 900 may be performed by the decision engine in accordance with instructions stored on a nonvolatile , machine - readable medium . furthermore , the actions described in the process 900 may not necessarily take place in the presented order . in some embodiments , more , fewer , or different actions may be implemented by devices participating in a reaction game . fig1 shows a flowchart illustrating an exemplary process 1000 for providing user safety in a mediated reaction game . while the process 1000 is generally described below as being performed by a single user behavioral safeguard subsystem , multiple of such subsystems may be implemented to improve the safety of a game session . for example , each device participating in a game session may have an associated user behavioral safeguard subsystem that acts as a safeguard for that device ( e . g ., preventing display of received data that is potentially offensive ) or for other devices ( e . g ., preventing transmission of potentially offensive data ). the user behavioral safeguard subsystem ( s ) may be integrated into or in communication with the participants &# 39 ; devices . the user behavioral safeguard subsystem may , in some embodiments , be integrated into a communications server supporting video transmission for the game session . at an action 1010 , the user behavioral safeguard subsystem may receive data from sensors on one or more devices participating in a game session . this data may include an image frame or portion of a video stream . in some embodiments , the user behavioral safeguard subsystem may also receive audio data and / or other information from or about the devices . at an action 1020 , the user behavioral safeguard subsystem may check whether it has received indication that a game is completed ( e . g ., from a decision engine associated with the game ). if the game is determined to have been completed , the process 1000 may end . otherwise , the process may continue to an action 1030 . at the action 1030 , the user behavioral safeguard subsystem may search the sensor data for objects stored in a flagged object database . the objects may be flagged by the community of the mediated reaction game or automatically ( e . g ., based on commonalities of image frames or video streams flagged by users as being inappropriate or otherwise not following rules associated with the game ). in some embodiments , this search may occur substantially in real time with respect to an input stream . at an action 1040 , the user behavioral safeguard subsystem may determine whether or not any flagged objects are present in the sensor data . if such objects are found , the process 1000 may continue to an action 1050 , where the safety protocol in initiated . if not , the process 1000 may continue to an action 1060 . at the action 1050 , the user behavioral safeguard subsystem may initiate a safety protocol . the safety protocol may dictate any of a varied set of procedures based on the degree and type of infraction . for example , in some scenarios , the safety protocol may dictate censoring ( e . g ., blurring or overlaying with censoring graphics ) only portions of image frames within a stream . this may be useful when the flagged object is incidentally in the background of one or more image frames and a receiving party indicates that they do not wish to see such content ( e . g ., a person who has a phobia of a typically - mundane object or who strongly dislikes a certain brand ). in these scenarios , the process 1000 may return to the action 1010 ( e . g ., such that the user behavioral safeguard subsystem continues to monitor sensor data for the game session ). in other scenarios , the safety protocol may entail automatically ending the game session and disconnecting the participants from one another . an account management server may track and store incidents where a player &# 39 ; s video stream or actions prompted the safety protocol so as to allow for more strict and / or permanent actions for those with frequent and / or serious infractions . at the action 1060 , the user behavioral safeguard subsystem may verify whether or not a face ( or another object potentially required for the game ) is detected within the sensor data . if a face is not detected , the process 1000 may continue to the action 1050 where the safety protocol is initiated . if a face is detected , the process 1000 may continue to the action 1050 and the safety protocol may be initiated . otherwise , the process 1000 may return to the action 1010 , where the user behavioral safeguard subsystem receives a new set of sensor data for analysis . the actions described in the process 1000 may be performed by the user behavioral safeguard subsystem in accordance with instructions stored on a nonvolatile , machine - readable medium . furthermore , the actions described in the process 1000 may not necessarily take place in the presented order . in some embodiments , more , fewer , or different actions may be implemented by devices participating in a reaction game . other features for improving the safety and / or general enjoyability of a reaction game include allowing players to block other players with which they do not wish to interact . a blocked player may be prevented from challenging or randomly being matched with another player requesting the block . furthermore , individuals who are repeatedly found and / or reported to abuse the mediated reaction game platform ( e . g ., by not following terms and conditions for which acceptance may be required prior to gameplay ) may have their accounts suspended or terminated . by storing and blacklisting device - identifying information such as a phone number or serial number , such users may be prevented from creating a new account and further misusing the service . while various embodiments in accordance with the disclosed principles have been described above , it should be understood that they have been presented by way of example only , and are not limiting . thus , the breadth and scope of the disclosure should not be limited by any of the above - described exemplary embodiments , but should be defined only in accordance with the claims and their equivalents issuing from this disclosure . furthermore , the above advantages and features are provided in described embodiments , but shall not limit the application of such issued claims to processes and structures accomplishing any or all of the above advantages . it is contemplated that the decision engines , emotion detection engines , user behavioral safeguard subsystems , communications servers , account management servers , personal electronic devices , and other elements be provided according to the structures disclosed herein in integrated circuits of any type to which their use commends them , such as roms , ram ( random access memory ) such as dram ( dynamic ram ), and video ram ( vram ), proms ( programmable rom ), eprom ( erasable prom ), eeprom ( electrically erasable prom ), earom ( electrically alterable rom ), caches , and other memories , and to microprocessors and microcomputers in all circuits including alus ( arithmetic logic units ), control decoders , stacks , registers , input / output ( i / o ) circuits , counters , general purpose microcomputers , risc ( reduced instruction set computing ), cisc ( complex instruction set computing ) and vliw ( very long instruction word ) processors , and to analog integrated circuits such as digital to analog converters ( dacs ) and analog to digital converters ( adcs ). asics , plas , pals , gate arrays and specialized processors such as digital signal processors ( dsp ), graphics system processors ( gsp ), synchronous vector processors ( svp ), and image system processors ( isp ) all represent sites of application of the principles and structures disclosed herein . memory devices may store any suitable information . memory devices may comprise any collection and arrangement of volatile and / or non - volatile components suitable for storing data . for example , memory devices may comprise random access memory ( ram ) devices , read only memory ( rom ) devices , magnetic storage devices , optical storage devices , and / or any other suitable data storage devices . in particular embodiments , memory devices may represent , in part , computer - readable storage media on which computer instructions and / or logic are encoded . memory devices may represent any number of memory components within , local to , and / or accessible by a processor . implementation is contemplated in discrete components or fully integrated circuits in silicon , gallium arsenide , or other electronic materials families , as well as in other technology - based forms and embodiments . it should be understood that various embodiments of the invention can employ or be embodied in hardware , software , microcoded firmware , or any combination thereof . when an embodiment is embodied , at least in part , in software , the software may be stored in a non - volatile , machine - readable medium . networked computing environment such as those provided by a communications server may include , but are not limited to , computing grid systems , distributed computing environments , cloud computing environment , etc . such networked computing environments include hardware and software infrastructures configured to form a virtual organization comprised of multiple resources which may be in geographically disperse locations . various terms used in the present disclosure have special meanings within the present technical field . whether a particular term should be construed as such a “ term of art ” depends on the context in which that term is used . “ connected to ,” “ in communication with ,” “ associated with ,” or other similar terms should generally be construed broadly to include situations both where communications and connections are direct between referenced elements or through one or more intermediaries between the referenced elements . these and other terms are to be construed in light of the context in which they are used in the present disclosure and as one of ordinary skill in the art would understand those terms in the disclosed context . the above definitions are not exclusive of other meanings that might be imparted to those terms based on the disclosed context . words of comparison , measurement , and timing such as “ at the time ,” “ immediately ,” “ equivalent ,” “ during ,” “ complete ,” “ identical ,” and the like should be understood to mean “ substantially at the time ,” “ substantially immediately ,” “ substantially equivalent ,” “ substantially during ,” “ substantially complete ,” “ substantially identical ,” etc ., where “ substantially ” means that such comparisons , measurements , and timings are practicable to accomplish the implicitly or expressly stated desired result . additionally , the section headings herein are provided for consistency with the suggestions under 37 c . f . r . 1 . 77 or otherwise to provide organizational cues . these headings shall not limit or characterize the subject matter set forth in any claims that may issue from this disclosure . specifically and by way of example , although the headings refer to a “ field of the disclosure ,” such claims should not be limited by the language chosen under this heading to describe the so - called technical field . further , a description of a technology in the “ background ” is not to be construed as an admission that technology is prior art to any subject matter in this disclosure . neither is the “ summary ” to be considered as a characterization of the subject matter set forth in issued claims . furthermore , any reference in this disclosure to “ invention ” in the singular should not be used to argue that there is only a single point of novelty in this disclosure . multiple inventions may be set forth according to the limitations of the multiple claims issuing from this disclosure , and such claims accordingly define the invention ( s ), and their equivalents , that are protected thereby . in all instances , the scope of such claims shall be considered on their own merits in light of this disclosure , but should not be constrained by the headings set forth herein .

mobile devices or other client devices generally support applications that provide content to users . emotional analytics entails making inferences about a user &# 39 ; s emotions based on sensor data such as a video stream of the user . when combined with a videoconferencing application or other digital media , emotional analytics may be employed to make games that respond to user emotions . video streams from a game may also be analyzed in real time to ensure that the game &# 39 ; s rules are obeyed . disclosed are techniques for administering and managing a digital media - based game using emotional analytics and object recognition .

referring now in more detail to the drawing , in which like numerals refer to like parts throughout the several views , the mounting of the birds to the machine takes place by hand on the non - visible side of the machine . lines a and b of fig2 indicate , with respect to the bird , the relative positions of the rotating blades 1 and 2 of the breast cutter illustrated in fig4 . therefore , the breast pieces can be collected at b in fig3 . both of the lines c and the single line d of fig1 indicate , with respect to the bird , the relative positions of the rotating blades 3 , 4 and 5 of the wing cutter and longitudinal cutter both illustrated in fig5 . the wings can be collected at c in fig3 . since fig1 is the breast view of the bird it will be clear that the bird should be rotated 90 ° between positions b and c of fig3 . lines e and f of fig1 indicate , with respect to the bird , the relative positions of the rotating blades 6 and 7 of the cross - bisection means and the drum - stick cutter both illustrated in fig6 . at e in fig3 the backs can be collected and at f the thighs . in the machine only the so - called drum - sticks are left then . since the cuttings e and f are shown in fig2 it will be clear that the birds will be rotated back again 90 ° between positions d and e in fig3 . the cut up machine represented in fig3 comprises a frame provided with longitudinal beams 8 , cross - beams 9 and uprights 10 . the represented frame has six legs 11 , but of course it can be mounted in a elevated way with respect to the floor otherwise . a surface belt conveyor ( not illustrated ) usually is positioned beneath the lower longitudinal beams 8 to collect the segments of the birds dropped from the cut up machine . at least the side of the machine which is visible in fig3 is completely covered by doors ( not illustrated ) during operation of the machine , and a security system ( not shown ) is provided which makes the rotating blades stop as soon as one of said doors is opened . in order to be able to illustrate the interior of the machine only one door 12 is provided on the remote end of the machine . as illustrated in fig3 a sprocket wheel system comprises an upper chain 13 and a lower chain 14 . on the end of the machine which is nearby in fig3 the chains 13 and 14 engage with chain wheels 15 and 16 supported on a vertical sprocket wheel shaft 17 . the end of the machine which is remote in fig3 has been carried out in an identical but not visible way . one of the sprocket wheel shafts is provided with a drive means for driving the sprocket wheel system . a plurality of bird support modules m are positioned in series about the machine , and each module includes upper carriages 18 and 19 with upper carriage 18 connected to upper and lower chain 13 and lower carriage 19 connected to lower chain 14 . the upper carriages 18 are provided with wheels 20 which protrude from the lower side of the carriage and which travel along the upper surface of guide rail 21 and lower carriages 19 ( fig6 ) are provided with wheels 20 which protrude from the upper side of the carriages and which travel along the lower surface of guide rail 22 . at least at the places about the machine where the birds are cut the wheels 20 run over upper and lower guide rails 21 and 22 , respectively . from fig6 it appears that the guide rail 22 may be a tube having an annular cross - section ; in that case the wheels are provided with two flanges . each of the upper carriages 18 carries a laterally extending support element 18 &# 39 ; that supports an upper coupling member 23 which is rotatable about a vertical shaft 39 ( fig7 ), to which coupling member two vertical guide bars 24 are suspended . each of the lower carriages 19 carries a laterally extending support element 19 &# 39 ; that supports a lower coupling member 25 which is rotatable about a vertical shaft that is aligned with the vertical shaft 39 . the lower ends of the guide bars 24 are , as shown in fig6 connected to the lower coupling member 25 . a block 26 is slidably mounted along guide bars 24 of each module m . the blocks 26 normally are supported by the coupling members 25 , by each block resting on the upper surface of its coupling member 25 . each block 26 is moved upwardly along guide bars 24 when a cam wheel ( not illustrated ) on the back of each block 26 engages cam track 27 ( fig3 ), so that each block 26 moves through a curved path starting between the longitudinal cutter d and the cross - bisection means e in fig3 . the downward movement of the blocks 26 is obtained on the not visible rear side of the machine by a downwardly sloped incline of cam track 27 before the end of the cycle of movement of the blocks about the machine . on each block 26 a specially designed stretching cone or mandrel 28 is suspended which , during the passage of the birds through the breast cutters a and b , the wing cutters c and the longitudinal cutter d , is placed in its bird , which positions and stabilized the bird and keeps the bird slightly under tension from the inside . by each lower coupling member 25 a supporting plate 29 ( fig6 ) is suspended , which is laterally spaced behind the mandrel 28 . as illustrated in fig4 - 6 , from said supporting plate 29 on both sides of the mandrel 28 extend a fixed pair of upper forks 30 , a tiltable pair of supporting forks 31 positioned therebelow , a pair of bows 32 and a pair of arms 33 . the members 30 - 33 provide together somewhat cup - like support from support plate 29 , so that the bird is retained in the ideal position during the cutting operation . the tiltable pair of supporting forks 31 are tilted by gravity to an up position when the birds are supplied to the side of the machine which is not visible in fig3 . after the birds have passed the longitudinal cutter d , the positioning by the mandrel 28 is no longer sufficient . the tiltable pair of supporting forks 31 are tilted &# 34 ; downwardly &# 34 ; then in a way which will be illustrated later on , in order to put the legs under tension from the knee - joint up to the thigh . this downward tilting of the forks 31 moves the forks out of the path of the drum - stick cutter f . from fig5 and 6 it appears that both the mandrel 28 and the support plate 29 have aligned slots 34 . said slots 34 serve to give passage to the large rotating blade 5 of the longitudinal cutter d through both the support plate and the mandrel . in the total view of fig3 finally reference should be made to an inverted channel 35 positioned above the upper chain 13 , a special part of which is represented in fig7 . said inverted channel 35 alternatingly houses the wheels 36 and 37 which are provided on the ends of a hooked horizontal lever 38 which is fastened to the vertical shaft 39 which on the other hand is fixedly connected to the upper coupling member 23 ( fig3 ) of each carriage 18 . on two places the side walls of the inverted channel are bent outwardly , viz ., on the one hand between the breast cutters a and b and the wing cutter c , and on the other hand between the longitudinal cutter d and the cross - bisection means e . in fig7 the first mentioned place is shown . the wheel 36 there runs against an outwardly bent side wall 41 of the inverted channel , whereby the vertical shaft 39 is rotated 90 °. the wheel 37 , which was in the channel , wants to turn to the outside now and is enabled thereto in that in the opposite side wall of the inverted channel 35 also a part 42 is bent outwardly . the wheel 37 assures in the secondly meant place that the vertical shaft 39 is rotated back again 90 °. fig4 shows details of the breast cutters a and b . the rotating blades 1 and 2 are driven by electromotors 43 and 44 respectively but other drive means are within the scope of the invention . the mandrels or stretching cones 28 have a recess which is limited by a surface 45 parallel to the surface of the blade 1 , and surface 46 parallel to the surface of the blade 2 . in fig4 it can be seen that the stretching cones after passing the breast cutters a and b begin to rotate 90 °. fig5 shows details of the wing cutters c and the longitudinal cutter d . the rotating blades 3 and 4 of the wing cutters c are driven by electromotors 47 and 48 , respectively . before the chickens arrive at the rotating blades 3 and 4 , the wings are lifted between left and right hand pairs of wing guide straps 49 / 50 and 51 / 52 respectively . the rotating blade 5 of the longitudinal cutter d is driven by an electromotor 53 . also here other drive means are within the scope of the invention . fig6 shows details of the cross - bisection means e and the drum - stick cutter f . the rotating blades 6 and 7 are driven by electromotors 54 and 55 , respectively . in fig6 it can be seen from the position of the slot 34 of the stretching cone 28 , that it has been rotated back again over 90 ° with respect to the position of fig5 . in front of the rotating blade 6 of the cross - bisection means e a pair of guide straps 56 / 57 is provided , and in front of the rotating blade 7 of the drum - stick cutter f another single guide strap 58 . the supporting forks 31 are enabled to tilt about a shaft 59 which is connected to the supporting plate 29 . the tilting is controlled by a rising curve 60 which pushes a roller 61 , which is connected with the forks behind the supporting plate 29 , upwardly whereby the supporting forks will tilt &# 34 ; downward &# 34 ; and put the chicken legs under tension from the knee - joint up to the thigh . the backward or &# 34 ; upward &# 34 ; tilting and remaining in said position of the supporting forks 31 occurs under influence of gravitation . therefore the mass behind shaft 59 is larger than in front of shaft 59 . after all above - mentioned operations have been carried out on the chicken , only the drum - sticks , which are suspended in the fixed pair of upper forks 30 , are left . said drum - sticks can be removed in a simple ( not indicated ) way . it should be understood that embodiments other than that shown in the drawing are within the scope of the invention as set forth in the following claims .

a worker hangs birds on a series of movable modules m by placing the hocks of previously slaughtered and eviscerated birds in the pair of forks 30 affixed to the support plate 29 of each module . the thighs are received in the pair of tiltable forks 31 . as the modules are conveyed about the machine a mandrel 28 carried by each module moves down into the cavity of the bird to stabilize the bird , and the bird is moved with the module through several cutting discs 1 - 7 which cut the carcasses into sections . the modules are rotated to orient the bird with respect to the cutting discs , and the legs of the bird are stretched by the tiltable forks 31 as the leg joint is cut .

the expression “ production line ” designates all of the pipes and elements of the method such as pumps , heat exchangers , a homogenizer and a holder in which the dairy composition circulates . the expression “ continuous injection ” designates a method consisting of a mixing of two fluids ( in the present case a dairy composition and molten sterol and / or stanol ester ) initially conveyed in separate lines , then mixed by joining these lines at a particular point of the method ( before homogenization ), and corresponds to an in - line injection . the expression “ milk - based initial composition ” designates the starting dairy composition before any treatment , whereas the expression “ dairy composition ” corresponds to the initial milk - based composition which has undergone a treatment , in particular a heat treatment . the expression “ via the production line ” refers to the fact of introducing the molten sterol and / or stanol ester via a production line into the production line of the dairy composition . the temperature t 2 of the dairy composition into which the sterol and / or stanol ester is injected is equal to or higher than the temperature t 1 at which said ester is found , this temperature t 1 itself being equal to or higher than the melting temperature of the ester . according to an advantageous embodiment of the invention , the temperature t 2 is approximately 5 ° c . higher than the melting temperature of the ester , and the temperature t 1 is approximately 2 ° c . higher than the melting temperature of the ester . according to another embodiment , the temperature t 1 is approximately 5 ° c . to 10 ° c . higher than the melting temperature of the ester . an advantageous method according to the present invention comprises a stage of continuous introduction of a sterol and / or stanol ester at a temperature t 1 ranging from 35 to 80 ° c ., in particular from 40 to 70 ° c ., and more particularly from 45 to 60 ° c ., into the dairy composition as defined above . the present invention relates to a method as defined above , comprising a stage of continuous introduction of a stanol ester at a temperature t 1 ranging from 60 to 80 ° c ., and preferably from 65 to 70 ° c ., into the dairy composition as defined above . the present invention also relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of preheating the initial composition as defined above , said preheating stage being carried out at a temperature t 2 of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of introduction by continuous injection of the sterol and / or stanol ester at a temperature t 1 as defined previously , into the abovementioned dairy composition at the preheating temperature , in order to obtain a mixture , and a stage of homogenization of said mixture . the present invention also relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of heating a dairy composition corresponding to an initial milk - based composition , containing milk proteins and without emulsifier , said heating stage being carried out at a temperature t 2 of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a dairy composition at the heating temperature , a stage of introduction of the sterol and / or stanol ester at a temperature t 1 defined previously , into the abovementioned dairy composition at the heating temperature , in order to obtain a mixture , and a stage of homogenization of said mixture . the present invention also relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of heating a dairy composition corresponding to an initial milk - based composition , containing milk proteins and without emulsifier , said heating stage being carried out at a temperature t 2 of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a dairy composition at the heating temperature , a stage of introduction of the sterol and / or stanol ester at a temperature t 1 defined previously , into the abovementioned dairy composition at the heating temperature , in order to obtain a mixture , and a stage of holding said mixture , said holding stage being carried out for a period sufficient to maintain the dairy composition originating from the heating stage for a period at the heating temperature , sufficient to destroy the vegetative microbial flora , in order to obtain a held mixture , and a stage of homogenization of the abovementioned held mixture . the abovementioned holding stage corresponds to a stage allowing destruction of the vegetative microbial flora , including the pathogenic forms , for in particular approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably being carried out for approximately 6 minutes . the present invention also relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of introduction into the abovementioned dairy composition at the preheating temperature , of at least one sterol and / or stanol ester at the temperature t 1 defined previously , in order to obtain a mixture , a stage of homogenization of the abovementioned mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized mixture , a stage of heating the abovementioned homogenized mixture , said heating being carried out at a heating temperature of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out approximately 95 ° c ., in order to obtain a heated homogenized mixture , and a stage of holding the abovementioned heated homogenized mixture , said holding stage being carried out at a temperature more or less equal to that of the preceding stage , namely the heating stage , in order to obtain a heated and homogenized held mixture . according to an advantageous embodiment of the invention , the abovementioned holding stage is carried out in particular for approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . the present invention also relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of heating the abovementioned dairy composition , said heating being carried out at a heating temperature t 2 of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a dairy composition at the heating temperature , a stage of introduction into the abovementioned dairy composition at the preheating temperature of at least one sterol and / or stanol ester at a temperature t 1 defined above , in order to obtain a mixture , a stage of homogenization of the abovementioned mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized mixture , and a stage of holding the abovementioned homogenized mixture , in order to obtain a homogenized held mixture . according to an advantageous embodiment of the invention , the abovementioned holding stage is carried out in particular for approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . the present invention also relates to a preparation method for a dairy product of the invention , characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of heating the abovementioned dairy composition , said heating being carried out at a heating temperature t 2 of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a dairy composition at the heating temperature , and a stage of introduction into the abovementioned dairy composition at the preheating temperature of at least one sterol and / or stanol ester at a temperature t 1 defined previously , in order to obtain a mixture , a stage of holding the abovementioned mixture , in order to obtain a held mixture , and a stage of homogenization of the abovementioned held mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized held mixture . according to an advantageous embodiment of the invention , the abovementioned holding stage is carried out in particular for approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . the present invention also relates to a preparation method for a dairy product as defined previously , characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of heating the abovementioned dairy composition , said heating being carried out at a heating temperature t 2 of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a dairy composition at the heating temperature , a stage of holding the abovementioned dairy composition at the heating temperature , in order to obtain a held dairy composition , said holding stage being carried out at a temperature more or less equal to that of the preceding stage , namely at the heating temperature , a stage of introduction into the abovementioned held dairy composition of at least one sterol and / or stanol ester at a temperature t 1 defined previously , in order to obtain a mixture , a stage of homogenization of the abovementioned mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized mixture . according to an advantageous embodiment of the invention , the abovementioned holding stage is carried out in particular for approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . according to an advantageous embodiment , a preferred method according to the present invention is characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of introduction into the abovementioned dairy composition at the preheating temperature , of at least one sterol and / or stanol ester at a temperature t 1 defined previously , in order to obtain a mixture , a stage of heating the abovementioned mixture , said heating being carried out at a heating temperature t 2 of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a mixture at the heating temperature , a stage of holding the abovementioned mixture at the heating temperature , in order to obtain a held mixture , said holding stage being carried out at a temperature more or less equal to that of the preceding stage , namely at the heating temperature , and a stage of homogenization of the abovementioned held mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized mixture . according to an advantageous embodiment of the invention , the abovementioned holding stage is carried out in particular for approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . an advantageous method according to the present invention is a method as defined above , in which the holding stage is followed by the following stages : a stage of fermentation of the heated and homogenized held mixture as defined above , carried out at a temperature of approximately 30 ° c . to approximately 47 ° c ., in particular approximately 35 ° c . to approximately 45 ° c ., and preferably approximately 38 ° c . to approximately 42 ° c ., in order to obtain a fermented mixture , and an optional stage of smoothing the abovementioned fermented mixture , in order to obtain a final white mass , comprising a fatty phase , corresponding to the sterol and / or stanol ester , included by the homogenization stage in the protein network formed by the milk proteins and the milk of the abovementioned initial composition as defined previously , said final white mass being characterized in that it exhibits homogeneity between the fatty phase and the protein network , and exhibits no phase difference between the aqueous phase and the protein network . according to an advantageous embodiment of the invention , the duration of the fermentation stage is from a few hours to a few days , and in particular approximately 3 hours to approximately 24 hours , and is preferably approximately 3 to approximately 12 hours , in particular approximately 5 to approximately 10 hours , and preferably approximately 6 to 9 hours . within the framework of the fermentation stage , the consumption of lactose by the lactic bacteria causes the formation of lactic acid and thus reduces the ph , which leads to the formation of the protein network . within the framework of the smoothing stage , in order to obtain a so - called “ stirred ” texture , the white mass is sheared and the fermentation is stopped by cooling down . an absence of serum is then observed on visual examination of a firm yogurt , as well as a homogeneity between the fatty phase and the protein network , according to the following two parameters : the size of the fatty globules is comprised between 0 . 2 and 2 μm , in particular between 0 . 2 and 1 μm , and the organoleptic properties ( no oily taste and no sandy appearance linked to the crystals of fatty material ). an advantageous method according to the present invention is a method as defined above , in which the smoothing stage is followed by a stage corresponding to the addition of a fruit preparation without sterol and / or stanol in any form whatever . an advantageous method according to the present invention is a method as defined above , in which the smoothing stage is followed by a stage corresponding to the addition of a cereal - based composition without sterol and / or stanol in any form whatever . an advantageous method according to the present invention is a method as defined above , characterized in that the fruit preparation comprises a thickener , in particular chosen from : xanthan gum , pectin , starch , in particular gelatinized , gelan gum , cellulose and its derivatives , guar and carob gum , and inulin , the concentration of these thickeners being approximately 0 . 4 % to approximately 3 % relative to the fruit preparation . the present invention also relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature t 2 of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of introduction into the abovementioned dairy composition of at least one sterol ester at a temperature t 1 defined previously , in order to obtain a mixture , a stage of homogenization of the abovementioned mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized mixture , a stage of heating the abovementioned homogenized mixture , said heating being carried out at a heating temperature of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a heated homogenized mixture , and a stage of holding the abovementioned heated homogenized mixture , in order to obtain a heated and homogenized held mixture , a stage of fermentation of the abovementioned heated and homogenized held mixture , carried out at a temperature of approximately 30 ° c . to approximately 47 ° c ., in particular approximately 35 ° c . to approximately 45 ° c ., and preferably approximately 38 ° c . to approximately 42 ° c ., in order to obtain a fermented mixture , and an optional smoothing stage of the abovementioned fermented mixture , in order to obtain a final white mass , comprising a fatty phase , corresponding to the sterol and / or stanol ester , included by the homogenization stage in the protein network formed by the milk proteins and the milk of the abovementioned initial composition as defined above , said final white mass being characterized in that it exhibits a homogeneity between the fatty phase and the protein network , and exhibits no phase difference between the aqueous phase and the protein network . according to an advantageous embodiment of the invention , said holding stage being carried out for a period of approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . this method makes it possible to obtain a dairy product of natural , firm or stirred yogurt type . in the absence of a smoothing stage , a firm yogurt is obtained , and in the presence of a smoothing stage , a stirred yogurt is obtained . an advantageous method according to the present invention is a method as defined above , characterized in that the initial composition is without thickener . this advantageous embodiment of the present invention makes it possible to obtain a product which exhibits a better homogeneity between the protein network and the fatty phase , insofar as the thickeners placed in an initial composition contribute to reducing the effectiveness of the protein network . the present invention relates to a preparation method for a dairy product as defined above , characterized in that it comprises the following stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature t 2 of approximately 50 ° c . to approximately 70 ° c ., in particular approximately 55 ° c . to approximately 65 ° c ., and preferably being carried out at approximately 65 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of introduction into the abovementioned dairy composition of at least one sterol and / or stanol ester at a temperature t 1 defined previously , in order to obtain a mixture , a stage of homogenization of the abovementioned mixture at a pressure of approximately 100 bars to approximately 280 bars , in particular approximately 100 bars to approximately 250 bars , advantageously approximately 100 bars to approximately 200 bars , and preferably approximately 200 bars , in order to obtain a homogenized mixture , a stage of heating the abovementioned homogenized mixture , said heating being carried out at a heating temperature of approximately 85 ° c . to approximately 100 ° c ., in particular approximately 87 ° c . to approximately 97 ° c ., advantageously approximately 87 ° c . to approximately 95 ° c ., and preferably being carried out at approximately 95 ° c ., in order to obtain a heated homogenized mixture , and a stage of holding the abovementioned heated homogenized mixture , in order to obtain a heated and homogenized held mixture , a stage of fermentation of the abovementioned heated and homogenized held mixture , carried out at a temperature of approximately 30 ° c . to approximately 47 ° c ., in particular approximately 35 ° c . to approximately 45 ° c ., and preferably approximately 38 ° c . to approximately 42 ° c ., in order to obtain a fermented mixture , and a smoothing stage of the abovementioned fermented mixture , in order to obtain a final white mass , comprising a fatty phase , corresponding to the sterol and / or stanol ester , included by the homogenization stage in the protein network formed by the milk proteins and the milk of the abovementioned initial composition as defined above , said final white mass being characterized in that it exhibits a homogeneity between the fatty phase and the protein network , and exhibits no phase difference between the aqueous phase and the protein network , a stage of addition of a fruit preparation without sterol and / or stanol in any form whatever , and a stage of mixing of the abovementioned final white mass using a dynamic or static mixer , before said dairy product is put into pots . according to an advantageous embodiment of the invention , said holding stage is carried out for a period of approximately 4 minutes to approximately 10 minutes , in particular approximately 5 to approximately 8 minutes , and preferably for approximately 6 minutes . this method makes it possible to obtain a dairy product of stirred fruit yogurt type . an advantageous method according to the present invention is a method as defined above , characterized in that the fruit preparation contains a thickener , in particular chosen from : alginates , xanthan gum , pectin , starch , in particular gelatinized , gelan gum , cellulose and its derivatives , guar and carob gum , and inulin , the concentration of these thickeners being approximately 0 . 4 % to approximately 3 % relative to the fruit preparation . according to an advantageous embodiment , the method according to the invention is characterized in that the initial composition comprises milk , milk powder , milk proteins and an agent in a concentration such that it limits syneresis , said agent being in particular chosen from : the alginates , maltodextrins , pectins , soluble fibres , starch and inulin , and preferably being starch . by “ agent limiting syneresis ” is meant a compound having a strong hydrophilic character allowing it to retain water ( serum ) not retained by the protein network formed during the acidification . the agent used within the framework of the present invention is of a nature and concentration such that it has no viscosing effect on the lactic gel ( structure formed by the milk proteins ). the present invention also relates to a method as defined above , characterized in that the sterol and / or stanol ester is chosen from the group comprising : 22 - dihydroerogo sterol , 7 , 24 ( 28 )- erogostadienol , campesterol , neospongosterol , 7 - ergostenol , cerebisterol , corbisterol , stigmasterol , focosterol , α - spinasterol , sargasterol , 7 - dehydrocryonasterol , poriferasterol , chondrillasterol , β - sitosterol , cryonasterol ( γ - sitosterol ), 7 - stigmasternol , 22 - stigmastenol , dihydro - γ - sitosterol , β - sitostanol , 14 - dehydroergosterol , 24 ( 28 )- dehydroergosterol , ergosterol , brassicasterol , ascosterol , episterol , fecosterol and 5 - dihydroergosterol , and their mixtures and is advantageously β - sitosterol , β - sitostanol , β - sitostanol ester , campesterol or brassicasterol . the present invention also relates to a method as defined above , characterized in that the ratio of the sterol and / or stanol ester flow rate to the initial milk - based composition flow rate ranges from approximately 0 . 5 to approximately 3 . the present invention also relates to a product as obtained according to the method of the invention as defined above . the present invention also relates to a product as obtained according to the method of the invention , being presented in the form of a dairy product of firm natural yogurt type . the present invention also relates to a product as obtained according to the method of the invention , being presented in the form of a dairy product of natural or fruit stirred yogurt type or of drinking yogurt type . the present invention also relates to a product as defined above , containing approximately 0 . 1 % to approximately 3 % sterol and / or stanol ester , and in particular approximately 0 . 5 % to approximately 2 . 5 % sterol and / or stanol ester , advantageously approximately 1 % to approximately 1 . 6 % sterol and / or stanol ester . the present invention also relates to a device for the implementation of the method as defined above , of continuous introduction , via a production line , of at least one sterol and / or stanol ester at a given temperature t 1 , higher than or equal to the melting temperature of said ester , and in particular ranging from 35 to 80 ° c ., into a dairy composition at a temperature t 2 higher than or equal to the temperature t 1 , characterized in that it comprises the following elements : means making it possible to maintain the abovementioned sterol and / or stanol ester at the temperature t 1 , such as a heat - insulated tank or a thermostatically controlled vat , means making it possible to circulate said ester towards a production line supply means , whilst maintaining said ester at the temperature t 1 , such as a heat - insulated tube , and supply means making it possible to introduce said ester at the temperature t 1 , into the production line , such as a positive pump . an advantageous device of the invention comprises means for circulation of the dairy composition heated to the abovementioned temperature t 2 , and is such that the abovementioned pump circulates the ester at a flow rate proportional to the circulation flow rate of the abovementioned dairy composition heated to the temperature t 2 . the present invention also relates to a preparation method for a dessert - type product . said method is carried out starting with an initial dairy composition containing at least one thickener and / or at least one gelling agent . this method corresponds to that of the invention and comprises more particularly a stage of preheating the initial dairy composition , a stage of injection of the molten sterol and / or stanol ester , a stage of homogenization , a heating stage at a temperature of approximately 85 ° c . to approximately 130 ° c ., in particular at 120 ° c . fig1 represents the preparation method for a firm yogurt , into which a molten sterol and / or stanol ester is introduced after the preheating stage . more precisely the tank containing the dairy composition ( dairy mix ) is represented by ( 1 ). the dairy composition is preheated to a temperature of approximately 50 ° c . to approximately 70 ° c . represented by ( 2 ). the introduction of the sterol and / or stanol ester into the preheated dairy composition in a quantity of approximately 0 . 5 % to approximately 3 %, molten at a temperature of approximately 35 ° c . to approximately 80 ° c ., is represented by ( 3 ). the stage of homogenization of the mixture obtained in the preceding stage , at a pressure of approximately 100 to approximately 250 bars is represented by ( 4 ). the stage of heating the homogenized mixture obtained in the preceding stage at a temperature of approximately 87 ° c . to approximately 97 ° c . is represented by ( 5 ), and the stage of holding the heated homogenized mixture for approximately 4 to 10 minutes by ( 6 ). the heated and homogenized held mixture is then cooled down to a temperature of approximately 47 ° c . to approximately 30 ° c . ( 7 ) then the ferments are added ( 8 ). the mixture is then put into pots ( 9 ) followed by oven drying at fermentation temperature ( 10 ), then the fermentation is stopped by refrigerating ( 11 ). the stages indicated above correspond to the “ method ” part represented by the bracketed section ( a ) in fig1 . stages ( 9 ), ( 10 ) and ( 11 ) correspond to the “ conditioning ” part represented by the bracketed section ( b ) in fig1 . the firm yogurt obtained contains 0 . 5 % to 3 % sterol and / or stanol ester . fig2 represents a variant of the preparation method for a firm yogurt , in which the introduction ( 3 ) of the sterol or stanol , in the form of approximately 0 . 1 % to approximately 3 % molten ester sterol at a temperature of approximately 35 to approximately 80 ° c . or approximately 0 . 5 % to approximately 3 % molten ester sterol at a temperature of approximately 60 to approximately 80 ° c . is carried out after the stage of heating ( 5 ) the dairy composition preheated in ( 2 ). the introduction ( 3 ) of the sterol or stanol ester is followed by a homogenization stage ( 4 ) at a pressure of approximately 100 to approximately 250 bar of the mixture obtained in the preceding stage , then followed by a holding stage . it should be noted that in this figure , the figures and numbers ( 1 to 11 ) and letters ( a and b ) used have the same meanings as those indicated in fig1 . the firm yogurt obtained contains 0 . 5 to 3 % sterol or stanol ester . fig3 represents a variant of the preparation method for firm yogurt , in which the introduction ( 3 ) of the sterol or stanol , in the form of sterol ester or stanol ester is carried out in the quantities and at the melting temperatures indicated in fig2 . the introduction ( 3 ) of the sterol or stanol is followed by a holding stage ( 6 ) then by a homogenization stage ( 4 ) which makes it different from the method of fig2 , in which the stage of introduction of the sterol or stanol is followed by a homogenization stage ( 4 ) then a holding stage ( 6 ). in this figure , the figures and numbers ( 1 to 11 ) and letters ( a and b ) used have the same meanings as those indicated in fig1 and fig2 . the firm yogurt obtained contains 0 . 5 to 3 % sterol or stanol ester . fig4 represents the preparation method for a stirred yogurt , into which a molten sterol ester is introduced after the preheating stage . more precisely the tank containing the dairy composition ( dairy mix ) is represented by ( 1 ). the dairy composition is preheated to a temperature of approximately 50 ° c . to approximately 80 ° c . represented by ( 2 ). the introduction of the sterol and / or stanol ester into the preheated dairy composition in a quantity of approximately 0 . 5 to approximately 3 %, molten at a temperature of approximately 35 ° c . to approximately 80 ° c . is represented by ( 3 ). the stage of homogenization of the mixture obtained in the preceding stage , at a pressure of approximately 100 to approximately 250 bars is represented by ( 4 ). the stage of heating the homogenized mixture obtained in the preceding stage , at a temperature of approximately 87 ° c . to approximately 97 ° c ., is represented by ( 5 ) and the stage of holding the heated homogenized mixture , for approximately 4 to 10 minutes , by ( 6 ). the heated and homogenized held mixture is then cooled down to a temperature of approximately 47 ° c . to 30 ° c . ( 7 ) then ferments are added ( 8 ) followed by fermentation at a temperature of approximately 30 ° c . to approximately 47 ° c . ( 9 ). smoothing is then carried out followed by cooling down in order to stop the fermentation ( 10 ) in order to obtain a final white mass ( 11 ) which corresponds to the natural stirred finished product , which put into pots in stage ( 12 ). in the case of the preparation of a stirred fruit yogurt , a fruit preparation is introduced ( 13 ) into the final white mass followed by mixing using a dynamic or static mixer ( 14 ) then putting into pots ( 12 ). stages ( 1 ) to ( 10 ) indicated above correspond to the “ method ” part represented by the bracketed section ( a ) in fig4 . the stages ( 12 ), ( 13 ) and ( 14 ) correspond to the “ conditioning ” part represented by the bracketed section ( b ) in fig4 . the firm yogurt obtained contains 0 . 5 % to 3 % sterol or stanol ester . fig5 represents a variant of the preparation method for a stirred natural or fruit yogurt , into which the introduction ( 3 ) of the sterol or stanol , in the form of approximately 0 . 5 % to approximately 3 % molten sterol ester at a temperature of approximately 35 to approximately 80 ° c . or approximately 0 . 5 % to approximately 3 % molten ester sterol at a temperature of approximately 60 to approximately 80 ° c . is carried out after the stage of heating ( 5 ) of the dairy composition preheated in ( 2 ). the introduction ( 3 ) of the sterol or stanol ester is followed by a homogenization stage ( 4 ) at a pressure of approximately 100 to approximately 250 bars of the mixture obtained in the preceding stage , followed by a holding stage . it should be noted that in this figure , the figures and numbers ( 1 to 4 ) and letters ( a and b ) used have the same meanings as those indicated in fig4 . the firm yogurt obtained contains 0 . 5 to 3 % of sterol or stanol ester . fig6 represents a variant of the preparation method for stirred natural or fruit yogurt , in which the introduction ( 3 ) of the sterol or of the stanol , in the form of sterol ester or stanol ester is carried out in the quantities and at the melting temperatures indicated in fig5 . the introduction ( 3 ) of the sterol or stanol is followed by a holding stage ( 6 ) then a homogenization stage ( 4 ) which makes it different from the method of fig5 , in which the stage of introduction of the sterol or stanol is followed by a homogenization stage ( 4 ) then by a holding stage ( 6 ). in this figure , the figures and numbers ( 1 to 14 ) and letters ( a and b ) used have the same meanings as those indicated in fig4 and fig5 . the firm yogurt obtained contains 0 . 5 % to 3 % sterol or stanol ester . fig7 represents a so - called “ in - line ” injection system , comprising a thermostatically controlled vat ( 1 ) containing the molten stanol and / or the sterol ester , the latter being maintained at a temperature of 45 - 70 ° c . ( higher than the melting temperature ) by a warm water circulation system the temperature of which is regulated in the jacket of the vat ( 2 ), the stanol and / or sterol ester being stirred in this vat by the rotation of blades about a shaft ( 3 ) in order to render the temperature in this vat homogeneous . the stanol and / or sterol ester in the liquid form is then pumped by a pcm positive - type pump ( 4 ) via a heat - insulated pipe ( 5 ) at a continuously determined and measured flow rate d 1 , this flow rate d 1 being proportional to the flow rate d 2 of the pipe ( 6 ) in which the dairy composition heated to a temperature higher than the melting temperature of the stanol and / or sterol ester circulates . the pipes ( 5 ) and ( 6 ) join at a point ( 7 ). thus a homogeneous dispersion of the stanol and / or sterol ester is made possible by ensuring the turbulent flow of the dairy composition . this mixture is then conveyed towards the homogenizer ( 8 ) in order to disperse the stanol and / or sterol ester in the protein matrix in optimum manner . milk with 0 . 50 % fat , at a rate of approximately 70 % to approximately 97 %, in particular at a rate of 94 . 6 %; skimmed milk powder at a rate of approximately 0 to 5 %, in particular at a rate of 3 . 7 %; milk proteins at a rate of approximately 0 . 2 to approximately 0 . 8 %, in particular at a rate of 0 . 6 %; native starch in a quantity such that it limits syneresis , and in particular 0 to approximately 0 . 5 %, and in particular 0 . 3 %; 0 to approximately 10 % sugar and 0 to approximately 25 % water . this initial dairy composition is placed in a float hopper in the production line , at a temperature of approximately 10 ° c ., for a sufficient time to rehydrate all of the dairy ingredients defined above , then preheated to a temperature of approximately 70 to 80 ° c . after the preheating of the initial dairy composition , molten sterol esters are introduced in quantities such that they are present in the finished product in a quantity of 0 . 5 % to 2 . 5 %, followed by homogenization at a pressure of 100 to 250 bars . the mixture obtained above is heated at a temperature of 90 to 95 ° c . in order to pasteurize , for 3 to 8 minutes , then cooled down to a temperature of 35 ° c . to 45 ° c ., and the cooled mixture is seeded with lactic strains and packaged in pots , to carry out the fermentation in the pots to ph 4 . 8 - 4 . 5 , in order to obtain a firm natural yogurt . the firm natural yogurt thus obtained is refrigerated in order to stop the fermentation . in order to obtain a stirred natural yogurt , smoothing was carried out by stirring the fermented white mass and the fermentation of the white mass obtained is stopped by passing the latter over a plate heat exchanger , cooling down to 20 ° c . then packaging in pots . in order to obtain a drinking yogurt , the fermentation of the final white mass obtained is stopped by passing over a plate heat exchanger , cooling down to 4 ° c ., then smoothed by passing into a smoothing nozzle making it possible to obtain a drinking yogurt texture , followed by packaging . a stirred fruit yogurt is prepared by proceeding as in example 1 , into which , after smoothing and cooling down , a fruit preparation containing 48 . 3 % concentrated fruits , 44 . 4 % sugar , 0 . 3 % pectin , 1 . 4 % starch , 0 . 02 colouring , 0 . 5 % flavouring and 5 . 08 % water is introduced . a stirred fruit yogurt is prepared by proceeding as in example 1 , into which , after smoothing and cooling down , a fruit preparation containing 55 . 7 % concentrated fruits , 36 . 3 % sugar , 0 . 12 % xanthan , 1 . 5 % starch , 0 . 019 % colouring , 0 . 5 % flavouring and 5 . 861 % water is introduced . by proceeding as in example 1 , a fruit drinking yogurt is prepared , into which , after smoothing and cooling down , a fruit preparation containing 42 % concentrated fruits , 32 . 4 % sugar , 1 % colouring , 0 . 6 % flavouring , 0 . 7 % starch and 23 . 3 % water is introduced . the results of this example clearly show that it is more difficult to obtain a satisfactory product when hydrocolloids ( such as thickeners ) are added to the product . thus , the method used is the method according to the present invention comprising the following characteristic stages : a stage of preheating an initial milk - based composition , containing milk proteins and without emulsifier , at a preheating temperature of approximately 50 ° c . to approximately 70 ° c ., in order to obtain a dairy composition at the preheating temperature , a stage of introduction into the abovementioned dairy composition at the preheating temperature , of at least one sterol and / or stanol ester at a temperature t 1 of approximately 50 ° c . to approximately 65 ° c ., in order to obtain a mixture , a stage of heating the abovementioned mixture , said heating being carried out at a heating temperature t 2 of approximately 95 ° c ., in order to obtain a mixture at the heating temperature , a stage of holding the abovementioned mixture at the heating temperature , said holding stage being carried out for a period of approximately 6 minutes , in order to obtain a held mixture , a stage of homogenization of the abovementioned held mixture at a pressure of approximately 200 bars , in order to obtain a homogenized mixture . for comparison , the method was used for an initial dairy composition free of hydrocolloids , and to an initial dairy composition containing hydrocolloids ( xanthan and starch ). it is noted that the initial dairy composition which is free of hydrocolloids has a dense protein network with a fairly good homogeneity of the fatty phase ( dispersed fatty phase well inserted into the protein network ). the product thus obtained is very firm , whereas the initial dairy composition containing hydrocolloids has a strong heterogeneity ( phase separation between the milk proteins and the xanthan gum ). the heterogeneity of the mixture is also visible on a macroscopic scale due to the granular texture of the finished product . these results make it possible to demonstrate the benefit of not using hydrocolloids in the initial dairy composition , as the hydrocolloids prevent the suitable formation of the protein network . the purpose of this example is to compare the method of the present invention comprising the in - line injection of the molten sterol or stanol esters in a method comprising the heating of a dairy composition after the incorporation of molten sterol or stanol esters into a non - heated initial dairy composition . ingredients : 0 . 5 % milk : 95 . 4 % skimmed milk powder : 3 . 7 % dairy protein : 0 . 6 % rice starch : 0 . 3 % proteins : 5 . 0 % caseins : 3 . 65 % serum proteins : 1 . 35 % casein / serum proteins ratio : 2 . 7 0 . 5 % milk : 82 . 65 % water : 10 . 0 % sugar : 7 . 0 % dairy protein : 0 . 35 % proteins : 3 . 0 % caseins : 2 . 18 % serum proteins : 0 . 79 % casein / serum proteins ratio : 2 . 7 this method corresponds to the heating of a dairy composition comprising the initial dairy composition and the molten sterol or stanol esters . thus the ingredients in paragraph 1 are mixed in order to form an initial dairy composition , into which the molten sterol or stanol esters are incorporated . the dairy composition thus obtained is heated to 70 ° c .- 80 ° c . under stirring , making it possible to produce a homogeneous suspension for a maximum period of 2 hours . this case corresponds to the introduction of sterol and / or stanol esters into the milk in the same way as the other ingredients introduced into the composition of the dairy preparation . in this case , there is therefore a standard utilization of the ingredients for yogurt technology . this method corresponds to the in - line injection of the molten sterol or stanol esters . thus the ingredients mentioned in paragraph 1 are mixed for a maximum period of 2 hours at a maximum temperature of 10 ° c ., which makes it possible to obtain an initial dairy composition in which the milk proteins have been rehydrated . then , the abovementioned initial dairy composition is preheated to a temperature of approximately 70 ° c .- 80 ° c ., in order to obtain a preheated dairy composition , into which molten sterol or stanol esters are injected in - line . the succession of the following stages concerning in particular homogenization and fermentation is identical in the two cases and corresponds to the method of the present invention . p 1 firm yogurt obtained from a heated dairy composition with ester p 1 ′ firm yogurt obtained from the injection of ester p 2 stirred yogurt obtained from a heated dairy composition with ester p 2 ′ stirred yogurt obtained from the injection of ester p 3 drinking yogurt obtained from a heated dairy composition with ester p 3 ′ drinking yogurt obtained from the injection of ester that the yogurts obtained according to the method of the invention have a greater viscosity than those obtained by the comparison method , which corresponds to a greater firmness ; that the gels ability to retain water under stress is greater in the case of the yogurts obtained according to the invention ; that the peroxide index is significantly high in the case of the yogurts obtained according to the comparison method , than in the case of the invention . as regards the organoleptic measurements carried out on a sample of consumers : with regard to the serum , a low mark was obtained corresponding to the fact that , when the yogurt is cut , the serum is not released from the lactic gel in the yogurts according to the invention ; with regard to the homogeneity of the gel , a higher mark was obtained for the yogurt of the invention , corresponding to the fact that the gel is more brittle in the yogurt of the invention , as it is more homogeneous than that obtained with the comparison method , with regard to thickness in the mouth , the yogurt of the invention obtained a higher mark than that obtained by the comparison method , as it is less thick ; with regard to the rancid taste , a mark of zero was obtained for the yogurt of the invention ; moreover , the consumers noted a “ cooked ” taste for the yogurt obtained according to the comparison method . the comparison method , corresponding to the heating of a dairy composition comprising the initial dairy composition and the molten sterol or stanol esters , has the following drawbacks : a ) this dairy composition is heated in the presence of air dissolved because of stirring ; it is therefore capable of oxidizing the unsaturated fatty acids of the esters ( esterification in the presence of rapeseed oil naturally rich in c18 : 2 , and c18 : 3 ), which produces peroxides , then hydroperoxides known to generate rancid tastes which are unacceptable for a food product . moreover , these compounds are capable of oxidizing of the nutritionally useful molecules such as vitamins ( c , e and a ) as well as certain amino acids ( methionine and tryptophan ). b ) the long stage of heating between 70 ° c . and 80 ° c . of the dairy composition comprising the initial dairy composition and the molten sterol or stanol esters ( up to 2 hours ) is also capable of degrading the serum proteins , which have a considerable functional importance in the yogurt - production technologies ( emulsification of the fats , serum retention , viscosity ). c ) the “ maillardization ”, in the presence of sugar ( lactose ) and amino acids , of the molecular polymerization reactions can result in colour changes ( browning ) as well as “ cooked ” tastes ; moreover this reaction mobilizes lysine , an essential amino acid .

a method for preparing a dairy product in a production line , includes a step of continuously injecting at least one sterol and / or stanol ester through the production line at a predetermined temperature t 1 no lower than the melting point of the ester , and particularly at a temperature of 35 - 80 ° c ., and into a dairy composition at a predetermined temperature t 2 no lower than the temperature t 1 , which composition consists of an initial emulsifier - free milk - based composition containing milk proteins , to give a mixture , wherein the step of injecting at least one sterol and / or stanol ester is carried out before a step of homogenizing the mixture .

in order to work with computer peripheral device , the design of pc games at early stage mostly used a keyboard or mouse as the input source ; therefore , a keyboard motion mapping table is designed by software programming in each pc game , in which the keyboard motion mapping table records the correspondence between each motion command of the pc game and any key command on a keyboard . the purpose of the keyboard motion mapping table is to allow the pc game to be able to resolve the motion command issued by the user through a specific key , and then , using the keyboard motion mapping table , to facilitate execution of corresponding motions to the pc game . for example , jump up motion is represented by the up key (↑) on the keyboard , jump down motion indicated by the down key (↓), forward motion by the left key (←) and backward motion by the right key (→). however , as the drawbacks caused by the keyboard motion mapping table in the prior art set forth hereinbefore , this may largely weaken the entertaining effect created by existing pc games . besides , since people &# 39 ; s demands may increase and health - care issues may become noticeable in the future , long - term use of the pc game employing existing keyboard motion mapping table by the user can result in specific injuries to user &# 39 ; s body ( e . g . fingers ), so conventional pc games using the keyboard motion mapping table will inevitably vanish on the market gradually . in order to allow existing popular pc games to survive on the current market , the present invention provides a new mapping tool to substitute the conventional keyboard motion mapping table , and the mapping tool of the present invention can also get rid of limitation in keyboard using a remote device as the input device . refer conjunctively to fig1 a and 1b , wherein fig1 a shows a diagram for an embodiment of the mapping tool according to the present invention , and fig1 b shows a flowchart for the method of producing the mapping tool according to the present invention . in implementation , the mapping tool set forth hereinafter may be a software application . in fig1 a , the mapping tool 10 ′ according to the present invention is linked with the original keyboard mapping table 10 , wherein the up key (↑), down key (↓), left key (←) and right key (→) each represents respective direction key on the keyboard , while the alphabets a , a ′ indicate jump up motions , the alphabets b , b ′ indicate jump down motions , the alphabets c , c ′ indicate forward motions and the alphabets d , d ′ are for backward motions . each motion in the mapping tool 10 ′ according to the present invention is not instructed by the keyboard , but enabled by a remote motion signal generated by an external remote device , and then the key press signal on the keyboard is simulated based on the generated remote motion signal so as to replace the effect of the keyboard mapping table 10 , further using the remote motion signal to control the pc game . details of the method for producing the mapping tool 10 ′ according to the present invention can be shown as fig1 b , and will be explained infra . in the method shown as fig1 b , it generates a plurality of remote motion commands with an external remote device , and creates a remote motion database consisting of the remote motion commands based on the remote motion commands ( s 100 ), wherein such remote motion commands may be motions such as , but not limited thereto , swing up , swing down , swing left , swing right , circling , swing upper right to lower left , swing upper left to lower right , stab forward or retract backward , then the mapping tool 10 ′ determines on each remote motion command to define an actual motion . next , it reads the keyboard mapping table 10 ( s 102 ) to further resolve the plurality of keyboard commands and plurality of motion commands in the keyboard motion mapping table 10 ( s 104 ); upon completion of the resolution , the mapping tool 10 ′ appreciates the correspondence between the keyboard commands in the keyboard motion mapping table 10 and the motion commands . subsequently , the mapping tool 10 ′ searches for the corresponding remote motion command based on the motion command ( s 106 ), and when the corresponding remote motion command being searched is located , the mapping tool 10 ′ links the remote motion command with the keyboard command included in the keyboard motion mapping table 10 ; as the linking operation is done , the production of the mapping tool 10 ′ is completed ( s 108 ). refer now conjunctively to fig2 a and 2b , wherein fig2 a shows a diagram for the architecture of a pc game system having the mapping tool according to the present invention , and fig2 b shows a diagram for an embodiment of a pc game system having the mapping tool according to the present invention . as shown in fig2 b , the system comprises a host 12 , a remote device 14 , a mapping tool 124 and a screen 16 . the host 12 can be a desktop computer , and consists of a wireless reception device 120 , a mapping tool 124 and at least one pc game 122 . the wireless reception device 120 can be a wireless receiver used to receive the remote motion signal transmitted from the remote device 14 , and the wireless reception device 120 can employ various types of connection interfaces to connect to the host 12 , and such connection interfaces may be a usb interface , ieee interface or rs - 232 interface . the pc game 122 has a keyboard motion mapping table 1220 , the keyboard motion mapping table 1220 recording the correspondence between each motion command of the pc game and any key command pressed on a keyboard . the mapping tool 124 consists of a remote motion resolution section 1240 and a remote motion mapping table 1242 , the remote motion resolution section 1240 being used to resolve the remote motion signal and generating the remote motion mapping table 1242 based on the result of the resolution ; meanwhile , the remote device 14 controls the pc game 122 through the remote motion mapping table 1242 and displays the control result on the screen 16 . as shown in fig2 a , the mapping tool 124 can be loaded in the host 12 by at least two fashions . the first approach is to download the mapping tool 124 included in the server host 18 to the host 12 via the network 20 , and the second way is to , with a recordable media 22 , transfer the mapping tool 124 included in the recordable media 22 to the host 12 by manual loading . the said recordable media 22 may be a compact disk ( cd ), a floppy disc or a usb thumb drive . the remote device 14 is used to generate a remote motion signal and transmit it to the wireless reception device 120 . the remote device 14 consists of an inertia sensing module 140 , a sensing signal operation unit 142 and a wireless transmission module 144 . the inertia sensing module 140 can sense the acceleration and angular speed of the remote motion that the user performs through the remote device 14 along x axis , y axis and z axis and accordingly generates a signal ; in the present embodiment , the remote device 14 is held in hand by the user . the inertia sensing module 140 consists of at least one accelerometer or at least one gyroscope . the sensing signal operation unit 142 is used to receive the acceleration and angular speed of the remote motion generated by the inertia sensing module 140 , and generates the remote motion signal indicating the acceleration and angular speed of the remote motion through computation ; the wireless transmission module 144 receives the remote motion signal generated by the sensing signal operation unit 142 , further transmitting such a remote motion signal to the wireless reception device 120 wirelessly ( e . g . bluetooth ™, radio frequency ) refer now conjunctively fig2 a , 2 b and 3 , wherein fig3 shows a flowchart for the operation method of a pc game using the mapping tool according to the present invention . initially , the user first loads in at least one pc game containing the keyboard motion mapping table 1220 ( s 200 ), the keyboard motion mapping table 1220 recording the correspondence between each motion command of the pc game and any key command pressed on a keyboard . the pc game 122 may be an action game , a heuristic game , an adventure game , a shooting game , a simulation game , a sport game or a strategic game , shown on the screen 16 of fig2 a as a tennis sport game . next , it installs the mapping tool 124 into the host 12 ( s 202 ), the mapping tool 124 comprising a remote motion resolution section 1240 and a remote motion mapping table 1242 . the mapping tool 124 can be installed in two ways ; the first approach is to download the mapping tool 124 included in the server host 18 to the host 12 via the network 20 and then install it , and the second way is to , with a recordable media 22 ( e . g . a compact disk ( cd ), a floppy disc or a usb thumb drive ), install the mapping tool 124 stored therein into the host 12 . the wireless reception device 120 of the host 12 receives the remote motion signal transmitted by the remote device 14 ( s 204 ), the remote motion signal being the signal generated by the acceleration and angular speed of the remote motion that the user performs through the remote device 14 along x axis , y axis and z axis , and the remote motion resolution section 1240 of the mapping tool 124 receives the remote motion signal transmitted by the wireless reception device 120 , then the remote motion resolution section 1240 resolve the received remote motion signal ( s 206 ). the remote motion resolution section 1240 can be a motion algorithm which resolves the meaning of the remote motion signal based on the rules defined in the motion algorithm , and creates a remote motion database with each of the resolved remote motion signal , in which the remote motion database can be defined beforehand . the mapping tool 124 next separates the motion command and keyboard key command included in the keyboard motion mapping table 1220 to acquire the keyboard key command ( s 208 ), and the mapping tool 124 links the resolved remote motion signal stored in the remote motion database with the separated keyboard key command of the keyboard motion mapping table 1220 ( s 210 ); upon completion of such a linkage , the production of the remote motion mapping table 1242 is done . the mapping tool 124 simulates the keyboard key signal based on the remote motion signal through the remote motion mapping table 1242 ( s 212 ), and at this moment , the user can now operate the pc game using the mapping tool 124 ( s 214 ). the mapping tool 124 according to the present invention can replace the conventional keyboard motion mapping table 1220 . it senses the acceleration and angular speed generated by the user &# 39 ; s body with the inertia sensing module 140 of the remote device 14 , thereby creating signals indicating motion states of the user &# 39 ; s body such as rotation , rhyme , swing or force , then transmitting wirelessly the generated remote state signal to the host 12 ; in this way , it is possible to provide the feature of high sensitivity , thus satisfying the demand for real - time control . through the resolution on the remote state signal performed by the remote motion resolution section 1240 of the mapping tool 124 and then using the mapping tool 124 to operate the pc game , it allows the present invention to meet the requirement for real - time operation of high sensitivity . 1 . the user , during pc game operations , may be exempted from the limitation of keyboard , better conforming to humanized operation condition and achieving the goal of natural ergonomics , without causing injuries or negative influences on specific portions of user &# 39 ; s body ( e . g . fingers ). it is also possible to enhance the effect of entertainment by exploiting the features of the mapping tool ; 2 . the game design company needs not to abandon popular pc games developed in earlier days , the user can still play the existing pc game through the mapping tool ; hence , the game design company is able to significantly reduce the cost of game development . the aforementioned descriptions simply set forth the preferred embodiments of the present invention , rather than limiting the scope of the present invention thereto . it is noted that all effectively equivalent technical modifications and changes made in accordance with the disclosure of the present invention and appended drawings thereof are deemed to be included in the scope of the present invention delineated in the following claims .

a method for producing a mapping tool , a pc game having the mapping tool and operation method therefore is disclosed . the mapping tool is created by means of linking a remote motion signal generated from a remote device which is operated by user with a keyboard signal from the inside of the conventional keyboard mapping table . user may operate the pc game through the mapping tool . the present invention employs the said mapping tool to replace the conventional keyboard motion mapping table , thereby achieving the objectives of providing natural ergonomic and consistently using the existing pc game having the keyboard motion mapping table .

fig1 is a schematic view of an upper part of a pair of trousers 1 according to a first embodiment of the invention . a front part of the pair of trousers 1 , i . e ., the part which is arranged on a front side of a person wearing the trousers 1 , is shown . the pair of trouser 1 is shown inside out , i . e ., two inner parts 2 in the form of pockets are visible and extending from side seams 3 to a front seam 4 . a fly 5 with a zipper ( not shown ) is arranged at the front seam 4 . an outer part 6 constitutes the part of the trousers 1 which is visible when the trousers 1 are worn by a person . the outer part 6 is made from a fabric having an elasticity which is significantly higher than the elasticity of the fabric which the inner part 2 is made from . since the inner parts 2 are arranged along the entire width of the front part of the outer part 6 , i . e ., between the side seams 3 , the inner parts 2 restrict the elasticity or stretchability of the front part of the outer part 6 in the sense that the front part of the outer part 6 is prevented from stretching more than the fabric of the inner parts 2 allows , even though the fabric of the outer part 6 would allow the front part to stretch further if the inner parts 2 had not been arranged along the front part . each of the inner parts 2 is provided with three stitchings 7 , each extending from a side seam 3 to the fly 5 . the stitchings 7 may advantageously be flat lock stitchings . the stitchings 7 are arranged side - by - side , each stitching 7 defining a slope relative to a lining 8 of the pair of trousers 1 , and in such a manner that the distance between neighbouring stitchings 7 is larger at the fly 5 than at the side seam 3 . each of the stitchings 7 is arranged closer to the lining 8 at the side seam 3 than at the fly 5 . furthermore , the stitchings 7 arranged on a given inner part 2 do not cross . thus , the stitchings 7 are arranged in a manner which follows the natural shape of the abdomen of a person wearing the pair of trousers 1 , and the stitchings 7 , in combination with the elasticity properties of the fabric of the inner parts 2 , therefore provide support for the abdomen , thereby ‘ tucking ’ the abdomen in and ensuring that the person wearing the trousers 1 appears slimmer . the distance between neighbouring stitchings 7 is sufficiently small to prevent that parts of the abdomen are allowed to protrude between the stitchings 7 . it is also important that the lowest arranged stitchings 7 , i . e ., the stitchings 7 which are arranged closest to the crotch of the trousers 1 , are arranged sufficiently low to be able to support the lowest part of the abdomen of the person wearing the trousers 1 . accordingly , the number of stitchings 7 as well as their arrangement on the inner parts 2 depends on the size of the pair of trousers 1 . thus , the embodiment shown in fig1 is suitable for trousers 1 of approximately european size 36 - 44 . in the embodiment of fig1 , at the side seams 3 the stitchings 7 are arranged in such a manner that the stitchings 7 arranged closest to the lining 8 are arranged at a distance within the interval 5 cm to 8 cm , such as at a distance within the interval 6 cm to 7 cm from the lining 8 , depending on the size of the trousers 1 . the stitchings 7 arranged furthest away from the lining 8 are arranged at a distance within the interval 8 cm to 14 cm , such as at a distance within the interval 9 cm to 13 cm from the lining 8 , depending on the size of the trousers 1 . the middle stitchings 7 are arranged approximately half way between the stitchings 7 arranged closest to and furthest away from the lining 8 , the stitchings 7 thereby being arranged substantially equidistantly at the side seams 3 . similarly , at the fly 5 the stitchings 7 are arranged in such a manner that the stitchings 7 arranged closest to the lining 8 are arranged at a distance within the interval 15 cm to 17 cm , such as at a distance within the interval 15 . 8 cm to 16 . 1 cm from the inseam ( not shown ), depending on the size of the trousers 1 . the stitchings 7 arranged furthest away from the lining 8 are arranged at a distance within the interval 7 cm to 11 cm , such as at a distance within the interval 8 . 3 cm to 9 . 5 cm from the inseam , depending on the size of the trousers 1 . the middle stitchings 7 are arranged approximately half way between the stitchings 7 arranged closest to and furthest away from the lining 8 , the stitchings 7 thereby being arranged substantially equidistantly at the fly 5 . fig2 is a schematic view of a pair of trousers 1 according to a second embodiment of the invention . the pair of trousers 1 shown in fig2 is very similar to the pair of trousers shown in fig1 , and it will therefore not be described in further detail here . however , in fig2 , each of the inner parts 2 is provided with four stitchings 7 . this makes the embodiment shown in fig2 suitable for larger sizes than the embodiment shown in fig1 . thus , the embodiment shown in fig2 is suitable for trousers 1 of approximately european size 46 - 50 . in the embodiment of fig2 , at the side seams 3 the stitchings 7 are arranged in such a manner that the stitchings 7 arranged closest to the lining 8 are arranged at a distance within the interval 6 cm to 9 cm , such as at a distance within the interval 7 cm to 8 cm from the lining 8 , depending on the size of the trousers 1 . the stitchings 7 arranged furthest away from the lining 8 are arranged at a distance within the interval 13 cm to 15 cm , such as at a distance within the interval 13 . 5 cm to 14 . 5 cm from the lining 8 , depending on the size of the trousers 1 . the remaining stitchings 7 are substantially evenly distributed between the stitchings 7 arranged closest to and furthest away from the lining 8 , the stitchings 7 thereby being arranged substantially equidistantly at the side seams 3 . similarly , at the fly 5 the stitchings 7 are arranged in such a manner that the stitchings 7 arranged closest to the lining 8 are arranged at a distance within the interval 15 cm to 19 cm , such as at a distance within the interval 16 . 2 cm to 17 . 7 cm from the inseam ( not shown ), depending on the size of the trousers 1 . the stitchings 7 arranged furthest away from the lining 8 are arranged at a distance within the interval 7 cm to 10 cm , such as at a distance within the interval 7 . 7 cm to 9 . 2 cm from the inseam , depending on the size of the trousers 1 . the remaining stitchings 7 are substantially evenly distributed between the stitchings 7 arranged closest to and furthest away from the lining 8 , the stitchings 7 thereby being arranged substantially equidistantly at the fly 5 . fig3 is a schematic view of a pair of trousers 1 according to a third embodiment of the invention . the pair of trousers 1 shown in fig3 is very similar to the pair of trousers shown in fig1 and 2 , and it will therefore not be described in further detail here . however , in fig3 , each of the inner parts 2 is provided with five stitchings 7 . this makes the embodiment shown in fig3 suitable for even larger sizes than the embodiments shown in fig1 and 2 . thus , the embodiment shown in fig3 is suitable for trousers 1 of approximately european size 52 - 60 . in the embodiment of fig3 , at the side seams 3 the stitchings 7 are arranged in such a manner that the stitchings 7 arranged closest to the lining 8 are arranged at a distance within the interval 8 cm to 10 cm , such as at a distance within the interval 8 . 5 cm to 9 . 5 cm from the lining 8 , depending on the size of the trousers 1 . the stitchings 7 arranged furthest away from the lining 8 are arranged at a distance within the interval 15 cm to 17 cm , such as at a distance within the interval 15 . 5 cm to 16 . 5 cm from the lining 8 , depending on the size of the trousers 1 . the remaining stitchings 7 are substantially evenly distributed between the stitchings 7 arranged closest to and furthest away from the lining 8 , the stitchings 7 thereby being arranged substantially equidistantly at the side seams 3 . similarly , at the fly 5 the stitchings 7 are arranged in such a manner that the stitchings 7 arranged closest to the lining 8 are arranged at a distance within the interval 17 cm to 21 cm , such as at a distance within the interval 18 . 2 cm to 20 . 1 cm from the inseam ( not shown ), depending on the size of the trousers 1 . the stitchings 7 arranged furthest away from the lining 8 are arranged at a distance within the interval 8 cm to 11 cm , such as at a distance within the interval 8 . 7 cm to 10 . 6 cm from the inseam , depending on the size of the trousers 1 . the remaining stitchings 7 are substantially evenly distributed between the stitchings 7 arranged closest to and furthest away from the lining 8 , the stitchings 7 thereby being arranged substantially equidistantly at the fly 5 . it should be noted that even though fig1 - 3 show trousers 1 with three , four and five stitchings 7 on each inner part 2 , it is not ruled out that a pair of trousers 1 according to the present invention comprises fewer or more stitchings 7 on each inner part 2 , such as two stitchings 7 , six stitchings 7 , seven stitchings 7 , etc . fig4 and 5 show a pair of trousers 1 according to an embodiment of the invention . in fig4 , the pair of trousers 1 is shown with the outer part 6 facing outwards , i . e ., in the manner they are normally worn . in fig5 the pair of trousers 1 is shown inside - out , i . e ., with the inner parts 2 facing outwards . this allows stitchings 7 on the inner parts 2 to be seen . each inner part 2 is provided with three stitchings 7 , and the embodiment shown in fig4 and 5 is therefore similar to the first embodiment illustrated in fig1 . the remarks set forth above are therefore equally applicable here . the pair of trousers 1 shown in fig4 and 5 is a full length pair of trousers 1 . fig6 and 7 show a pair of trousers 1 according to an alternative embodiment of the invention . in fig6 , the pair of trousers 1 is shown with the outer part 6 facing outwards , i . e ., in the manner they are normally worn . in fig7 the pair of trousers 1 is shown inside - out , i . e ., with the inner parts 2 facing outwards . this allows stitchings 7 on the inner parts 2 to be seen . each inner part 2 is provided with three stitchings 7 , and the embodiment shown in fig6 and 7 is therefore similar to the first embodiment illustrated in fig1 . the remarks set forth above are therefore equally applicable here . the pair of trousers 1 shown in fig6 and 7 is a pair of shorts , i . e . the length of the pair of trousers 1 shown in fig6 and 7 is shorter than the length of the pair of trousers 1 shown in fig4 and 5 . it should be noted that even though fig4 - 7 show trousers 1 having two specific lengths , it is not ruled out that a pair of trousers 1 according to the invention could have a length which differs from the length of the pair of trousers 1 illustrated in fig4 and 5 , and from the length of the pair of trousers 1 illustrated in fig6 and 7 . thus , aspects of the present invention also cover trousers 1 having a length which is between the length of the pair of trousers 1 of fig6 and 7 and the length of the pair of trousers 1 of fig4 and 5 . furthermore , aspects of the present invention cover trousers 1 which are longer than the pair of trousers 1 of fig4 and 5 and trousers 1 which are shorter than the trousers 1 of fig6 and 7 . while the invention has been illustrated by a description of the various embodiments , and while these 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 will readily appear to those skilled in the art . the invention in its broader aspects is therefore not limited to the specific details , representative methods , and illustrative examples shown and described . accordingly , departures may be made from such details without departing from the spirit and scope of the general inventive concept .

a pair of trousers has two side seams , a front seam , a back seam , an inseam , an outer part , and an inner part . the outer part constitutes the trousers and is formed by sub - parts joined at the seams . the inner part is arranged along a front part of the outer part and is joined to the outer part at the side and front seams . the outer part is made from a first material and the inner part is made from a second material , the first material having a higher elasticity than the second material . the inner part includes at least two stitchings extending from a first side seam towards the front seam , and at least two stitchings extending from a second side seam towards the front seam which follow the shape of an abdomen of a person wearing the trousers to thereby support the abdomen .

reference is now made to fig2 , which illustrates schematically a model of the patient &# 39 ; s spine , generated using data from preoperative ct scanning of the vertebrae . the model is built such that the separate vertebrae can be mutually virtually moved to enable insertion of the artificial disc between the desired vertebrae . the vertebrae are moved virtually by any of the generally available computer - based techniques , the most convenient being by use of the computer mouse , with the system software translating mouse movements to vertebral position movements . the vertebrae can be manipulated in all directions , both vertically , laterally and angularly , to enable correct insertion of the selected disc . the model takes into account the disc size and vertebral inclination . this is illustrated in fig3 and 4 , which are respectively anterior and lateral views of the spinal model , showing how the artificial disc 30 is inserted virtually between the relevant adjacent vertebrae 32 , 34 . the optimum ap position of the disc within the plane between the vertebrae must now be defined . this is done using the geometrical centers of rotation of the neighboring vertebrae . according to a currently widely accepted view , the preferred position is considered to be 2 mm dorsal to the sagittal vertebral midline , and laterally on the midline of the vertebral body . it is possible that this determination , though a good generally applicable rule of thumb , does not take into account individual features of the personal spinal anatomy of the patient being treated . according to a preferred embodiment of the present invention , the system enables the disc to be virtually maneuvered within its inter - vertebral space until the facet joints , as viewed on the virtual ct images of the model of the spine , are in the optimum bio - mechanical position , closest to their natural stance , as compared to that of the facet joints of neighboring vertebrae . this experimentally determined position takes into account any actual anatomical anomalies of the neighboring vertebrae to the new disc . this position should result in the minimum stress and loading of the facet joints , such that the success and the recovery rate of the procedure , as determined by recovered , pain - free mobility , should be optimized . this is in contrast to previously used procedures , where the standard location used for positioning the disc may not be the optimum for successful , pain - free motion recovery . in practice , the correct disc configuration is chosen from a library of optional discs , according to the type , lateral size , angle and thickness required . the orientation , position and angle of the disc endplates is calculated , and , using a virtual representation of the disc size chosen , the disc endplates are placed on the operation plan by inserting the disk virtually into the spinal ct model . the vertebra can be moved apart and re - oriented in the model in order to obtain the correct positioning for the disc chosen , either according to a conventionally accepted standard position configuration , or by viewing the stress or distortion generated on the facet joints . the operation plan , showing the planned vertebrae orientation / position is analyzed , preferably including the spine orientation during motion , and this then completes the creation of the preoperative plan , which is stored in the system for later intra - operative use . hardware elements of the system are utilized during the operation itself . the procedure is first described using a removable target plate and k - wires for position determination . reference is first made to fig5 and 6 , which are fluoroscope images taken of the spinal region where the degenerated disc is being replaced . fig5 is an ap image , while fig6 is a 60 ° obliquely acquired image , though a lateral view could equally well be used . the outer set of fiduciary balls 50 seen in the images are from the conventional c - arm dewarping jig , used to calibrate the c - arm , as is known in the art . the closely spaced rectilinear array of balls 52 in the vicinity of the neighboring vertebrae is from a three dimensional registration target , used to define the co - ordinate system of the real time fluoroscope images . these fluoroscope images are first registered with the preoperative ct images on which the planning was performed , preferably by means of image processing procedures to match vertebral anatomic features between the two sets of images , as is known in the art . the preoperative ct images can thus be aligned with any real life fluoroscope image taken of the patient in real time during the surgical procedure , the fluoroscope image orientation and position being determined initially by means of the target . the target is preferably mounted on one of the vertebrae adjacent the disc to be replaced . such a target can take a number of alternative forms , and preferably contains two separated planes of radio - opaque fiduciary marker balls , with a known geometric relationship between the two planes . a schematic example of such a target plate is shown in fig7 . in each of fig5 and 6 , four k - wires 54 can be seen , two inserted into each of the disc - adjacent vertebrae . k - wires , or equivalent devices such as steinman pins , are conventionally used during anterior surgical exposure of the vertebrae , in order to retract the vasculature and soft tissues from the site of the disc . the k - wires of the embodiments of the system of the present invention shown in fig5 and 6 differ from conventional k - wires in that they have two spatially spaced balls on the lengths of the shafts , close to the insertion end . knowledge of the distance between the positions of the balls on the shafts is not necessary , though it can be used to increase the accuracy of the registration process . therefore , besides their above - mentioned use in the surgical procedure as simple pins , the k - wires of the present invention can be used to provide 3 - dimensional positional data relating to the vertebrae . this function will be described below . although the k - wires are shown with 2 fiduciary balls per wire , it is to be understood that a larger number of balls can be used per wire , such that the redundant data so provided enables a higher accuracy coordinate registration process . alternatively and preferably , since the minimal number of spatial marker points required to define a three - dimensional co - ordinate system is three , it is possible to use a single pin in each vertebra , each pin having three spatial markers whose mutual positions are known . in this manner , not all of the ancillary surgical hardware required for use in the operation , such as the retracting pins mentioned above , need necessarily be associated with the marker function , since only one marker pin per vertebra is required . additionally , as mentioned hereinabove , it is possible to use k - wires with less fiducial marker information , such a k - wires with only one ball , or k - wires without any marker balls , since the k - wire shape itself and its alignment can be used as fiducial marker information . the number of k - wires required per vertebra is determined according to the amount of fiducial data associated with each wire . since the vertebrae can move relative to each other , each vertebra whose position is important to the procedure , which generally means the two vertebrae either side of the replacement disc , requires its own set of k - wires to define its position in the fluoroscope images . in those surgical procedures where k - wires are not used , the operating table mounted retractors can be equipped with markers , and used for providing the spatially defined data for use in the registration processes . the assumption is made that there is no significant relative motion between the retractors and the vertebra , though this may limit the accuracy of a procedure using markered retractors . the elements of the system of the present invention are utilized in this first preferred embodiment according to the following procedure . using the target mounted on one of the vertebrae , the position and orientation ( pose ) of the x - ray imaging source relative to the target , and hence relative to the vertebra , is calculated , in the manner known in the art for such imaging systems . once the source position is known , then from the imaged positions of the balls on the k - wires , the co - ordinate transformation between the target and the k - wires can be calculated . once this transformation is known , then the target itself may be removed , and any further procedures can be carried out based on the now known positional information using the k - wire ball positions . the target is preferably removed , since the very limited space within the operation site would make it impossible to insert and manipulate the new disc if the target was in the way . the target could be held on an extension arm to avoid this problem , but this is less desirable since a long extension arm would add to the positional error . according to this first embodiment , the use of the special k - wires of the present invention therefore enables the real time fluoroscope images to be correlated with the preoperative ct scanned data , without the continued presence of a target plate during the surgical procedure . according to a second preferred embodiments of the present invention , it is also possible to perform the disc insertion without removing the target plate , and hence without the use of the special k - wire markers , or special retractor markers . where conditions are such that the target plate can remain in situ without disturbing the insertion procedure and the surgeon &# 39 ; s field of view , and yet still provides a stable and accurate reference source , this embodiment enables the use of a simpler registration procedure . according to a third preferred embodiment of the present invention , it is also possible to perform the disc insertion procedure without use of a target plate at all , by relying only on the special k - wire markers or special retractor markers to provide the data required regarding the position and orientation of the vertebrae . the k - wire positional data obtained from any fluoroscope image is used to determine any movement of the vertebrae between successive fluoroscope images . comparison of this data then enables the position of any vertebra to be referenced back to the position of the first fluoroscope image , which itself was registered to the preoperative ct images , preferably by means of feature comparison , as explained hereinabove . thus , any subsequent fluoroscope image can undergo co - ordinate transformation to the ct image co - ordinate system , such that the subsequent fluoroscope images can be displayed superimposed on the ct preoperative image , with the desired virtual disc position , as originally positioned on the virtual ct model of the spinal region of interest of fig3 and 4 , but now shown on the real time , intraoperative fluoroscope image . reference is now made to fig8 , which is an ap fluoroscope image of the operation site , showing the two adjacent vertebrae 80 , 81 between which the artificial disc 82 is to be inserted . implanted onto the real life fluoroscope image is a virtual image of the desired disc , whose position is the optimized position , determined from the preoperative planning using the ct spinal model of fig3 and 4 . this virtual disc then defines the optimum position of the real life disc which the surgeon has to insert , and is used as a guide for the surgeon as he manipulates the disc into place , until its fluoroscope image exactly covers the outline of the optimally positioned virtual disc from the ct scans . as a result of the preliminary registration procedure , regardless of which of the above mentioned procedures is used , the surgeon can view the real life images from differently oriented fluoroscope images , with the virtual disc displayed in the images in its planned intended position , such that he can position the disc correctly and accurately in both directions , fine tuning the final position by successive viewing of the disc positioning from different directions . according to further preferred embodiments of the present invention , it is also possible to use a surgical robot to position the replacement disc into position . in this embodiment , the robot base plate is registered relative to the vertebrally fixed target , such as is described in u . s . pat . no . 6 , 837 , 892 , and in co - pending international published applications no . wo2003 / 105 , 659 and wo2005 / 032325 , all hereby incorporated by reference , each in its entirety . the robot may be mounted either directly on one of the bones in the vicinity , or on the operating table adjacent to the patient , who then has to be immobilized . the transformation between the target plate and the special k - wires is then performed , such that the robot position is then known relative to the k - wires . the target plate may then be removed and the robot utilized to insert the disc using the appropriate tool , into a position determined preoperatively on the ct model , and now known to the spatial control system of the robot from the registration procedure . in such cases , and if appropriate from the specific surgical configuration , the k - wires can be dispensed with , and the target used throughout the procedure , including during the robotic disc positioning . the target then has the multiple functions of being the co - ordinate reference frame for the ct , for the fluoroscopic images and for the registration between them , for the virtual disc ( as in fact already defined in the ct image ), and for the robot guidance control . alternatively and preferably , in those embodiments where a target plate is not used , and the registration is performed directly using the marked k - wires , the robotic placement is performed against the k - wire positions only . reference is now made to fig9 which is a schematic illustration of the use of a pointer 90 attached in a known manner to the neighboring vertebrae , to assist the surgeon in positioning the artificial disc 91 , according to further preferred methods of the present invention . in the illustration shown , the pointer 90 is carried in a sleeve 92 attached rigidly to two k - wires 93 , 94 inserted into the neighboring vertebrae . the pointer can preferably be adjusted within the sleeve to a predetermined position . as an alternative to use of such a sleeve and k - pins , any other suitable jigging arrangement which spatially defines the pointer position relative to the neighboring vertebrae , can equally well be used in this embodiment . the system uses the same preoperative ct imaging and planning as in the previously described embodiments . as previously , the optimum predetermined position of the disc is implanted onto a fluoroscope image of the vertebrae of the subject after registration , and the surgeon then brings the pointer to a position between the vertebrae , such that its tip defines in real space , where a predetermined feature of the disc , such as the forward - most edge , is to be positioned . once this relationship between the pointer and the optimum disc position has been established , no further fluoroscope images need be taken , thus significantly reducing the level of radiation used during the disc positioning procedure . the surgeon simply inserts the disc until it is located in the predetermined position relative to the tip of the pointer . since the lateral position can often be accurately judged by the surgeon visually , the more critical positioning operation is the a - p position . in practical use , the pointer can be pre - aligned using the ct and first fluoroscopic image , so that its tip points , according to one preferred embodiment , to where the forward edge of the disc in its optimum position should be . the pointer is then withdrawn so that the disc can be inserted to close to its correct insertion depth , and the pointer reinserted in the sleeve to its predetermined position to see whether the disc is already in the correct position . this process can be repeated iteratively until the optimum position is achieved although the use of one pointer may provide sufficient accuracy to position the disc in both planar directions between the vertebra , more accuracy may be achieved using two such pointers , preferably with one defining the lateral position , and one the a - p position . by use of these methods of the present invention , the level of radiation used during the disc positioning procedure is significantly reduced . reference is now made to fig1 a and 10b which illustrate schematically how , according to a further preferred embodiment of the present invention , the system and methods of the present invention can be used for the accurate positioning of a kyphoplasty needle 100 inserted into a subject &# 39 ; s vertebra 102 through the pedicle region . fig1 a shows a schematic axial ct image of a vertebra with a kyphoplasty needle inserted into the vertebral body from an extrapedicular direction . as is evident from the axial view , the surgeon requires great skill in order to ensure that the needle follows the desired path . such an axial view is not generally available using a c - arm mounted fluoroscope system , and the surgeon must rely on ap or other laterally angled fluoroscope images for intra - operative guidance . fig1 b is a single oblique fluoroscopic image of the same procedure , showing the path of the needle into the vertebral body . according to this preferred embodiment , the planned entry path of the needle is determined using preoperatively obtained ct images , and this optimum path is saved in the system memory . during the surgical procedure , a target with radio - opaque features is attached to the vertebra to be treated . as previously described , this target can be a conventional three - dimensional target plate , or one or more special marker attached k - wires inserted into the vertebra , or any other method which provides three dimensional definition of the position of the vertebra in the fluoroscope images . the fluoroscope images with the marker positions are registered to the preoperative ct image set , using image comparison as is known in the art , and a virtual image of the desired needle position and orientation can then be projected from the ct data , onto any fluoroscope image taken intra - operatively . as shown schematically in fig1 b , this desired path could preferably be marked as a dotted or colored line 103 , so that it is clearly distinguishable from the image features . during the procedure , the surgeon can then view the progress of the needle insertion on the fluoroscope images , and can verify that the needle is following the desired path indicated on the fluoroscope image . in order to ensure correct adherence to the desired path , lateral and a - p images , or oblique images need to be viewed by the surgeon . this procedure , according to the methods of the present invention , can be used for increasing the positioning accuracy for any surgical insert or tool which is amenable to the construction of a preoperative ct model of the surgical site and the definition thereon of the optimum position for the surgical insert or tool , and the registration of this ct model to intra - operatively generated fluoroscope images showing the actual progress of the insert or tool position , together with the predetermined optimum position . reference is now made to fig1 , which illustrates the use of the hardware elements of the present invention in performing an artificial disc insertion into the l5 - s1 disc space . the special k - wires of the present invention 110 , with the marker balls on their shafts are shown inserted into the vertebrae , together with the three dimensional target 111 , aligned such that it will be readily imaged in the fluoroscopic images of the region , which are taken using the schematically shown x - ray source 112 and camera 113 . once the registration to the special k - wire features has been performed , the target may be removed so that it does not impede the surgeon &# 39 ; s view of the region . the target 111 in fig1 is shown smaller than its preferable size , in order not to occlude details of the drawing . the artificial disc 114 is shown being inserted between the vertebrae using an insertion rod 115 . the whole of the process is viewed on the fluoroscope images generated by the x - ray c - arm source and camera . according to further preferred embodiments , the disc could be guided into position by means of a surgical robot , whose control system coordinates are registered to those of the preoperative ct scans , such that the robot can guide the disc into a predetermined position without any , or with minimal surgeon intervention . the robot could be either floor or bed mounted , or bone mounted , as is known in the art . reference is now made to fig1 , which illustrates schematically the control and computing elements of the system of the present invention . the preoperative ct data is stored in a storage medium 121 , from where it can be transferred to the spine model generator 122 for building the virtual spinal model for use in planning the disc insertion position . once the disc position has been determined , the registration processor 123 is actuated , to relate the coordinate system of the preoperative ct images , to that of the fluoroscope images , preferably by means of image feature comparison . finally , the disc insertion position determined in the spine model generator is implanted onto the fluoroscope images displayed on the fluoroscope display unit 124 , such that the surgeon can compare the actual disc position with the intended disc position on screen . the whole process and the computing steps are overseen by means of the system computer 120 . it is appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove . rather the scope of the present invention includes both combinations and subcombinations of various features described hereinabove as well as variations and modifications thereto which would occur to a person of skill in the art upon reading the above description and which are not in the prior art .

a tracking and positioning system and method to enable the precise positioning of an object or tool relative to its surgical surroundings , and in accordance with preoperative ct images of the operating site . when used for artificial spinal disc positioning , the system comprises a computing system incorporating in memory the preoperative ct data showing the two vertebrae and the predetermined disc position between them ; a 3 - d target having radio - opaque markers for attaching to one of the vertebrae to define the position of the vertebra in an intra - operative fluoroscope image of the spine ; a tool for intra - operative insertion of the artificial disc , and a registration system for relating the intra - operative fluoroscope image to the preoperative ct data , such that the predetermined disc position is displayed in the fluoroscope image of the subject , thereby enabling the surgeon to place the artificial disc accurately in its intended position .

referring now to fig1 the board game includes a playing board , generally denoted as the numeral 50 , which is of substantially circular configuration . the board 50 may be stiff and adapted to be folded together according to conventional practices and consists of recycled paper or cardboard material which can be laid upon a flat surface , such as a table top , when the game is being played . thus , it will be understood that the term &# 34 ; board &# 34 ; includes only a stiff , self - supporting recycled paper or cardboard member . the playing board 50 comprises a first or outer circular peripheral playing piece movement path , generally denoted as the numeral 52 , and a second or inner circular playing piece movement path , generally denoted as the numeral 54 , smaller in circumference than the first path 52 and concentrically located relative to the first path 52 . the first or outer circular movement path 52 is directed into a plurality of spaces , for example twenty - four spaces , disposed in a side - by - side relation to form the continuous first path 52 completely about the board , and are numbered in sequence 1 through 24 in a clockwise direction along the first circular path 52 . the second or inner circular movement path 54 is divided into a like plurality of spaces , for example twenty - four spaces , disposed in side - by - side relationship to form the continuous second path 54 completely about the board and numbered in sequence 25 through 48 . each of the spaces 1 through 24 of the first or outer path 52 is in radial alignment with a different one of the spaces 25 through 48 of the second or inner path 54 . the numbers 1 through 48 of the spaces of the first and second paths 52 and 54 , respectively , are printed in relatively small rectangular shaped boxes at the bottom of each space . in addition , the playing board 50 includes a plurality of , for example six , &# 34 ; enter start &# 34 ; spaces 56 - 61 , circumferentially spaced apart from each other in the circular space between the first circular path 52 and second circular path 54 . each &# 34 ; enter start &# 34 ; space 56 - 61 is in alignment with one of the spaces 1 through 24 of the first path 52 and the one of the spaces 25 through 48 of the second path 54 in radial alignment with that space of the first path 52 . for example , as shown , enter / start space 56 is in radial alignment with and extends between space 3 of the first path 52 and space 25 of the second path 54 , enter / start space 57 is in radial alignment with and extends between space 7 of the first path 52 and space 29 of the second path 54 ; enter / start space 58 is in radial alignment with and extends between space 11 of the first path 52 and space 33 of the second path ; enter / start space 59 is in radial alignment with and extends between space 15 of the first path 52 and space 37 of the second path 54 ; enter / start space 60 is in radial alignment with and extends between space 19 of the first path 52 and space 41 of the second path 54 ; and , enter / start space 61 is in radial alignment with and extends between space 23 of the first path 52 and space 45 of the second path 54 . the board game 50 further includes stacks of cards which are marked with categories in conformity with the legends shown in fig2 - 4 . for example , the board game includes three separate stacks of cards , the first stack is designated environment ( see fig2 ), the second stack is designated lifestyle ( see fig3 ), and the third stack is designated hazard ( see fig4 ). with continued reference to fig1 each of the spaces 1 through 24 of the first path 52 and each of the spaces 25 through 48 of the second path 54 are marked with various self - explanatory player tasks to be completed by the player whose playing piece lands on that space during a turn of play , or marked with a category corresponding to the stacks of cards mentioned above . for example , spaces 1 , 2 , 4 , 6 , 8 , 9 , 11 , 13 , 14 , 16 , 18 , 20 , 21 , and 23 of the first path 52 are marked with the card category environment ; spaces 25 , 26 , 28 , 32 , 33 , 35 , 37 , 39 , 40 , 42 , 44 , 45 , and 47 of the second path 54 are marked with the card category lifestyles ; and , spaces 7 , 14 of the first path 52 and spaces 34 , 46 of the second path 54 are marked with the card category hazard . when the playing piece of any player lands on a space 1 through 48 , the appropriate action to be taken by the player is indicated on that space , which as mentioned above , includes instructions either to draw a card from a pack of designated cards and follow the instruction thereon , or to complete the task designated or marked in that space . the player must follow the instructions on the drawn card or complete the task during that playing turn . for example , when the player lands on a space marked with a card category , the player draws a card from the stack of cards relating to that category . for example , when a player lands on any of the spaces designated by the numerals 1 , 2 , 4 , 6 , 8 , 9 , 11 , 13 , 14 , 16 , 18 , 20 , 21 , or 23 , the player draws a card from the first stack designated environment . turning to fig2 each of the environmental cards in the stack bears a legend recognizing the environment . as shown in fig2 each environmental card contains seven designated instructions such as questions , tasks , or actions related to various environmental categories or concerns such as air pollution , global warning , chemical use , wild life preservation , rain forests , ocean pollution , toxic waste and the like . when a player &# 39 ; s playing piece lands on a space 1 , 2 , 4 , 6 , 8 , 9 , 11 , 13 , 14 , 16 , 18 , 20 , 21 , or 23 , that player draws an environmental card and follows the instruction thereon which relates to the environmental indicia thereon . for example , the environmental indicia on the space may be air pollution , for which the player will follow the instruction on the environmental card for the section identified as air pollution . in fig2 the numeral 201 illustrates the back side of one environmental card and the numeral 202 illustrates the face side of the same card . only one designated instruction on a card shall be used . it is required that the player complete only the appropriately designated instruction , that is , question , task , or action to complete their turn . upon completion or correctly answering the appropriate question or completing the required task or action , the player may then acquire a game piece ( 1 of 7 ) necessary to proceed with the game . in the event that the player does not successfully complete the question , task , or action on the card , the player does not acquire any game pieces and the turn proceeds to the next appropriate player . referring to fig3 each lifestyle card of the second stack bears the legend concerning the lifestyle . as shown in fig3 each lifestyle card contains seven instructions , such as activities , tasks , or questions related to various lifestyles . when a player &# 39 ; s playing piece lands on a space 25 , 26 , 28 , 30 , 32 , 33 , 35 , 37 , 39 , 40 , 42 , 44 , 45 or 47 , that player draws a lifestyle card and follows the instructions thereon which relates the lifestyle indicia thereon . for example , the lifestyle indicia on the space may be a picture that corresponds to an identical picture on one of seven sections of the card , for which the player will follow the instruction on the lifestyle card identified by the picture . in fig3 the numeral 301 illustrates the back side of one lifestyle card and the numeral 302 illustrates the front side of the same card . only one designated instruction on a card shall be used . referring to fig4 each of the hazard cards in the third stack bears a legend recognizing a hazard , for example an environmental hazard . as shown in fig4 each of the cards in the hazard category relates to a different specific environmental hazard . as shown , each hazard card contains an instruction such as an action and direction statement related to an environmental hazard . for example , the face side of card 402 relates to litter , the face side of card 404 to a land fill , the face side of card 406 to an incinerator , and the face side of card 408 to a token card , directing the player to perform corrective action in order for them to complete their turn . the action may be , for example , a penalty which will inhibit the player in his efforts to complete the objective of the game . the numeral 410 shows one typical back side of the hazard cards . in fig1 the spaces 5 , 17 , 29 , 41 of the game board 50 are marked with the task denoted as an active statement . there are no cards corresponding to this category . the active statements are various instructions such as , phrases and directions which appear on the gaming space 5 , 17 , 29 , 41 and are able to be completed during the player &# 39 ; s turn . fig5 illustrates two examples of active statements that are set forth in two of the active statement spaces in fig1 . one such active statement is identified by numeral 501 and a second active statement space is identified by numeral 502 . when a player &# 39 ; s game piece lands on one of these active statement spaces 5 , 17 , 29 , 41 , the player is to respond to the phrase or direction on that space . the player will be rewarded for completion of the active statement by being allowed to roll for another play . the penalty for non - completion is to not be able to take the rewarded turn . in fig1 the spaces 12 and 24 of the game board 50 are marked with the task denoted as free item . again , there are no cards corresponding to this category . when a player &# 39 ; s game piece lands on one of these free item spaces 12 , 24 , the player is allowed to obtain a gaming piece in order to complete the objective of the game . ( gaming pieces are shown in fig6 .) no penalties are associated with these free item spaces . any player retaining any number of gaming pieces is still required to obtain an additional piece at the end of their roll , if their gaming piece lands on one of these free item spaces 12 , 24 . in fig1 the spaces 10 and 22 of the game board 50 are marked with the task denoted as think tank . there are no cards corresponding to this category . when a player &# 39 ; s game piece lands on one of these think tank spaces 10 , 22 , the player is required to generate an idea concerning an environmental problem and a creative solution concerning the problem . the idea generated by the player will then be voted upon and rated by the other players . the player must adhere to the voted decision of the other players set forth in the rules of play based upon the ratings guide set forth in the rules of play discussed hereinafter . in fig1 the spaces 3 and 38 of the game board 50 are marked with the task denoted as car pool . there are no cards corresponding to this category . when a player &# 39 ; s game piece lands on one of these car pool spaces 3 , 38 , it is required that the player immediately join the next player on that player &# 39 ; s gaming space , and complete their turn with them exactly as dictated by the instructions of that next player &# 39 ; s space by performing any tasks or penalties required thereby . the duration of play will last only as long as the rolling player has control of the board . when the play is returned to the next person , individuality resumes and each player continues on their own turn . in fig1 the spaces 15 and 27 of the game board 50 are marked with the task denoted as change direction . there are no cards corresponding to this category . when a player &# 39 ; s game piece lands on a change direction space 15 , 27 , the player is required to roll the die an additional time to determine the number of spaces used during the play . the player will then move in a counter - clockwise direction equal to the number of spaces indicated by the die . this penalty will only affect the player &# 39 ; s one turn and the player will resume a clockwise direction on their next play . in fig1 the spaces 36 and 48 of the game board 50 are marked with the task denoted as consumer choices . there are no cards corresponding to this category . when a player &# 39 ; s game piece lands on these consumer choices spaces 36 and 48 , the player is required to generate an answer which relates to an item in the player &# 39 ; s household which is purchased on a frequent basis . remaining players will then vote as set forth in the rules of play discussed hereinafter , and appropriate action must be taken by the player as also set forth in that rating system in the rules of play . in fig1 the spaces 31 and 43 of the game board 50 are marked with the task denoted as recycle . there are no cards corresponding to this category . when a player &# 39 ; s game piece lands on one of these recycle spaces 31 , 43 , the player is allowed to recycle or &# 34 ; turn in &# 34 ; a gaming piece having indicia denoting a recyclable item . these recycle spaces 31 and 43 allow the player landing thereon to accomplish this without performing any tasks set forth by the gaming board , thus assisting the player to achieve the player &# 39 ; s goal of winning the game . only a recyclable game piece shall be affected as set forth in the rules of play . all non - recyclable game pieces shall be retained by the player during his / her turn on this gaming space . in fig1 the spaces 56 , 57 , 58 , 59 , 60 , and 61 include the phrase start / enter therein . these start / enter spaces 56 , 57 , 58 , 59 , 60 , and 61 are used for the players to gain access to both the first path 52 and second path 54 as set forth in the rules of play to be discussed hereinafter . these start / enter spaces hold no penalties or rewards for the player , and are only used to move between the first path 52 and second path 54 . with reference to fig6 the game pieces of the game board 50 are examples of items and materials found in the environment . some of these items and materials are recyclable or biodegradable . the game pieces shown in fig6 are cards with appropriate words thereon exemplifying the items and materials they represent . for example , the card identified by the numeral 602 includes the word &# 34 ; newspaper &# 34 ; thereon ; the card identified by the numeral 604 includes the words &# 34 ; aluminum cans &# 34 ;; card 606 includes &# 34 ; glass bottle &# 34 ;; card 608 includes &# 34 ; plastic jug &# 34 ;; card 610 includes &# 34 ; colored glass &# 34 ;; card 612 includes &# 34 ; corrugated cardboard &# 34 ;; card 614 includes &# 34 ; styrofoam &# 34 ;; and , card 616 includes &# 34 ; paint &# 34 ;. even though game pieces are shown as cards with items and materials found in the environment inscribed thereon , other illustrative replicas of the same or other items and materials found in the environment may be utilized . a . each player provides their own playing piece or replica thereof as currently found in their household . a playing piece suggestion list may also be provided . each playing piece selected shall then be placed on a different one of the start / enter spaces 56 , 57 , 58 , 59 , 60 , 61 . b . all stacks of environmental and lifestyle cards are placed face up and hazard cards are placed face down near to , but not covering , any part of the designated area known as the game board 50 as indicated in fig1 . each player rolls the die to determine who starts the roll of play . the player with the highest roll starts the play and play continues in a clockwise motion from player to player . after rolling , the player starting the game moves his playing piece from the start / enter space 56 , 57 , 58 , 59 , 60 , and 61 and onto the first or outer path 52 and moves the gaming piece in a clockwise direction thereon from a start / enter space 56 , 57 , 58 , 59 , 60 , 61 as seen in fig1 the number of spaces indicated by the die . the player then takes a card or performs the appropriate action indicated by the space upon which his piece has landed . if a card is to be drawn , the player draws the appropriate card and follows the instructions thereon or completes a task if that is required . play turn passes clockwise to each player taking his turn as above and moving his piece accordingly . each gaming piece that the players will encounter contains specific individualities particular to that player . the following descriptions are detailed as to the appropriate action necessary of each player to complete their turn should they land on any specific space . each player is required to obtain seven recyclable items as shown in fig6 before he can move his game piece to the second or inner path 54 of the game board 50 . each player must use caution not to obtain any items not able to be recycled . each player must also be aware that the focus of the game is to complete the recycling of their collected pieces while their game piece is in the second or inner path 54 . the player who accomplishes this task first is then declared the winner and the game comes to an end . each gaming space along with the necessary details affecting each player are listed as follows . a different one of the start / enter spaces 56 , 57 , 58 , 59 , 60 , 61 is used for each player or team of players as a reference point to move their gaming piece to the first or outer path 52 . the gaming piece that leaves the start / enter space immediately joins the motion of play in a clockwise direction of the first path 52 . each player whose gaming piece lands on an environment space 1 , 2 , 4 , 6 , 8 , 9 , 11 , 13 , 14 , 16 , 18 , 20 , 21 , 23 is then required to draw an environment card . each card is appropriately designated as in fig2 . each environment space is generally designated by a colored border , however , each space has a specific focus . on each environment card contains categories relating to the focus of that environmental space . when a player draws an environment card , the player then reads the appropriate designated question or statement on the face side which relates to the designation of the space he has landed upon , which may include descriptions or pictures of objects thereof . after taking an environment card , the player will either answer an appropriate question , perform a task , or comply with a statement on the face side of the card . if the designated category requires an answer , the player must give the answer before he turns the card over . if the player is successful in answering correctly , they will receive a gaming piece necessary to complete the first or outer path 52 . if the player is told to complete a task such as &# 34 ; roll again &# 34 ; or a &# 34 ; go to &# 34 ;, then the player simply completes the task without obtaining a collectable piece . each player landing on a car pool space 3 immediately joins the player who rolls next and lands on the car pool space 3 . these players then move their gaming pieces jointly and together completing all tasks in that turn . should a &# 34 ; roll again &# 34 ; or &# 34 ; lose one turn &# 34 ; or a &# 34 ; reverse direction &# 34 ; or any other task be encountered , both car pool joined players must complete the task . the car pool condition of the game may be completed regardless of the number of players . for example , player &# 34 ; a &# 34 ; lands on a car pool space 3 , and then moves to player &# 34 ; b &# 34 ; space , who is currently on the environment space 23 . player &# 34 ; b &# 34 ; then rolls a 4 on the die and both players &# 34 ; a &# 34 ; and &# 34 ; b &# 34 ; then move to the next player &# 39 ; s space on their path 52 . should there be no other players on path 52 , or players &# 34 ; a &# 34 ; and &# 34 ; b &# 34 ; are the only players in the game , the players &# 34 ; a &# 34 ; and &# 34 ; b &# 34 ; will then roll the die separately to continue the game from that point on . the car pool space of the game , when used correctly , encourages cooperative use of resources as well as encouraging the collective concern for obtaining the objective of the game . upon landing upon an active statement space 5 , 17 , the player must verbally acknowledge to the other players the information regarding that space . each of the active statement spaces have a directive statement and the player will have to tell the other players what they are doing to adhere to that statement . successfully responding to the directive statement allows the player to roll the die again . when a player lands on a think tank space 10 , 22 , the player will address an environmental problem and attempt to create a solution to that particular problem . if the player is unable to complete this task , the player will lose one turn on their next play . once the player successfully solves the environmental problem , the other players will rate the solution in the following manner . a point system consisting of 1 to 3 being a negative or penalty score and will result in the player losing a recyclable piece ; a score of 4 to 7 allows the play to move to the next player ; and , a score of 8 to 10 allows the player to gain one recyclable piece . these scoring points will be assessed by the other players . if the other players are unable to come to an agreement on a score , each of the other players will individually rate the solution from 1 to 10 . the score points will be added , and an average will be taken by dividing the sumed score points by the number of players voting . this final point score will then be rated in the above - mentioned manner . when a player lands on a hazard space 7 , 19 , the player takes a card from the hazard deck of cards . the player will read the card out loud and complete the penalty task set forth on the card . reusable positive cards when drawn from the hazard deck may be retained until needed . if a token card is drawn , the token card can only be used by a player when his gaming piece is in the second or inner path 54 as hereinafter explained . when a free item space 12 , 24 is landed upon , the player will obtain one recyclable item as shown in fig6 without performing any necessary tasks . the acquired recyclable item must be accepted by the player regardless of the number of recyclable items already in that player &# 39 ; s possession . when a player lands on a change direction space 15 , 17 , the player then immediately rolls the die again and moves his gaming piece in a counter - clockwise direction of the path 52 equal to the number rolled on the die . the player must then complete all tasks of the space then landed upon . this penalty only lasts for one turn and the player resumes a clockwise motion on his next roll . the enter / start space 56 , 58 , 59 , 60 , 61 functions both as the start position and serves as a reference point in which to move the gaming piece from the path 52 to the second path 54 . the player must count the enter / start space 56 , 58 , 59 , 60 , 61 on the way from the first path 52 to the second path 54 , but may not land on it . once entering the second path 54 , the motion of play resumes in a clockwise pattern . each person landing on a car pool space 38 immediately joins the player who rolls the die next and lands on the car pool space 38 . these players then move their gaming pieces jointly and together complete all the tasks in that turn . should a &# 34 ; roll again &# 34 ; or &# 34 ; lose one turn &# 34 ;, or a &# 34 ; reverse direction &# 34 ;, or any other task be encountered , both car pool joined players must complete the task . the car pool condition of the game must be completed regardless of the number of players . each player whose gaming piece lands on a lifestyle space 25 , 26 , 28 , 30 , 32 , 33 , 35 , 37 , 39 , 40 , 42 , 44 , 46 , 47 is required to draw a lifestyle card . each lifestyle space is generally designated by a colored border , however , each space has a specific focus . on each lifestyle card are categories relating to the focus of that lifestyle space . when a player draws a lifestyle card , the player reads the appropriately designated question or statement on the face side of the card which relates to the pictorial or other designation of that lifestyle space the player lands upon . after taking a lifestyle card , the player will either answer an appropriate question , perform a task , or comply with a statement thereon . if the category requires an answer , the player must answer the question before turning the card over . if the player successfully performs the task set forth on the lifestyle card or answer the question , that player is allowed to recycle or compost one of their gaming pieces necessary to complete the game . if the player is told to perform a task such as &# 34 ; roll again &# 34 ; or &# 34 ; go to &# 34 ;, then the player simply completes the task without returning an item . upon landing upon an active statement space 29 , 41 , the player must verbally acknowledge to the other players the information regarding that space . active statement spaces have a directive statement and the player will have to tell the other players what they are doing to adhere to that statement . successfully responding to the direction statement allows the player to roll the die again . when a player lands on a change direction space 27 , the player then immediately rolls the die again and moves their gaming piece in a counter - clockwise direction of the path 54 equal to the number rolled on the die . the player must then complete all tasks of the space landed upon . this penalty lasts for one turn and the player resumes a clockwise motion on their next roll of the die . when a player lands on a hazard space 34 , 46 , the player takes a card from from the hazard stack of cards . the player will read the card out loud and complete the penalty task set forth on the card . reusable token cards or positive cards when drawn from the hazard deck may be retained until needed . a token card drawn from the hazard card stack during a previous turn while the playing piece was moved in the first path 52 or second path 54 may be used at any time during the player &# 39 ; s turn while in the second path 54 , and allows the player to reuse or turn in a non - recyclable item in their possession . when a player lands upon a recycle space , recyclable items may be returned without any tasks necessary . it is the object of the game that when within the inner circle , the player returns all items in that player &# 39 ; s possession . when a player lands on a consumer choices space 36 , 48 , the player will verbally communicate to the other players a product that they purchase on a frequent ( weekly / monthly ) basis . if the player is unable to do this , a loss of one turn will result upon the player &# 39 ; s next turn . once given the product , the other players will rate the product in accordance with the following directions : a scoring system consisting of 1 to 3 points being a negative or penalty score will cause a player to gain one recyclable gaming piece ; 4 to 7 points allows play to resume by the next player ; and 8 to 10 points , being a positive score , allows the player to recycle or return one gaming piece . questions may be asked by the other players and discussion is encouraged . these points will be accessed by the other players , and if there is a disagreement on the score , then the point scores of all of the players will be added and an average will be taken by dividing the sumed score points by the number of players voting . this final point score will then be rated in the above - mentioned manner . in the foregoing description , a particular game has been illustrated and a particular type of style of game has been described . it will be understood , however , that the principles of the present invention are applicable to other types of games and game boards and different types of game pieces and the like may be employed while practicing the principles of the present invention . it will , therefore , be understood that it is desired to comprehend within the purview of the present invention all such modifications and adaptions thereof as may be considered to fall within the scope of the appended claims .

a game apparatus includes a circular game board having a movement path for game pieces along which a player moves playing pieces . the movement path is divided into separate spaces having specific indicia designations therein . the designations indicate rewards or penalties for a player whose playing piece lands in a space . the game apparatus also includes action cards disposed in stacks , each card indicating an activity to which a player is subjected . the game apparatus further includes a random number generating device , such as a die , a pair of dice , or the like to determine the movement of the playing pieces along the movement path .

fig1 is a schematic pictorial view of an electrical stimulation system 10 comprising an implantable stimulator 12 , for stimulation of a “ modulation target site ” ( mts ), as defined hereinabove , such as a sphenopalatine ganglion ( spg ) 22 , in accordance with an embodiment of the present invention . in fig1 , a human nasal cavity 20 is shown , and stimulator 12 is implanted between the hard palate and the mucoperiosteum ( not shown ) of the roof of the mouth . branches of parasympathetic neurons coming from spg 22 extend to the middle cerebral and anterior cerebral arteries ( not shown ). typically , one or more relatively short electrodes 26 extend from stimulator 12 to contact or to be in a vicinity of an mts , such as spg 22 . for some applications , stimulator 12 is implanted on top of the bony palate , in the bottom of the nasal cavity . alternatively or additionally , the stimulator is implanted at the lower side of the bony palate , at the top of the oral cavity . in this instance , one or more flexible electrodes 26 originating in the stimulator are passed through the palatine bone or posterior to the soft palate , so as to be in a position to stimulate the spg or another mts . further alternatively or additionally , the stimulator may be directly attached to the spg and / or to another mts . for some applications , stimulator 12 is delivered to a desired point within nasal cavity 20 by removably attaching stimulator 12 to the distal end of a rigid or slightly flexible introducer rod ( not shown ) and inserting the rod into one of the patient &# 39 ; s nasal passages until the stimulator is properly positioned . as appropriate , the placement process may be facilitated by fluoroscopy , x - ray guidance , fine endoscopic surgery ( fes ) techniques or by any other effective guidance method known in the art , or by combinations of the aforementioned . typically , skin temperature and / or cerebral blood flow ( cbf ) is measured concurrently with insertion . cbf may be measured with , for example , a laser doppler unit positioned at the patient &# 39 ; s forehead or transcranial doppler measurements . verification of proper implantation of the electrodes onto the appropriate neural structure may be performed by activating the device , and generally simultaneously monitoring cbf . for some applications , stimulator 12 is implanted using techniques described in u . s . patent application ser . no . 10 / 535 , 024 , filed dec . 27 , 2005 , entitled , “ surgical tools and techniques for stimulation ,” which is assigned to the assignee of the present application and is incorporated herein by reference , and / or in the above - mentioned pct publication wo 04 / 043218 . for some applications , techniques described herein are performed in combination with apparatus and / or methods that are described in u . s . patent application ser . no . 11 / 349 , 020 , filed feb . 7 , 2006 , entitled , “ spg stimulation via the greater palatine canal ,” which is assigned to the assignee of the present application and is incorporated herein by reference . fig2 is a schematic illustration of a stimulator control unit 30 positioned external to a patient &# 39 ; s body , in accordance with an embodiment of the present invention . at least one flexible electrode 32 typically extends from control unit 30 , through a nostril 12 of the patient , and to a position within the nasal cavity that is adjacent to spg 22 . in an embodiment of the present invention , techniques described herein are performed in conjunction with techniques described in us patent application publication 2004 / 0220644 , which is assigned to the assignee of the present application and is incorporated herein by reference . for example , the substantially rigid support element described therein may be initially quickly inserted into the stimulation site for acute treatment , and an implantable stimulator 12 may be subsequently implanted for longer - term treatment . it is to be understood that electrodes 26 ( fig1 ) and 32 ( fig2 ) may each comprise one or more electrodes , e . g ., two electrodes , or an array of microelectrodes . for applications in which stimulator 12 comprises a metal housing that can function as an electrode , typically one electrode 26 is used , operating in a monopolar mode . regardless of the total number of electrodes in use , typically only a single or a double electrode extends to spg 22 . other electrodes 26 or 32 or a metal housing of stimulator 12 are typically temporarily or permanently implanted in contact with other parts of nasal cavity 20 . each of electrodes 26 and / or 32 typically comprises a suitable conductive material , for example , a physiologically - acceptable material such as silver , iridium , platinum , a platinum iridium alloy , titanium , nitinol , or a nickel - chrome alloy . for some applications , one or more of the electrodes have lengths ranging from about 1 to 5 mm , and diameters ranging from about 50 to 100 microns . each electrode is typically insulated with a physiologically - acceptable material such as polyethylene , polyurethane , or a co - polymer of either of these . the electrodes are typically spiral in shape , for better contact , and may have a hook shaped distal end for hooking into or near the spg . alternatively or additionally , the electrodes may comprise simple wire electrodes , spring - loaded “ crocodile ” electrodes , or adhesive probes , as appropriate . reference is made to fig3 , which is a graph 100 illustrating electrical stimulation protocols , in accordance with an embodiment of the present invention . excitatory stimulation of an mts ( e . g ., the spg ) induces changes in cbf , induces the release of one or more neuroprotective substances , such as neuromodulators ( e . g ., nitric oxide ( no ) and / or vasoactive intestinal polypeptide ( vip )), and / or modulates permeability of the blood - brain barrier ( bbb ). the inventors have found that excitatory stimulation of an mts at least a minimum threshold strength increases cbf , and that the increase in cbf is related to the strength of the stimulation . the inventors have also found that at a sufficiently high strength , such stimulation modulates the permeability of the bbb , in addition to increasing cbf . “ strength ,” as used in the present application , including the claims , means a total charge applied to an mts in a given time period , e . g ., one minute , one hour , or one day . strength is increased or decreased by changing one or more parameters of the applied stimulation , such as the amplitude , number of cycles in a given time period , frequency , pulse width , or duty cycle ( e . g ., ratio of “ on ” to “ off ” time within a given cycle ), as described hereinbelow in greater detail . the y - axis of graph 100 indicates the strength of the stimulation of an mts . the strength of the stimulation is determined by the values of the parameters of the stimulation , such as voltage , current , frequency , cycles per time period , and duty cycle . stimulation at least a minimum cbf - increasing strength 102 increases cbf . stimulation at such a strength also typically induces the release of one or more neuroprotective substances , such as no and / or vip . a maximum cbf - increasing strength 106 is the strength at which cbf is maximally increased , i . e ., further increases in strength do not further increase cbf . the bbb is opened , i . e ., the permeability of the bbb to larger molecules or substances that do not cross the intact bbb is significantly increased , by stimulation having a strength in a range 108 between a minimum bbb - opening strength 110 and maximum bbb - opening strength 112 ( beyond which increased strength does not result in additional opening of the bbb ). although minimum bbb - opening strength 110 is shown in graph 100 as being greater than maximum cbf - increasing strength 106 , this is not necessarily the case . in the present application , including the claims , stimulation of an mts is considered capable of inducing a “ significant ” increase in the permeability of the bbb if the stimulation is capable of inducing at least one of the following : ( a ) an increase in concentration of evans blue ( eb ) in brain tissue of a subject , such as a rat , of at least 100 % compared to a baseline concentration measured in a control rat . to determine the increase , permanent middle cerebral artery occlusion ( pmcao ) is induced in the rat , such as using techniques described hereinbelow with reference to fig6 . three hours after pmcao , stimulation is applied to the mts , and a bolus of eb 2 % at 1 ml per kg body weight of the rat is administered intravenously . the rat is sacrificed one hour after application of the stimulation and administration of the eb . to determine the baseline concentration , pmcao is induced in a control rat , three hours after pmcao an identical eb bolus is administered intravenously , but no stimulation is applied , and the control rat is sacrificed one hour after the administration of the eb ; and ( b ) a serum s100beta level of the subject ( indicative of clearance of the protein from the brain into the systemic circulation ), at a measurement time 45 minutes after initiation of mts stimulation , that is at least 30 % greater than a serum s100beta level of the subject measured at the beginning of the mts stimulation . although the above are indications of the “ significance ” of an increase in permeability of the bbb , use of the apparatus and performance of the methods described and claimed herein typically do not include measuring any of these indications . in particular , indication ( a ) is generally only possible to measure in an animal model ; if it were desired to conduct a human experiment , different techniques would likely be used , such as measuring the concentration in the brain of a radioactive isotope that is normally excluded by the bbb . for some applications , it is desirable to apply stimulation to an mts , and configure the stimulation to have a strength that induces an increase in permeability of the bbb that is even lower than a “ significant ” increase , as defined above . such a “ sub - significant ” increase in permeability of the bbb is considered to occur if the stimulation is capable of inducing at least one of the following : ( i ) an increase in concentration of eb , under the conditions defined in indication ( a ) above , of at least 20 %, such as at least 30 %, e . g ., at least 50 %; and ( ii ) a serum s100beta level , under the conditions defined in indication ( b ) above , that is at least 10 %, e . g ., at least 20 %, greater than the level of the subject measured at the beginning of the mts stimulation . for some applications , it is useful to define increased cbf as a percentage increase in cbf over a baseline level of cbf , which increase has at least a certain duration , e . g ., at least 5 minutes . typically , the baseline cbf level is either : ( a ) a normal baseline level for a subject , i . e ., prior to an adverse brain event , such as a cerebrovascular event , e . g ., a stroke , or ( b ) a post - event baseline level , prior to stimulation using the techniques described herein , and , optionally , prior to other treatment of the event . cbf is typically expressed as volume of blood flow per time per mass of the subject , e . g ., ml / min / 100 g . for some applications , increased cbf is expressed as an area under the curve ( auc ) of cbf with respect to baseline over a certain time interval . in an embodiment of the present invention , electrical stimulation system 10 is configured to apply excitatory electrical stimulation to at least one mts of a subject , and to configure the stimulation to increase cbf of the subject and / or induce the release of neuroprotective substances , without substantially opening the bbb of the subject . in other words , the system sets the strength of stimulation equal to less than minimum bbb - opening strength 110 , such as less than 90 % of minimum bbb - opening strength 110 , e . g ., less than 80 %, 70 %, or 60 % of minimum bbb - opening strength 110 . for some applications , the system is configured to increase cbf of the subject and / or induce the release of neuroprotective substances without increasing the permeability of the bbb to a level that produces a measurably - harmful clinical effect for the subject . for some applications , system 10 sets an acute strength 122 equal to a level appropriate for treatment of an acute condition , such as an adverse brain event ( e . g ., a cerebrovascular event ), for which increased cbf and / or release of neuroprotective substances is beneficial , but for which opening the bbb is not indicated . for example , the system may set acute strength 122 equal to at least about 20 % of minimum bbb - opening strength 110 , e . g ., at least about 50 %, 60 %, 70 %, or 80 % of minimum bbb - opening strength 110 . in an embodiment of the present invention , system 10 is used for rehabilitative treatment after an adverse brain event , such as a cerebrovascular event , e . g ., a stroke , or for rehabilitative treatment of a non - acute cerebrovascular condition . such rehabilitative stimulation induces the release of neuroprotective substances and / or maintains a slightly elevated level of blood flow , typically over an extended period of time , such as at least 24 hours , at least one week , at least two weeks , at least four weeks , or at least three months . as a result , such stimulation typically rehabilitates damaged tissue , improves perfusion of the rehabilitating brain , and / or accelerates angiogenesis . ( see , for example , the above - mentioned article by zhang r et al . ( 2001 ), which reports that no donors administrated 24 hours after stroke significantly increased angiogenesis in the ischemic boundary regions .) for some applications , the system is configured to apply such rehabilitative stimulation intermittently , such as during one session per day , having a duration of between 1 minute and 6 hours , such as at least 5 minutes or at least 15 minutes , or between 2 and 4 hours , e . g ., about 3 hours or about 6 hours , or more than 6 hours . alternatively , the system is configured to apply such stimulation generally constantly , i . e ., 24 hours per day . further alternatively , the rehabilitative stimulation is applied less frequently than every day , such as once every other day ( e . g ., at least one minute during every 48 hours ), or more frequently than once per day , such as during two sessions per day . for some applications , such stimulation is applied beginning at least one hour after the adverse brain event , such as a cerebrovascular event , e . g ., a stroke , such as beginning at least 3 hours , at least 6 hours , at least 9 hours , at least 12 hours , at least 24 hours , or at least 48 hours after the brain event . for some applications , no released by stimulation at rehabilitation strength 122 is of particular neuroprotective benefit during rehabilitation . for some applications , such rehabilitative stimulation is applied during a plurality of stimulation periods which includes at least first and last stimulation periods . system 10 sets an inter - period interval between initiation of the first period and initiation of the last period to be at least 24 hours . for example , the first stimulation period may occur from 1 : 00 p . m . to 4 : 00 p . m . on a monday , and the last stimulation period may occur from 1 : 00 p . m . to 4 : 00 p . m . on a tuesday of the same week . optionally , stimulation is applied during at least one additional stimulation period between the first and last periods . for example , stimulation may be additionally applied from 1 : 00 a . m . to 4 : 00 a . m . on the tuesday . for some applications , the first period concludes simultaneously with the initiation of the last period , i . e ., the stimulation is applied constantly from the beginning of the first period until the conclusion of the last period . for example , the stimulation may be applied constantly from 1 : 00 p . m . on monday , january 1 to 4 : 00 p . m . on tuesday , january 2 , or constantly from 1 : 00 p . m . on monday , january 1 to 4 : 00 p . m . on monday , january 29 . alternatively , the initiation of the last stimulation period occurs after a conclusion of the first stimulation period , such that the stimulation is not applied during at least one non - stimulation period between the conclusion of the first stimulation period and the initiation of the last stimulation period . for some applications , the system sets the inter - period interval to be at least 48 hours , such as at least one week , at least two weeks , or at least four weeks . when using such greater inter - period intervals , the system typically , but not necessarily , applies stimulation during at least several additional stimulation periods between the first and last stimulation periods . for some applications , such additional stimulation periods may include a plurality of daily stimulation periods , applied on every day between the initiation of the first stimulation period and the initiation of the last stimulation period . for example , the first stimulation period may occur from 1 : 00 p . m . to 4 : 00 p . m . on monday , january 1 , the last stimulation period may occur from 1 : 00 p . m . to 4 : 00 p . m . on monday , january 8 , and the additional daily stimulation periods may occur from 1 : 00 p . m . to 4 : 00 p . m . on each day from tuesday , january 2 through sunday , january 7 , inclusive . for some applications , stimulation is applied for at least 30 minutes every day ( e . g ., at least 60 minutes every day ) between the initiation of the first stimulation period and the initiation of the last stimulation period . for some applications , stimulation is applied during a plurality of non - continuous stimulation periods during each 24 - hour period between the initiation of the first stimulation period and the initiation of the last stimulation period . for example , the first stimulation period may occur from 1 : 00 p . m . to 4 : 00 p . m . on monday , the last stimulation period may occur from 1 : 00 p . m . to 4 : 00 p . m . on wednesday , and stimulation may be applied during additional stimulation periods from ( a ) 1 : 00 a . m . to 4 : 00 a . m . on tuesday , ( b ) from 1 : 00 p . m . to 4 : 00 p . m . on tuesday , and ( c ) from 1 : 00 a . m . to 4 : 00 a . m . on wednesday , such that stimulation is applied during two stimulation periods during the 24 - hour period from 1 : 00 p . m . on monday to 1 : 00 p . m . on tuesday , and during two stimulation periods during the 24 - hour period from 1 : 00 p . m . on tuesday to 1 : 00 p . m . on wednesday . for some applications , the system is configured to set the inter - period interval to be no more than a maximum value , such as three , six , nine , or twelve months . for some applications , the system comprises a user interface , which enables a healthcare worker to enter a value for the inter - period interval . the system typically rejects values that are greater than the maximum value , such as by requiring the healthcare worker to enter another value , or by using the maximum value instead of the entered value . alternatively , the system notifies the healthcare worker if the entered value is greater than the maximum value ; optionally , the system allows the healthcare worker to override the notification . for some applications , the system is configured to store a maximum total time of stimulation per each time period having a given duration , and to apply the stimulation no more than the maximum total time per each time period having the given duration . for example , the given duration of each time period may be 24 hours . typical values for the maximum total time of stimulation per 24 - hour period include one hour , three hours , six hours , ten hours , and twelve hours . for some applications , the maximum total time of stimulation is predetermined , e . g ., by the manufacturer of the system , while for other applications , a healthcare worker enters the maximum total time of stimulation into the system . as used in the present application , including the claims , a “ stimulation period ” includes an entire period during which stimulation is applied , even though current is applied to the site only during a portion of the period , because of the duty cycle , on / off periods , and / or frequency of the current , for example . for some applications , system 10 sets the strength of stimulation during such long - term rehabilitation to a rehabilitation strength 120 , such as between about 10 % and about 40 % of minimum bbb - opening strength 110 , e . g ., between about 20 % and about 30 % of minimum bbb - opening strength 110 , or such as between about 10 % and about 40 % of maximum cbf - increasing strength 106 , e . g ., between about 20 % and about 30 % of maximum cbf - increasing strength 106 . alternatively or additionally , system 10 sets rehabilitation strength 120 to a level that causes an increase in cbf equal to less than about 40 % of a maximum cbf increase that system 10 is capable of inducing . in an embodiment of the present invention , system 10 sets the strength of stimulation to a preventive strength appropriate for preventing an occurrence of a brain event , typically a secondary brain event , e . g ., a secondary stroke . for example , such strength may be between about 5 % and about 50 % of the minimum bbb - opening strength 110 . for some applications , no released by stimulation at the preventive strength is of particular neuroprotective benefit during prevention , and has an anti - thrombolytic , vasodilatory , and / or anti - inflammatory effect . in an embodiment of the present invention , system 10 is configured to treat a complication of subarachnoid hemorrhage ( sah ), such as a cerebral vasospasm . the currently - preferred conventional treatment for safe includes a surgical procedure in which a medical vehicle is used to treat the sah . the medical vehicle may comprise , for example : ( a ) a tool for treating the sah such as by clipping the aneurysm that caused the sah , and / or ( b ) a pharmaceutical treatment . however , the presence of blood in the subarachnoid space sometimes causes increased sensitization of large cerebral arteries , resulting at a later time in cerebral vasospasms . these late - onset vasospasms , in turn , cause brain ischemia and often irreversible damage ( see the above - mentioned article by van gijn j et al .). therefore , the stimulation of the mts of this embodiment of the present invention is typically applied in conjunction with such a treatment ( e . g ., before , during or after the treatment ), typically to the spg , in order to counteract the reduced cbf sometimes caused by blood passage into the subarachnoid space . typically , for treating the complication of sah , system 10 configures the stimulation to increase cbf of the subject and / or induce the release of neuroprotective substances , without substantially opening the bbb of the subject . typically , system 10 is configured to set the strength of stimulation to at least acute strength 122 , but no more than maximum cbf - increasing strength 106 , so as not to substantially open the bbb . for some applications , the stimulation of the mts is initiated at a time after the treatment when the hemorrhage has already been substantially reduced ( at which time , in the absence of mts stimulation , cbf is frequently reduced below desired levels ). alternatively , the stimulation of the mts is initiated prior to this point , but generally has its strongest elevating effect on cbf once the hemorrhage has been substantially reduced . reference is again made to fig3 . in an embodiment of the present invention , electrical stimulation system 10 is configured to apply staged treatment of a brain event , such as an ischemic event ( e . g ., a stroke ). the system configures the stimulation to dilate cerebral vessels , thereby increasing cbf to affected brain tissue and tissue in a vicinity thereof , and / or to induce the release of one or more neuroprotective substances , such as neuromodulators ( e . g ., nitric oxide ( no ) and / or vasoactive intestinal polypeptide ( vip )). such increased cbf and / or release of neuroprotective substances decrease damage caused by the brain event . the system is typically configured to adjust at least one parameter of the applied stimulation responsively to an amount of time that has elapsed since the occurrence of the brain event . for some applications , system 10 calculates the elapsed time responsively to an estimated time of occurrence of the brain event , which is entered into the system by a healthcare worker , typically early in the treatment of the event . in these applications , the system typically automatically progresses from stage to stage based on the elapsed time from the occurrence of the event . alternatively , for some applications , a healthcare worker manually selects the stages . system 10 is typically configured to apply the stimulation in two or more stages . for some applications , during a first , acute stage 130 , the system sets the parameters of stimulation to acute strength 122 , which is sufficient to cause a high level of cerebral vessel dilation and / or a release of neuroprotective substances , but insufficient to substantially open the bbb . such stimulation is primarily intended to arrest the spreading of the initial ischemic core , such as by restoring blood flow to the penumbra in order to prevent damage to cells therein , and / or by releasing neuroprotective substances , such as no and / or vip . such stimulation may also save some cells within the ischemic core , such as neuronal cells . the first stage of stimulation is typically appropriate during the period beginning at the time of the event , and ending at about 4 to 8 hours after the time of the event , such as at about 6 hours after the event . alternatively , the first stage of stimulation is appropriate until about 24 hours after the time of the event . ( see , for example , the above - cited articles by davis s m et al . and phan t g et al .) for some applications , vip released by stimulation at acute strength 122 is of particular neuroprotective benefit . for some applications , hypoperfused areas of the brain are identified , such as by using mri or pet , which can potentially be saved using the stimulation techniques described herein . during a second , rehabilitative stage 136 , system 10 reduces the strength of the stimulation to rehabilitation strength 120 , and typically applies the stimulation intermittently , such as during one session per day , having a duration of between 1 minute and 6 hours , such as between 2 and 4 hours , e . g ., about 3 hours , or more than 6 hours . this rehabilitative level of stimulation continues to induce the release of neuroprotective substances , and / or maintains a slightly elevated level of blood flow . this stage of stimulation is typically applied during the period beginning at the conclusion of acute stage 130 , and lasting at least one week , such as at least two weeks , at least one month , at least three months , or at least six months . alternatively , the rehabilitative stimulation is applied generally constantly , i . e ., 24 hours per day . further alternatively , the rehabilitative stimulation is applied less frequently than every day , such as once every other day , or more frequently than once per day , such during two sessions per day . for some applications , system 10 is configured to apply stimulation during an additional , post - acute stage 132 , between acute stage 130 and rehabilitative stage 136 . during post - acute stage 132 , the system reduces the strength of the stimulation to a post - acute strength 134 , between acute strength 122 and rehabilitation strength 120 . this post - acute strength is sufficient to maintain an increased level of blood flow to and / or release of neuroprotective substances to the ischemic core and the penumbra . the lower strength is less likely to cause potential side effects , such as aneurysm , that might occur if the system maintained the higher level of stimulation of the first stage . typically , post - acute strength 134 is equal to between about 20 % and 70 % of minimum bbb - opening strength 110 , such as between about 40 % and 60 %. post - acute stage 132 typically begins at the conclusion of acute stage 130 , and ends at about 16 to 30 hours after the time of the event , such as about 24 hours after the event . the following table shows exemplary parameter ranges for some of the stimulation strengths and treatment protocols described hereinabove . as indicated in table 1 , for some applications system 10 provides stimulation by applying a plurality of cycles of stimulation , each cycle including an “ on ” period ( e . g ., between 2 and 90 seconds ) followed by an “ off ” period ( e . g ., between 8 and 90 seconds ). such cycles are applied a certain number of times per hour , typically spaced evenly throughout the hour . for example , if the cycles are applied four times per hour , the four cycles may be applied at the beginning of the hour , 15 minutes into the hour , 30 minutes into the hour , and 45 minutes into the hour , respectively . for some applications , each stimulation is applied in sets of two or more cycles . for example , if the stimulation is applied four times per hour , a set of two cycles may be applied at the beginning of the hour , 15 minutes into the hour , 30 minutes into the hour , and 45 minutes into the hour , respectively . for some applications , in order to apply different strengths for the different brain event protocols ( acute treatment , post - acute treatment , rehabilitation , and prevention of recurrence of the event ), system 10 changes the amplitude of the applied signal and / or the number of cycles per hour . alternatively or additionally , the system changes the frequency , pulse width , duration of the “ on ” periods , duration of the “ off ” periods , ratio of duration of the “ on ” to the “ off ” periods , number of cycles per set of cycles , or at least one other parameter of the stimulation . nitric oxide ( no ) influences infarct size after focal cerebral ischemia and also regulates neurogenesis in the adult brain . these observations suggest that therapeutic approaches to stroke that target no signaling may provide neuroprotection and also enhance brain repair through cell replacement ( see zhang r et al . ( 2001 ) and sun y et al ., cited hereinabove ). utilizing a rat model , zhang r et al . ( 2001 ) demonstrated that treatment of stroke with nitric oxide ( no ) donors reduces functional neurological deficits . zhang f et al . ( cited hereinabove ) demonstrated that no donors increase cbf to the ischemic territory and reduce the tissue damage resulting from focal ischemia . the protective effect may result from an increase in cbf to the ischemic territory , probably the ischemic penumbra . no and vip have been found to be potent neuroprotectants in cell culture models ( see the above - mentioned article by sandgren k et al .). khan m et al . ( cited hereinabove ), using s - nitrosothiols , a nitric oxide ( no ) donor , demonstrated that administration of no provided neuroprotection in a rat model of focal cerebral ischemia . ziche m et al . ( cited hereinabove ) discuss the role of no , as a factor responsible for vasodilation , in physiological and pathological angiogenesis . the inventors hypothesize that the release of no induced by the stimulation techniques described herein may have therapeutic benefits , even if such stimulation is applied beginning several hours , or even several days , after the stroke . in an embodiment of the present invention , stimulation during acute stage 130 and / or post - acute stage 132 is performed using a needle - like electrode , which is inserted , using a simple procedure , into a subject recently admitted to a hospital after a stroke . for example , the device described with reference to fig1 - 4b and / or fig1 a - c of the above - mentioned u . s . patent application ser . no . 11 / 349 , 020 may be used for the acute and / or post - acute stages . upon completion of one or both of these stages , and / or stabilization of the subject , the needle - like electrode is removed , and a longer - term stimulator is implanted and used for rehabilitative stage 136 and / or the preventive stage . for example , the device described with reference to fig5 a - d , 12 - 14 b , and / or 17 a - c of the &# 39 ; 020 application may be used for the rehabilitative and / or preventive stages . reference is made to fig4 , which is a graph 150 showing a rehabilitation protocol for treating stroke , in accordance with an embodiment of the present invention . in accordance with this protocol , system 10 is configured to alternatingly apply stimulation at a first , rehabilitative level of strength , and at a second bbb - opening level of strength in conjunction with administration of a drug for rehabilitation from stroke . for example , the drug may include a growth factor , such as bdnf , gdnf , or ngf . typically , the first rehabilitative level is rehabilitation strength 120 , described hereinabove with reference to fig3 , and the second bbb - opening level falls within bbb - opening range 108 , such as maximum bbb - opening strength 112 , described hereinabove with reference to fig3 . system 10 is typically configured to apply the rehabilitative stimulation intermittently , such as during one session per day , having a duration of between about 1 and about 6 hours , such as between about 2 and about 4 hours day , e . g ., about 3 hours . alternatively , the rehabilitative stimulation is applied less frequently than every day , such as once every other day , or more frequently than once per day , such as during two sessions per day . system 10 is typically configured to apply the bbb - opening stimulation intermittently , such as for between about 0 . 5 and about 1 hour per day , or for between about 3 and about 6 hours per day , e . g ., about 4 hours per day . alternatively , the bbb - opening stimulation is applied less frequently than every day , such as once every other day , or more frequently than once per day , such as twice per day , or 24 times per day . the drug administered in conjunction with applying the bbb - opening stimulation is typically administered systematically , before and / or during application of the bbb - opening stimulation . for some applications , the rehabilitative stimulation is applied immediately before or after the bbb - opening stimulation ( as shown in fig4 ), while for other applications the rehabilitative and bbb - opening stimulations are applied non - contiguously ( not shown in fig4 ). reference is made to fig5 , which is a graph showing changes in cbf vs . baseline using three different spg stimulation protocols , measured in accordance with an embodiment of the present invention . 16 naïve rats were anesthetized with a ketamine - xylazine combination , and a plastic holder was affixed to the skull for cbf measurement . a bipolar electrode was brought into contact with the spg and connected to a controller . the spg was stimulated for five minutes beginning after cbf stabilization , using the following signal parameters : 3 . 5 volts , 10 hz , and a 500 μsec pulse width . the rats were divided into four groups , one of which served as a control , and the other three received stimulation having different duty cycles : 4 seconds on / 15 seconds off , 60 seconds on / 12 seconds off , and 90 second on / 60 second off . as can be seen in fig5 and in table 2 below , cbf significantly increased in two of the stimulation groups ( 4 / 15 and 60 / 12 ) vs . cbf baseline . the maximum increase in cbf vs . baseline ( 193 %) was observed in the 60 / 12 stimulation group after two minutes of spg stimulation . cbf in this group remained elevated even 10 - 15 minutes after termination of spg stimulation . the minimum increase in cbf vs . baseline ( 141 %) was observed in the 90 / 60 stimulation group . it is clear from these results that spg stimulation at the described parameters significantly increases cbf , and that such increase was stable at 10 minutes following spg stimulation . reference is made to fig6 - 11c , which are graphs showing in vivo experimental results , measured in accordance with respective embodiments of the present invention . these animal experiments were performed to test the efficacy of the spg stimulation techniques described hereinabove for treating stroke . the experiments described with reference to fig6 - 11c used a rat middle cerebral artery occlusion ( mcao ) model of stroke . as described in detail hereinbelow , these experiments demonstrated that : spg stimulation starting three hours following mcao occlusion significantly improved cerebral blood flow ( cbf ), decreased infract size , and improved neuromuscular function ; spg stimulation reduced mortality ; spg stimulation for one or three hours per day for three days , beginning 24 hours after mcao , improved neuromuscular functions for nine days following the insult ; and spg stimulation for six hours per day for six days , beginning 24 hours after mcao improved neuromuscular function at 13 and 28 days following occlusion . reference is made to fig6 , which is a graph showing the effect of spg stimulation beginning three hours after permanent mcao ( pcmao ) in male rats , measured in accordance with an embodiment of the present invention . the graph shows changes in cbf vs . baseline , in an experimental group ( n = 12 ) and in a control group ( n = 12 ). the sprague dawley ® ( sd ) rats were anesthetized with a ketamine - xylazine combination ( 85 mg / kg and 5 mg / kg respectively ), and pmcao was performed as follows . the right common carotid artery ( cca ) was exposed through a midline neck incision and carefully dissected free from surrounding nerves and fascia , from its bifurcation to the base of the skull . the occipital artery branches of the external carotid artery ( eca ) were then isolated , and these branches were dissected and coagulated . the eca was dissected further distally and coagulated together with the terminal lingual and maxillary artery branches , which was then divided . the internal carotid artery ( ica ) was isolated and carefully separated from the adjacent vagus nerve , and the pterygopalatine artery was ligated close to its origin with a 5 - 0 nylon suture . a 4 - 0 silk suture was tied loosely around the mobilized eca stump , and a 4 cm length of 4 - 0 monofilament nylon suture ( the tip of the suture was blunted by using a flame , and the suture was coated with silicone , prior to insertion ) was inserted through the proximal eca into the ica , and from there into the circle of willis , effectively occluding the mca . the surgical wound was closed and the rats were returned to their cages to recover from anesthesia . these techniques for performing pmcao are similar to those described in the above - mentioned article by schmid - elsaesser r et al . spg stimulation was initiated at three hours following pmcao . the stimulation regime included a duty cycle of 60 seconds on / 12 seconds off , at 2 ma and 10 hz , with a 500 μsec pulse width . the stimulation was applied for five minutes every 30 minutes , for a period of 10 hours . as can be seen in fig6 , spg stimulation markedly and significantly increased cbf levels in rats after pmcao . the greatest increase was observed at 6 hours following mcao . fig7 and 8 are graphs showing results of an in vivo experiment assessing the effect of spg stimulation performed three hours following stroke , measured in accordance with an embodiment of the present invention . a rat pmcao model of stroke was used to evaluate the neuroprotective benefits of spg stimulation following stroke using techniques described herein . a three - hour delay prior to applying stimulation was chosen to simulate the relatively late - stage intervention common in clinical settings . the results of this experiment demonstrate that spg stimulation provided significant neuroprotection . spg stimulation reduced mortality , significantly improved neuromuscular function , and increased cbf . 32 sd rats were divided into an experimental group ( n = 15 ), and a control group ( n = 17 ). pmcao was performed using the techniques described hereinabove . a bipolar electrode was brought into contact with the spg ipsilateral to the pmcao , and connected to a controller . three hours after pmcao and prior to commencement of stimulation , all of the rats were subjected to the first of three neuroscoring ( behavioral ) tests . additional neuroscoring was performed at 24 and 48 hours post - pmcao . spg stimulation was initiated at three hours following pmcao occlusion . the stimulation regime included a duty cycle of 60 seconds on / 12 seconds off , at 2 ma and 10 hz , with a 500 μsec pulse width . the stimulation was performed for five minutes every 30 minutes , for a period of 10 hours . forty - eight hours following pmcao , the rats were sacrificed , and their brains were removed for triphenyltetrazolium chloride ( tic ) staining . infarct volume was quantified at each coronal level in the area of the contralateral hemisphere and the ipsilateral spared hemisphere . the volume of the total infarct was measured . the infarct volume was quantified by computerized morphometric analysis using an imaging program . as can be seen in fig7 and in table 3 below , spg stimulation increased cbf levels in the experimental group vs . the control group . spg stimulation also decreased the sub - cortical and cortical infarct volume in the experimental group vs . the control group , as measured at forty - eight hours following pmcao , as can be seen in fig8 , which shows the infarct volume as a percentage of the total volume of both hemispheres , and in table 3 . mortality was lower in the experimental group than in the control group , and neuroscore was higher in the experimental group than in the control group , as is shown in table 3 . fig9 a - c are graphs showing the results of in vivo experiments assessing the effect of spg stimulation performed three hours following stroke , measured in accordance with respective embodiments of the present invention . a rat pmcao model of stroke was used to evaluate the neuroprotective benefits of spg stimulation following stroke using techniques described herein . other than as described below , these experiments were conducted in the same manner as those described hereinabove with respect to fig7 and 8 and table 3 . 24 sd rats were divided into an experimental group ( n = 17 ), and a control group ( n = 12 ). as can be seen in fig9 a , spg stimulation increased cbf levels in the experimental group vs . the control group . spg stimulation also decreased the sub - cortical and cortical infarct volume in the experimental group vs . the control group , as measured at forty - eight hours following pmcao , as can be seen in fig9 b , which shows the infarct volume as a percentage of the total volume of both hemispheres . neuroscore was slightly lower in the experimental group than in the control group at 3 hours after pmcao , but was significantly ( p & lt ; 0 . 05 ) higher in the experimental group at 24 hours after pmcao , as shown in fig9 c ( neuroscore was assessed on a scale of 0 to 12 , with 12 representing the best performance ). reference is made to fig1 , which is a graph showing results of an in vivo experiment assessing the effect of rehabilitative spg stimulation , measured in accordance with an embodiment of the present invention . a rat mcao ( middle cerebral artery occlusion ) model of stroke was used to evaluate the neuromuscular benefits of rehabilitative spg stimulation using the techniques described herein . 47 rats were divided into three groups : a control group ( n = 18 ); a first experimental group ( n = 16 ), which received one hour of spg stimulation per day ; and a second experimental group ( n = 13 ), which received three hours of spg stimulation per day . pmcao was performed using the techniques described hereinabove with reference to fig6 . a bipolar electrode was brought into contact with the spg ipsilateral to the pmcao , and connected to a controller . spg stimulation was initiated at 24 hours after pmcao , in order to demonstrate the potential rehabilitative effects of such stimulation , rather than the acute benefits . the first and second experimental groups each received spg stimulation at 24 hours , 48 hours , and 72 hours after pmcao . the stimulation regime included a duty cycle of 60 seconds on / 12 seconds off , at 2 ma and 10 hz , with a 500 μsec pulse width . as mentioned above , the stimulation was performed for one hour per day in the first experimental group , and three hours per day in the second experimental group . at 24 , 48 , 72 , 96 , and 216 hours after pmcao , the rats were tested using a modified neuroscore battery , which assessed the severity of damage on a scale of 0 to 10 , with 10 representing the greatest deficit . as can be seen in fig1 , the rats in both the first and second experimental groups achieved better ( lower ) neuroscores than the control group at all tested time periods after pmcao , with statistical significance achieved for the second ( 3 hour stimulation ) experimental group at nine days after pmcao . reference is made to fig1 a - c , which are graphs showing results of an in vivo experiment assessing the effect of rehabilitative spg stimulation , measured in accordance with an embodiment of the present invention . a rat mcao model of stroke was used to evaluate the benefits , including neuromuscular benefits , of rehabilitative spg stimulation using the techniques described herein . 29 rats were divided into an experimental group ( n = 16 ) and a control group ( n = 13 ). transient mcao ( tmcao ) was performed as follows . the right common carotid artery ( cca ) was exposed through a midline neck incision and carefully dissected free from surrounding nerves and fascia , from its bifurcation to the base of the skull . the occipital artery branches of the external carotid artery ( eca ) were isolated , and these branches were dissected and coagulated . the eca was further dissected distally and coagulated together with the terminal lingual and maxillary artery branches , which were divided . the internal carotid artery ( ica ) was isolated and carefully separated from the adjacent vagus nerve , and the pterygopalatine artery was ligated close to its origin with a 5 - 0 nylon suture . a 4 - 0 silk suture was tied loosely around the mobilized eca stump , and a 4 cm length of 4 - 0 monofilament nylon suture ( the tip of the suture was blunted using a flame , and the suture was coated with silicone , prior to insertion ) was inserted through the proximal eca into the ica , and from there into the circle of willis , effectively occluding the mca . the suture was placed for three hours and thereafter removed . the surgical wound was closed , and the animals were returned to their cages to recover from the procedure . these techniques for performing tmcao are similar to those described in the above - mentioned article by schmid - elsaesser r et al . on the day of the tmcao procedure , a bipolar electrode was implanted in contact with the spg ipsilateral to the tmcao , and connected to a controller . at 24 hours after tmcao , and prior to commencement of the first stimulation , neurological evaluation was performed on the rats using the modified neurological severity score ( mnss ) scale . only animals with an overall score of at least 12 were included in the experiment . the rats in the experimental group received spg stimulation for 6 hours per day for 6 days , beginning 24 hours after tmcao . the stimulation regime included a duty cycle of 60 seconds on / 12 seconds off , at 2 ma and 10 hz , with a 500 μsec pulse width . neuroscores were assessed at days 6 , 13 , and 28 after tmcao , using behavioral tests aimed at studying neuromuscular function . fig1 a and 11b show results obtained at days 13 and 28 , respectively ( the mnss scale ranges from 0 to 12 , with best performance indicated by a 12 ). a significant improvement in neuromuscular function can be seen at both days 13 and 28 . fig1 c shows the results of a stepping test for the left and right paws . a significant improvement in motor function in the experimental group compared with the control group can be seen for the contralateral ( left ) paw . reference is made to fig1 a - h , which are graphs showing results of an in vivo experiment assessing the effect of long - term rehabilitative spg stimulation , measured in accordance with an embodiment of the present invention . a rat tmcao model of stroke was used to evaluate the benefits , including neuromuscular , motility , cognitive , somatosensory , somatomotor , infarct volume benefits , of rehabilitative spg stimulation using the techniques described herein . the stimulation was applied for seven consecutive days beginning at 24 hours after reperfusion in the tmcao model . 94 male sprague dawley ( sd ) rats were divided into six groups , as shown in table 4 : prior to performance of any surgical procedure on the rats , the rats were trained using a series of behavior tests . five parameter categories were evaluated using one or more tests , as follows : neuromuscular function — rotarod motor test , mnss test , beam walking and balance test , stepping test , and staircase skilled reaching test ; motility — open field test ; learning memory ( cognitive )— water maze test ; somatosensory sensation — adhesive removal test ; and somatomotor sensation — corner turn test . transient mcao ( tmcao ) was performed on the right hemisphere of all of rats except those of the sham group , using the techniques described hereinabove with reference to fig1 a - c . three hours after the occlusion , reperfusion was allowed in all groups . on the day of tmcao , the rats were anesthetized , and a bipolar electrode was implanted in contact with the spg ipsilateral to the pmcao ( i . e ., the right spg ), and connected to a controller . at 24 hours post - tmcao ( just prior to stimulation ), the rats were subjected to neuroscoring using the mnss scale , which has a score range of 0 - 18 , where 0 represents normal and 18 represents maximum neurological defect . rats scoring less than or equal to 9 were excluded from the experiment . spg stimulation was applied for seven consecutive days beginning at 24 hours post - tmcao , using the following regime : a duty cycle of 60 seconds on / 12 seconds off , with two cycles every 15 minutes , at 2 ma and 10 hz , with a 500 μsec pulse width . the stimulation was applied for fifteen minutes every 60 minutes . the number of hours of stimulation per day was as shown in table 4 above . in order to assess rehabilitation , on days 8 , 14 , and 35 post - tmcao , ( with limited exceptions for specific tests ), the rats were subjected to the same pre - procedure behavior tests used in the training , as described hereinabove . one day after the last behavior testing , the rats were sacrificed and perfused . their brains were harvested , infarct volume was measured , and neurons were counted . mortality in the spg - stimulated groups was lower than in the non - stimulated control group . spg stimulation generally improved neuromuscular functions ( rotarod , mnss , beam walk and balance , stepping and staircase tests ) in comparison to the non - stimulated control group . spg stimulation improved cognitive capabilities ( water maze test ) in comparison to the non - stimulated control group . there was a trend towards increased motility ( open field test ) in the spg - stimulated groups . somatosensory sensations were enhanced in the spg - stimulated groups in comparison to the non - stimulated control group . somatomotor competence was superior in the spg - stimulated groups than in the non - stimulated control groups . spg stimulation resulted in higher neurons counts in cortical layer v of the ipsilateral stimulated side in comparison to the non - stimulated control group . in summary , in the present experiment , spg stimulation initiated 24 hours after tmcao had advantageous results for all five parameter groups evaluated . in addition , spg stimulation increased the number of neurons in all regions counted . fig1 a is a graph showing neuroscores ( mnss test ) of all six groups , measured at 24 hours , 8 days , 14 days , and 35 days after tmcao , measured in accordance with an embodiment of the present invention . as can be seen in the graph , mnss scores of the spg - stimulated rats decreased in a time - dependent manner post - tmcao , indicating the occurrence of an active restorative , rehabilitative process . spg stimulation markedly and significantly ( p & lt ; 0 . 05 ) improved neurological function measured at days 8 , 14 , and 35 in all spg - stimulated groups . fig1 b is a graph showing the results of the stepping test performed on the left foreleg in all six groups , measured pre - tmcao and at 8 days , 14 days , and 35 days after tmcao , measured in accordance with an embodiment of the present invention . as can be seen in the graph , there was a significant ( p & lt ; 0 . 05 ) increase in left ( impaired ) foreleg stepping in all spg - stimulated rats in comparison to the non - stimulated control group ( with the exception of the 10 - hour stimulated group at day 35 ). maximum improvement was evident in the 3 - and 6 - hour stimulation groups at days 14 and 35 , respectively . fig1 c - f are graphs showing the results of the morris water maze ( wm ) task , measured in accordance with an embodiment of the present invention . the morris wm task is a standard test of learning in which the animal repeatedly searches for a rest platform hidden beneath the surface in a pool . the test is especially sensitive to hippocampal and cortical damage , and reflects attention , memory , and learning strategy . the morris wm task was performed on days 14 and 35 following tmcao . fig1 c is a graph showing the latency to the first occurrence in the old zone ( as described below ) in first and second trials at 14 days after tmcao , measured in accordance with an embodiment of the present invention . this parameter assesses the rats &# 39 ; functional memory . the rest platform was moved from the old zone ( its position during training ) to the new zone ( its position during testing ), and the rats were expected to seek the old zone . the first trial showed that the spg - stimulated rats ( 3 -, 6 -, and 10 - hour stimulation ) returned to the old zone significantly ( p & lt ; 0 . 05 ) more quickly than the non - stimulated rats in the control group . the second trial showed , although non - significantly , that the spg - stimulated rats returned to the old zone faster than the non - stimulated controls , even though introduced to the new zone rest platform in the first trial . the second trial thus confirmed that the spg - stimulated rats showed enhanced remnants of functional memory . fig1 d is a graph showing time spent in the old zone at day 14 after tmcao , measured in accordance with an embodiment of the present invention . this parameter also assesses the rats &# 39 ; functional memory . as can be seen in the graph , the 3 -, 6 -, and 10 - hour spg - stimulated groups spent significantly ( p & lt ; 0 . 05 ) more time seeking the rest platform in the old zone in comparison to the non - stimulated control group . fig1 e is a graph showing the latency to the first occurrence in the new zone in first and second trials at day 35 after tmcao , measured in accordance with an embodiment of the present invention . this parameter also assessed the rats &# 39 ; functional memory . in the first trial , the 3 -, 6 -, and 10 - hour spg - stimulated groups demonstrated superior , although non - significant , results in finding the new zone , compared with the non - stimulated control group . in the second trial , all of the spg - stimulated groups achieved better results than the non - stimulated control group . these results were significant ( p & lt ; 0 . 05 ) only in the 3 - hour stimulated group . fig1 f is a graph showing the distance moved to find the rest platform in the new zone in first and second trials at day 35 after tmcao , measured in accordance with an embodiment of the present invention . this parameter assessed the rats &# 39 ; long - term learning capability . in both trials the spg - stimulated rats demonstrated better performance than the control group . these results were significant ( p & lt ; 0 . 05 ) only in the 3 - hour stimulated group during the first trial . the staircase test ( results not shown ) was performed to assess the rehabilitation of foreleg fine motorics . at day 14 after tmcao the spg - stimulated groups demonstrated better performance in the left impaired foreleg than the control group ( 1 -, 3 -, and 6 - hour stimulation , significant ( p & lt ; 0 . 05 ) in the 3 - and 6 - hour stimulated rats only ). at day 35 after tmcao the spg - stimulated groups demonstrated better performance in the left impaired foreleg , significant ( p & lt ; 0 . 05 ) in the 3 - hour stimulated rats only . the rotarod test ( results not shown ) was performed to assess the rats &# 39 ; ability to remain on a rotating rod . it requires a high degree of sensorimotor coordination and is sensitive to damage in the basal ganglia and the cerebellum . the only significant ( p & lt ; 0 . 05 ) results were in the 3 - hour stimulated rats on the 35 day assessment , which remained on the rotarod significantly longer than the control group . fig1 g is a graph showing the time required for the rats to remove an adhesive patch from the left foreleg , measured in accordance with an embodiment of the present invention . this test assessed both cutaneous sensitivity and sensor motor integration , and is analogous to human neurological tests used clinically in stroke patients . in the left impaired foreleg , the spg - stimulated rats showed better results than the non - stimulated controls at all assessment days ( 8 , 14 , and 35 days ). these results were significant ( p & lt ; 0 . 05 ) at all three assessment days in the 3 - and 6 - hour stimulated groups only . the corner test ( results not shown ) was performed to evaluate the rats &# 39 ; tendency to favor a turn in the direction of the ipsilateral side of the tmcao ( i . e ., the right side in the experiment ). on all three assessment days ( 8 , 14 , and 35 days ), all spg - stimulated groups showed a decrease in right side turns in comparison to the non - stimulated control group . this decrease was significant ( p & lt ; 0 . 05 ) only on day 35 in the 1 - and 6 - hour stimulated rats . the beam walk test ( results not shown ) was performed to evaluate sensor motor integration , specifically hind limb function . in general , all spg - stimulated groups showed improved results in comparison to the non - stimulated control group . these results were significant ( p & lt ; 0 . 05 ) only on day 35 only in the 3 - hour stimulated group . the beam balance test ( results not shown ) was performed to assess gross vestibulomotor function , by requiring the rats to balance steadily on a narrow beam . this test is sensitive to motor cortical insults . on all assessment days ( days 8 , 14 , and 35 ), all of the spg - stimulated groups ( except the 1 - hour stimulated group on day 8 ) performed better than the non - stimulated control group . these results were significant ( p & lt ; 0 . 05 ) only on day 14 in the 3 - hour stimulated group . the open field test ( results not shown ) was performed to assess the following four parameters indicative of hippocampal and basal ganglia damage , as well as hind limb dysfunction : total distance moved , which decreases in cerebrally - insulted animals . all of the spg - stimulated groups achieved enhanced movement compared to the control group on day 14 after tmcao . these results were significant ( p & lt ; 0 . 05 ) only in the 3 - and 6 - hour stimulated groups . velocity , which is diminished in cerebrally - insulted animals . all of the spg - stimulated groups achieved enhanced velocity compared to the control group on day 14 after tmcao . these results were significant ( p & lt ; 0 . 05 ) only in the 3 - and 6 - hour stimulated groups . latency of first occurrence in center zone , all of spg - stimulated groups ( except the 10 - hour stimulated group on day 14 ) showed quicker entry into the center zone in comparison to the non - stimulated control group . these results were significant ( p & lt ; 0 . 05 ) only on day 35 in the 1 - and 3 - hour stimulated groups . total distance moved in center zone . on day 14 , the 3 - and 10 - hour stimulated groups achieved significantly ( p & lt ; 0 . 05 ) greater distance moved than the control group . fig1 h is a graph showing the number of neurons in cortical layer v and measured in accordance with an embodiment of the present invention . neuron counting was performed in cortical layers v and ii - iii in the non - stimulated control group and in the 3 - and 6 - hour spg - stimulated groups . the number of neurons in cortical layer v was significantly ( p & lt ; 0 . 05 ) greater in both of these spg - stimulated groups compared to the non - stimulated group . in cortical layers ii - iii there was no significant difference between the stimulated and non - stimulated groups . there were no significant differences in body weigh between the spg - stimulated groups and the non - stimulated control group . the inventors are currently performing an in vivo experiment to compare the application of spg stimulation for 28 days with the application of spg stimulation for 7 days , as applied in the experiment described hereinabove with reference to fig1 a - h . the experimental protocol is similar to that of this above - mentioned experiment . preliminary results of this current experiment indicate that application of spg stimulation for the longer 28 - day period has greater therapeutic benefits than application of the stimulation for 7 days . table 5 shows the results of an in vivo experiment performed to test whether long - term stimulation of the spg using a protocol appropriate for treating stroke damages the bbb , measured in accordance with an embodiment of the present invention . 31 rats ( males , wistar ™, 12 weeks , average body weight 300 g ) were divided to three groups : an spg stimulation group ( n = 13 ), which had an spg stimulator implanted ; a first control group ( n - 12 ), which was not stimulated , and had a sham operation ; and a second control group ( n = 6 ), which had a sham operation , and was exposed to an rf electromagnetic field for 24 hours . the spg stimulation group received 24 hours of continuous spg stimulation with a stimulation regime that included a duty cycle of 90 seconds on / 60 seconds off , at 5 v and 10 hz , with a 1 millisecond pulse width . upon completion of stimulation , a marker ( evans blue ( eb ) ( 2 %)), which normally does not cross the bbb , was intravenously ( 2 ml ) injected into the rats . 48 hours following the eb administration , 500 ml of cold saline was used for perfusion of blood and eb from the rats &# 39 ; circulation . thereafter , the rats &# 39 ; brains were removed , the left and right hemispheres were homogenized , and brain eb concentration was determined using an elisa reader at 630 nm . as can be seen in table 5 , stimulation for 24 hours did not cause leakage of eb into the brain , indicating that the stimulation did not cause damage to the bbb . the inventors performed in vivo experiments in rats to assess the safety of spg stimulation techniques described herein . these experiments showed that stimulation did not break down the bbb , and that stimulation was found to be safe in a battery of motor and cognitive tests , which were in general agreement with histological analysis . in an embodiment of the present invention , a calibration procedure is performed , in which a test molecule is injected into the systemic blood circulation of the subject , and a threshold stimulation strength is determined by stimulating at least one mts , and gradually increasing the stimulation strength until the bbb is opened ( e . g ., as determined using a radioactive scanning technique ). system 10 applies therapeutic stimulation to an mts using a strength equal to a certain percentage of the threshold strength , typically less than 100 %. reference is made to fig1 , which is a graph 160 showing a protocol for treating a brain tumor , in accordance with an embodiment of the present invention . in accordance with this protocol , a method for treating a brain tumor comprises : ( a ) during a first period of time 170 , applying excitatory electrical stimulation to at least one mts at a first , relatively low strength 152 , in conjunction with administration of a chemotherapeutic drug at a first , relatively high dosage 174 ; and ( b ) during a second period of time 176 , applying the stimulation at a second strength 178 greater than first strength 152 , in conjunction with administration of the drug at a second dosage 180 lower than first dosage 174 . alternatively , the drug is administered only at the first dosage , and the stimulation is applied at second strength 178 after the level of the drug in the systemic circulation has dropped because of ordinary metabolic drug clearance from the circulation . for some applications , the protocol shown for second period 176 is applied after first period 170 ( as shown ). for other applications , the protocol shown for the second period is applied before the protocol shown for the first period . alternatively , two different chemotherapeutic drugs are applied during the first and second periods , respectively , not necessarily at different dosages . the blood - tumor barrier ( btb ) of the core and tissue near the core of a growing brain tumor is generally damaged by the natural progression of the tumor . during first period 170 , stimulation applied at first strength 172 is thus sufficient to further open the btb of the core and tissue near the core , but not sufficient to open the bbb of the periphery of the tumor or of other cells in the brain . in other words , first strength 172 is between a btb opening strength 173 and maximum bbb - opening strength 112 . as a result , high dosage 174 of the chemotherapeutic drug is targeted at the core and tissue near the core of the tumor , since the drug is substantially unable to enter other brain cells , because of their intact bbb and the large molecular size of the drug . during second period 176 , stimulation at higher second strength 178 opens the bbb of other brain cells , including tumor cells in the periphery of the core and / or other areas of the brain . for some applications , second strength 178 is greater than or equal to maximum bbb - opening strength 112 , as shown in fig1 . alternatively or additionally , second strength 178 is sufficient to induce a significant increase in the permeability of the bbb . second dosage 180 is low enough not to substantially damage non - tumor cells . for some applications , the dosage is set to the highest level that does not cause systemic and / or brain toxicity ; this level is higher during first period 170 than during second period 176 , because of the lower level of mts stimulation during the first period than during the second period . for some applications , only the protocol for the first period is applied , when this is deemed sufficient to facilitate delivery of the drug to the core and tissue near the core while generally avoiding facilitating delivery of the drug into other brain cells . for some applications , in order to determine the appropriate parameters for increasing the permeability of the btb and / or bbb for this embodiment , a calibration procedure is performed in which the uptake of a substance across the btb and / or bbb is measured at a plurality of stimulation parameters ( e . g ., using a radioactive isotope or other marker known in the art ). in an embodiment of the present invention , bipolar stimulation is applied , in which a first electrode is applied to a first mts , and a second electrode is applied to a second mts . in an embodiment of the present invention , an spg of the subject is indirectly activated by stimulating a branch of cranial nerve v of the subject , including , for example , afferent fibers of cranial nerve v , either electrically , magnetically , or electromagnetically . a reflex response to such stimulation leads to activation of the spg . typically , the stimulation is performed while the subject is under general anesthesia or sedation . for some applications , cranial nerve v is stimulated by non - invasively attaching electrodes to the surface of the face of the subject , typically using techniques commonly used for transcutaneous electrical nerve stimulation ( tens ). in an embodiment of the present invention , an spg of the subject is indirectly activated by stimulating afferent fibers of the trigeminal nerve ( cranial nerve v ) of the subject , either electrically , magnetically , or electromagnetically . a reflex response to such stimulation leads to activation of the spg . ( for example , the maxillary branch of the trigeminal nerve directly contacts the spg .) typically , but not necessarily , such stimulation is performed while the subject is under general anesthesia or sedation . for some applications , cranial nerve v is stimulated by non - invasively attaching electrodes to the surface of the face of the subject , typically using techniques commonly used for transcutaneous electrical nerve stimulation ( tens ). for example , tens may be applied to a cheek or a tip of a nose of a subject . in an embodiment of the present invention , an oral appliance is provided that is configured to be brought into contact with a mucous membrane of a palate of an oral cavity of a subject . the appliance comprises one or more electrodes , which are driven to apply transmucosal electrical stimulation to nerve fibers within or immediately above the mucous membrane , which fibers directly innervate an spg of the subject . typically , but not necessarily , such stimulation is performed while the subject is under general anesthesia or sedation . such transmucosal stimulation may require less current than the transcutaneous stimulation described hereinabove . in some embodiments of the present invention , techniques described herein are practiced in combination with techniques described in one or more of the references cited in the background of the invention section hereinabove and / or in combination with techniques described in one or more of the patent applications cited hereinabove . the scope of the present invention includes embodiments described in the following patent applications , which are assigned to the assignee of the present patent application and are incorporated herein by reference . in an embodiment of the present invention , techniques and apparatus described in one or more of the following applications are combined with techniques and apparatus described herein : u . s . provisional patent application 60 / 203 , 172 , filed may 8 , 2000 , entitled , “ method and apparatus for stimulating the sphenopalatine ganglion to modify properties of the bbb and cerebral blood flow ” u . s . patent application ser . no . 10 / 258 , 714 , filed oct . 25 , 2002 , entitled , “ method and apparatus for stimulating the sphenopalatine ganglion to modify properties of the bbb and cerebral blood flow ,” or the above - referenced pct publication wo 01 / 85094 u . s . provisional patent application 60 / 364 , 451 , filed mar . 15 , 2002 , entitled , “ applications of stimulating the sphenopalatine ganglion ( spg )” u . s . provisional patent application 60 / 368 , 657 , filed mar . 28 , 2002 , entitled , “ spg stimulation ” u . s . provisional patent application 60 / 376 , 048 , filed apr . 25 , 2002 , entitled , “ methods and apparatus for modifying properties of the bbb and cerebral circulation by using the neuroexcitatory and / or neuroinhibitory effects of odorants on nerves in the head ” u . s . provisional patent application 60 / 388 , 931 , filed jun . 14 , 2002 , entitled “ methods and systems for management of alzheimer &# 39 ; s disease ,” pct patent application pct / il03 / 000508 , filed jun . 13 , 2003 , claiming priority therefrom , and a us patent application filed dec . 14 , 2004 in the national stage thereof u . s . provisional patent application 60 / 400 , 167 , filed jul . 31 , 2002 , entitled , “ delivering compounds to the brain by modifying properties of the bbb and cerebral circulation ” u . s . provisional patent application 60 / 426 , 180 , filed nov . 14 , 2002 , entitled , “ surgical tools and techniques for sphenopalatine ganglion stimulation ,” pct patent application pct / il03 / 000966 , filed nov . 13 , 2003 , which claims priority therefrom , and a us patent application filed may 11 , 2005 in the national stage thereof u . s . provisional patent application 60 / 426 , 182 , filed nov . 14 , 2002 , and corresponding pct patent application pct / il03 / 000967 , which claims priority therefrom , filed nov . 13 , 2003 , entitled , “ stimulation circuitry and control of electronic medical device ,” and a us patent application filed may 11 , 2005 in the national stage thereof u . s . patent application ser . no . 10 / 294 , 310 , filed nov . 14 , 2002 , entitled , “ spg stimulation for treating eye pathologies ,” which published as us patent application publication 2003 / 0176898 , and pct patent application pct / il03 / 000965 , filed nov . 13 , 2003 , claiming priority therefrom pct patent application pct / il03 / 000631 , filed jul . 31 , 2003 , entitled , “ delivering compounds to the brain by modifying properties of the bbb and cerebral circulation ,” which published as pct publication wo 04 / 010923 , and u . s . patent application ser . no . 10 / 522 , 615 in the national stage thereof u . s . pat . no . 6 , 853 , 858 to shalev u . s . patent application ser . no . 10 / 783 , 113 , filed feb . 20 , 2004 , entitled , “ stimulation for acute conditions ,” which published as us patent application publication 2004 / 0220644 u . s . provisional patent application 60 / 426 , 181 , filed nov . 14 , 2002 , entitled , “ stimulation for treating ear pathologies ,” pct patent application pct / il03 / 000963 , filed nov . 13 , 2003 , which claims priority therefrom , and which published as pct publication wo 04 / 045242 , and u . s . patent application ser . no . 10 / 535 , 025 in the national stage thereof u . s . provisional patent application 60 / 448 , 807 , filed feb . 20 , 2003 , entitled , “ stimulation for treating autoimmune - related disorders of the cns ” u . s . provisional patent application 60 / 461 , 232 to gross et al ., filed apr . 8 , 2003 , entitled , “ treating abnormal conditions of the mind and body by modifying properties of the blood - brain barrier and cephalic blood flow ” pct patent application pct / il03 / 00338 to shalev , filed apr . 25 , 2003 , entitled , “ methods and apparatus for modifying properties of the bbb and cerebral circulation by using the neuroexcitatory and / or neuroinhibitory effects of odorants on nerves in the head ,” and u . s . patent application ser . no . 10 / 512 , 780 , filed oct . 25 , 2004 in the national stage thereof , which published as us patent application 2005 / 0266099 u . s . provisional patent application 60 / 506 , 165 , filed sep . 26 , 2003 , entitled , “ diagnostic applications of stimulation ” u . s . patent application ser . no . 10 / 678 , 730 , filed oct . 2 , 2003 , entitled , “ targeted release of nitric oxide in the brain circulation for opening the bbb ,” which published as us patent application 2005 / 0074506 , and pct patent application pct / il04 / 000911 , filed oct . 3 , 2004 , claiming priority therefrom pct patent application pct / il04 / 000897 , filed sep . 26 , 2004 , entitled , “ stimulation for treating and diagnosing conditions ,” which published as pct publication wo 05 / 030025 u . s . provisional patent application 60 / 604 , 037 , filed aug . 23 , 2004 , entitled , “ concurrent bilateral spg modulation ” pct patent application pct / il05 / 000912 , filed aug . 23 , 2005 , entitled , “ concurrent bilateral spg modulation ,” which published as pct publication wo 06 / 021957 u . s . patent application ser . no . 10 / 952 , 536 , filed sep . 27 , 2004 , entitled , “ stimulation for treating and diagnosing conditions ,” which published as us patent application publication 2005 / 0159790 u . s . patent application ser . no . 11 / 349 , 020 , filed feb . 7 , 2006 , entitled , “ spg stimulation via the greater palatine canal ” in an embodiment of the present invention , electrical stimulation system 10 comprises circuitry described in one or more of the above - mentioned applications . in an embodiment of the present invention , an mts is stimulated using the magnetic stimulation apparatus and methods described in the above - mentioned u . s . patent application ser . no . 10 / 783 , 113 . as used in the present application and in the claims , the bbb comprises the tight junctions opposing the passage of most ions and large molecular weight compounds between the blood and brain tissue . as used in the present application and in the claims , the btb comprises a barrier opposing the passage of many ions and large molecular weight compounds between the blood and tissue of a brain tumor . it will be appreciated by persons skilled in the art 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 that are not in the prior art , which would occur to persons skilled in the art upon reading the foregoing description . for example , elements which are shown in a figure to be housed within one integral unit may , for some applications , be disposed in a plurality of distinct units . similarly , apparatus for communication and power transmission which are shown to be coupled in a wireless fashion may , alternatively , be coupled in a wired fashion , and apparatus for communication and power transmission which are shown to be coupled in a wired fashion may , alternatively , be coupled in a wireless fashion .

a method for treatment is provided , including identifying that a subject has suffered from an adverse cerebrovascular event , excluding alzheimer &# 39 ; s disease and parkinson &# 39 ; s disease . responsively to the identifying , beginning at least nine hours after the event , electrical stimulation is applied to a site of the subject selected from the group consisting of : a sphenopalatine ganglion , a greater palatine nerve , a lesser palatine nerve , a sphenopalatine nerve , a communicating branch between a maxillary nerve and an spg , an otic ganglion , an afferent fiber going into the otic ganglion , an efferent fiber going out of the otic ganglion , an infraorbital nerve , a vidian nerve , a greater superficial petrosal nerve , and a lesser deep petrosal nerve . the stimulation is configured to excite nervous tissue of the site at a strength sufficient to induce at least one neuroprotective occurrence selected from the group consisting of : an increase in cerebral blood flow of the subject , and a release of one or more neuroprotective substances .

unless otherwise indicated , all ingredient concentrations are listed as percent ( w / w ). according to the present invention , ophthalmic implants are coated with a composition comprising r is c 6 - c 18 alkyl having at least ⅓ of the carbons substituted with fluorine , provided that the fluorinated carbons are consecutive carbons ; and r is c8 - c 16 wherein at least ½ of the carbons are substituted with fluorine , provided that the fluorinated carbons are consecutive carbons ; and the use of a combination of acrylate and methacrylate monomers is desirable for manipulating the coating t g , however the use of both is not necessary . the thermodynamic stability of the liquid crystalline (“ lc ”) phase and its position relative to the coating copolymer &# 39 ; s t g is important . the copolymer &# 39 ; s t g should be such that it does not override or freeze the lc phase ; the copolymer &# 39 ; s t g should be below the temperature that the copolymer converts from a lc phase to an isotropic phase . the identity of the monomers ( i ) and ( ii ) and their relative amounts are chosen so as to provide a lc phase transition temperature ( from lc phase to an isotropic phase ) at a temperature above room temperature ( generally 18 - 25 c ) and below the temperature of the eye ( generally 34 - 37 c ). the amount of monomer ( i ) relative to monomer ( ii ) should be about 1 : 3 - 3 : 1 . preferably , the coating consists essentially of the two monomers described above . generally , the coating composition will contain about 33 - 66 % of monomer ( i ) and about 33 - 66 % of monomer ( ii ). most preferred are coatings containing the two monomers in approximately a 1 : 1 ratio . the coating compositions optionally include one or more ingredients selected from the group consisting of uv absorbers and blue - light blocking colorants , provided that they do not interfere with the ability of the coating to form a lc phase . the uv absorber and / or blue - light blocking colorant may be added either prior to polymerization or at the time the copolymer is dissolved to form a coating solution . if added prior to polymerization , the polymerization initiator should be chosen so that the uv absorber and / or blue - light blocking colorant do not significantly interfere with the polymerization . ultraviolet absorbing chromophores can be any compound which absorbs light having a wavelength shorter than about 400 nm , but does not absorb any substantial amount of visible light . it is preferred to use an ultraviolet absorbing compound that is copolymerizable with the monomers ( i ) and ( ii ) or the can be covalently bound to the coating / iol substrate during the application of the coating to the substrate . suitable copolymerizable ultraviolet absorbing compounds are the substituted 2hydroxybenzophenones disclosed in u . s . pat . no . 4 , 304 , 895 and the 2 - hydroxy - 5 - acryloxyphenyl - 2h - benzotriazoles disclosed in u . s . pat . no . 4 , 528 , 311 . the most preferred ultraviolet absorbing compound is 2 -( 3 ′- methallyl - 2 ′- hydroxy - 5 ′- methyl phenyl ) benzotriazole . if a uv - absorber is added prior to polymerization , it is unlikely that a uv polymerization initiator may be used . in such cases , the polymerization initiator will likely have to be either a thermal initiator or a blue - light initiator in order to avoid interference with the uv - absorber . if a blue - light absorbing compound , e . g . a yellow dye , is included in the coating compositions of the present invention prior to polymerization , then the polymerization initiator will likely not be a blue - light photoinitiator . in the event the coating composition contains both a uv - absorber and a blue - light absorbing compound prior to polymerization , the polymerization initiator will likely be a thermal initiator . preferably , the blue - light absorber is copolymerizable with the monomers ( i ) and ( ii ) or can be covalently bound to the coating / iol substrate during the application of the coating . suitable polymerizable blue - light blocking chromophores include those disclosed in u . s . pat . no . 5 , 470 , 932 . the coatings of the present invention may be applied to any ophthalmically acceptable implant material . suitable materials include silicones and hydrogels . preferably , the substrate material is a hydrophobic acrylic material . as used herein , “ hydrophobic acrylic material ” means a ( meth ) acrylic material having an equilibrium water content of not more than about 5 % by weight as determined gravimetrically in deionized water at ambient conditions . examples of such ( meth ) acrylic materials are disclosed in the following u . s . pat . nos . : 5 , 290 , 892 ; 5 , 693 , 095 ; and 5 , 331 , 073 , the entire contents of which are hereby incorporated by reference the coatings of the present invention may be applied to any ophthalmic implant including , but not limited to , iols designed for anterior or posterior chamber implantation ; intracorneal lenses ; keratoprostheses ; and corneal inlays or rings . in the case where the ophthalmic implant is an iol , the coatings of the present invention may be used in conjunction with substrate materials that are “ hard ” ( that is , materials that are inserted in an unfolded state ) or “ foldable ” or “ soft ” ( that is , materials that are capable of being inserted in a folded or compressed state ). the coating may be applied to the portion of the iol material constituting the optic &# 39 ; s entire posterior surface or to only a peripheral band of the posterior surface . additionally , the optic &# 39 ; s anterior surface or a peripheral band of the anterior surface may be coated . in order to prepare the ophthalmic implant to be coated so that it is capable of receiving the coating , it may be necessary or desirable to expose the surface to be coated to a reactive plasma gas prior to applying the coating composition of the present invention . suitable reactive plasma gases include oxidizing gases , such as oxygen gas . a suitable plasma chamber is the p 2 cim b - series plasma chamber made by advanced plasma systems , inc . the coating composition of this invention is applied using known coating techniques . for example , the coatings can be applied by first polymerizing a mixture of monomers ( i ) and ( ii ) using a thermal initiator , such as benzoyl peroxide or photoinitiator . after polymerization , the coating material is dissolved in an organic solvent , such as butyl acetate , to form a coating solution . the coating solution is then applied to the ophthalmic implant using conventional dip - or spin - coating techniques . alternatively , the monomers ( i ) and ( ii ) can be loaded into a plasma chamber and deposited onto the surface of an ophthalmic implant using conventional plasma deposition techniques . regardless of the method of applying the coating to the ophthalmic article , the thickness of the coating should be at least about 0 . 3 μm , preferably at least about 1 - 2 μm , but may be thicker provided that the coating remains transparent . a reaction flask containing a magnetic stir bar was charged with 1 . 508 g heptadecylfluorodecyl acrylate , 0 . 967 g octadecyl methacrylate and 2 . 547 g butyl acetate . nitrogen was bubbled through the mixture with stirring for 15 min , then 0 . 023 g of benzoyl peroxide was added with continued nitrogen bubbling . the flask was closed with a glass stopper and immersed in a 70 ° c . oil bath for 6 . 5 hr . the reaction product was precipitated directly in 300 ml of methanol , filtered , rinsed with methanol and dried for 24 hrs under vacuum . yield : 1 . 524 g ( 62 %) of a white solid . the solid became fluid just about body temperature as a small piece would become tacky on warming slightly . the cooled material was non - tacky . examination between cross polarizers on the microscope revealed a lc texture on shearing . the resulting polymer was soluble in butyl acetate . differential scanning calorimetry revealed a phase transition at 31 ° c . on cooling , 39 ° c . on heating . the invention has been described by reference to certain preferred embodiments ; however , it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics . the embodiments described above are therefore considered to be illustrative in all respects and not restrictive , the scope of the invention being indicated by the appended claims rather than by the foregoing description .

the application of switchable tackiness coating compositions to ophthalmic implants provides the benefits of body temperature tackiness without the disadvantages of room temperature tackiness .

it has now been found that bioconjugates comprising hematoporphyrin ( hp ) and carrier protein transferrin ( tf ) significantly improve the specificity and efficiency of pdt for erythroleukemic cells , when applied with luminol . the observed synergistic toxic effect does not depend on the order in which the cells are contacted with a chemiluminescent agent and with a ligand - photosensitizer conjugate . it is known that chemiluminescent agents ( cl ), such as luminol or isoluminol or lucigenin , emit light when being oxidized . without wishing to be bound by theory , luminol appears , in a method according to the invention , to be induced to emit light after activation by in situ existing oxidizing factors which include molecular oxygen , or chemical groups and molecules capable of providing oxygen atoms or peroxides or other reactive oxygen species ( ros ). said oxidizing factors , such as oxygen or ros , will induce the light emission , setting in motion a cascade of events including the formation of further ros , activating the ps component of the ligand - toxin conjugate , and ending with the cell destruction . this ros and oxygen source , whether metabolically produced or provided by outside oxygen supply , prolongs the pdt cycle . a surprisingly low concentration of cl agent , not expected to be toxic by itself , is sufficient to kill the target cells . furthermore , since the pdt components of the invention need not be present simultaneously , another problem of the prior art pdt is obviated , i . e ., the requirement of the coordinated presence of several factors in the cell . the preferred conjugate of the invention , tf - hp conjugate , was separated from tf and hp by hplc and characterized by uv - vis spectrophotometry ( fig1 ). the tf spectrum reveals a typical maximum at λ = 280 nm , whereas hp absorption maximum is at λ = 375 nm . the hp - tf conjugate has two absorption peaks at λ = 280 nm and 412 nm and the spectrum is characterized by a red shift of the maximum and is not a simple superposition of the spectra of its components . fig2 depicts the dose - response effect of hp or tf - hp ltc treatment on the viability of fl , k562 and u - 76 cells . incubating the cells with various concentrations of hp or tf - hp in the dark followed by overnight exposure to ambient fluorescent light showed that for all cell types , tf - hp was much more cytotoxic than hp alone . fig3 ( table 1 ) shows that the concentration of tf - hp required to achieve ld 50 was more than 6 - fold lower than for hp . furthermore ld 100 values were only obtained with the tf - hp . u - 76 hybridoma cells were relatively insensitive to pdt . the concentration of tf - hp required to reach ld 90 in these cells was & gt ; 19 . 4 fold higher than for fl cells and & gt ; 3 . 5 fold higher than for k - 562 cells . this order of sensitivity was retained at the concentrations required for ld max ( 3 . 37 for fl and 0 . 8 for k562 ). furthermore , 100 % cytotoxicity was only obtained when the conjugate was used against the erythroleukemic cell lines . a similar pattern of sensitivity was also seen with free hp treatment . while a similar ( 90 %) ld max was reached for both erythroleukemic lines , fl cells were 16 . 6 more sensitive than k - 562 . further evidence for the increased cytotoxicity of tf - hp over free hp was obtained from fluorescence microscopy , which illustrated the presence and location of the ps in fl cells after 45 and 60 minutes incubation with either hp or tf - hp . at both time points , relatively faint ( as no anti bleaching solution was used ) hp fluorescence was observed mainly constrained to the plasma membrane region . significantly greater fluorescence was apparent in cells treated with tf - hp . after 45 minutes the conjugate localized in membrane patches ( possibly demarcating endolysosomal compartments ) and had infiltrated much of the cytoplasm by 60 minutes further , the ability of an intracellular chemiluminescent light signal to induce pdt was tested . fig4 illustrates the cytotoxicity induced in fl cells cultured in the dark with hp or tf - hp either alone or together with 10 μm luminol . the cells were not exposed to ambient fluorescent light at any stage of the procedure . it was found that i ) luminol alone induced about 15 % cytotoxicity , ( ii ) hp alone had little effect on cell viability , ( iii ) cytotoxicity reached a maximum of 30 % in the presence of hp and luminol and iv ) luminol induced a significant ( 95 %) pdt effect upon addition of tf - hp . fig5 further demonstrates that the cytotoxic luminol - induced pdt effect is dependent on the concentration of both tf - hp and luminol with a combination of 10 μm luminol and 3 μm of conjugate producing maximum cytotoxicity . a reduction in tf - hp concentration had less effect on cytotoxicity than did lowering the level of luminol . it was checked whether the synchrony in exposure to luminol and tf - hp is a requirement for this cytotoxicity by incubating cells first with tf - hp , washing and then exposing them to luminol following various delay times . the time taken to wash the cells and return them to culture was approximately 15 minutes . while delaying the exposure to luminol by 30 minutes had no effect on the cytotoxicity ( fig6 a ), after 60 minutes of delay , the pdt effect was reduced by 50 %. however by reversing the protocol , ( fig6 b ) it was found that pre - incubation with luminol for 24 hrs sensitized the cells to the delayed exposure to tf - hp and the pdt effect was dose dependent . this invention addresses two problems of pdt technology . the first problem concerns the development of pdt systems to enhance the efficiency of ps delivery to target cells . most targeted pdt studies have used monoclonal antibodies as the address moiety . as the use of antibodies poses several practical limitations , an alternate approach may target a tf - ps conjugate to tf receptors . the therapeutic potential of tf - protein [ weaver m . et al . : j neurooncol . 65 ( 2003 ) 3 - 13 ], and tf - chemical [ singh m . et al . : anticancer res . 18 ( 1998 ) 1423 - 7 ] toxin conjugates have already been examined , but less is known about tf - ps conjugates particularly with regard to hp which , although having been used successfully in free form in the clinic for over a decade [ dolmans d . e . et al . : nature reviews cancer 3 ( 2003 ) 380 - 7 ], it has been little tested in targeted pdt [ hamblin m . r . et al . : j . photochem . photobiol . 26 ( 1994 ) 45 - 56 ]. the instant invention provides tf - hp conjugates that are at least 6 - fold more effective in inducing cell death even at the ld 50 level ( fig2 and table 1 ). aside from increasing target specificity and efficiency , pdt induced cell death is faster when tf - hp is used . for example during optimization of the ltc cytotoxicity assay , it was found by us that while almost 100 % cytotoxicity was achieved after only 30 minutes exposure to tf - hp , about 2 hr were required for maximum activity ( 24 %) of free hp . moreover , fluorescence microscopy of hp and tf - hp - treated fl cells demonstrated that tf - hp is taken up more rapidly and that it reaches intracellular organelles , and this would provide for more effective disruption of intracellular membranes . the second problem of pdt technology is addressed by the invention , concerning the source of the luminescent activating signal delivered to the ps . an external radiation provides homogeneous excitation of ps in the tissue culture or during subcutaneous injection , however the penetration of visible light into internal tissue is limited to a few millimeters , precluding the use of pdt for deeper tissue targets . efforts to overcome this limitation have concentrated on new external light devices or improved catheters . the aim of the invention was to provide a molecular light - emitting mechanism within the ps - loaded target cell . this strategy is non - invasive , does not expose normal tissue to irradiation and a molecular illuminator can be transported to target cells in vivo . we use the term intracellular activation of pdt ( iap ) to describe such molecular systems . luminol is a chemiluminescent activator that undergoes a light emitting process catalyzed by metal ions and hydrogen peroxide . this process is employed in chemiluminescent detection techniques and in cell physiology studies , but the invention takes advantage of luminol as an energy source in the field of pdt of cancer cells . the emission spectrum of luminol comprises two major peaks , at 424 and 485 nm . it was observed by us that the first peak corresponded to a crest in the absorption spectrum of tf - hp ( 412 nm , fig1 ), suggesting , together with the enhanced intracellular uptake of the tf - hp relative to hp , that an iap involving luminol is effective . initially hp or tf - hp was mixed with luminol and added to fl cell culture in the dark ( fig4 ). high concentrations of tf - hp alone induced low - level cytotoxicity in accordance with previous reports [ supino r . et al . : chem . biol . interact . 57 ( 1986 ) 258 - 94 ; luksiene z . et al . : medicina 39 ( 2003 ) 677 - 82 ], an effect that may be related to the ability of hp to inhibit the activity of protein kinase c . not only was there a significant pdt effect when both tf - hp and luminol were added to the cells , but the cytotoxic efficiency of tf - hp over hp was even more enhanced than that seen with the external light source ( fig2 ). however the concentration of tf - hp required to reach ld max in the iap system was 6 . 7 times higher than with external radiation ( fig4 and table 1 ). in a previous study , carpenter [ carpenter s . et al . : proc . natl . acad . sci . usa 91 ( 1994 ) 12273 - 7 ] described a bioluminescent iap system for pdt that induced killing of virus - infected cells , involving the activation of hypericin following oxidation of luciferin by luciferase . additional experiments assessed whether or not the ps and iap systems need to be applied simultaneously in order to produce an effective pdt response ( fig6 ). delaying addition of luminol to tf - hp - loaded cells by 45 minutes did not reduce cytotoxicity and as the cells were thoroughly washed before exposure to luminol these results reflect activation of intracellular tf - hp rather than material loosely bound to the membrane . delaying exposure to luminol by a further 30 minutes decreased the pdt effect by half suggesting that the tf - hp residence time is a limiting factor in this system . when the components were added in the reverse order luminol - loaded cells remained very sensitive to pdt even when addition of tf - hp was delayed for 24 hrs . as mentioned , photodynamic therapy ( pdt ) involves a two - stage process . in the first step , a light - absorbing photosensitizer ( ps ) ( for instance hematoporphyrin , hp ), is endocytosed . in the second step , the ps is activated by light , transferring energy to a cytoplasmic acceptor molecule that activates molecular oxygen , yielding reactive oxygen species ( ros ) that damage the cellular components , particularly membrane phospholipids . the outcome of this process leads to cytolysis . efforts to expand the use of pdt in the clinic have been hindered by the lack of ps target cell specificity and lack of tissue penetration of external light radiation . the invention provides bioconjugates comprising the carrier protein transferrin and hp ( tf - hp ) that significantly improve the specificity and efficiency of pdt for erythroleukemic cells by a factor of almost 20 - fold at the ld 50 level . fluorescence microscopy showed that the conjugates are endocytosed and accumulate in intracellular vesicles whereas free hp was mostly membrane bound . in addition , it was shown by the inventors that the use of external radiation for ps activation can be bypassed by incubating the cells with luminol either prior to or together with tf - hp . luminol is activated intracellularly to yield chemiluminescent radiation that stimulated pdt - induced cytotoxicity in 95 % of cells . these strategies provide safer and more effective applications of pdt . the present invention provides a new approach to overcome the limitations of pdt applications . the efficacy of the targeted ltc strategy using the tf - hp system is first established , and then in vitro applicability of luminol is demonstrated , wherein luminol can be used as a powerful molecular inducer of intracellular cl for the destruction of leukemic cells , obviating the use of external light sources in pdt . in conclusion , the invention provides tf - hp conjugates as a viable vehicle for pdt induced cytotoxicity . enhanced targeting of the ps with carrier proteins that are efficiently endocytosed increase therapeutic efficacy of pdt by reducing dosage and overcoming toxicity to normal tissue inevitably produced with free ps . the invention thus provides means for destroying cells associated with proliferative diseases , for example cancer . the invention will be further described and illustrated in the following examples . hp , rabbit anti - human transferrin , goat anti - bovine serum albumin , transferrin , n - hydroxysuccinimide ( nhs ) and luminol were purchased from sigma - aldrich chemical co . n , n - dicyclohexyl carbodiimide ( dcc ) and tetrahydrofuran ( thf ) were from carlo erba . horse serum ( hs ), fetal calf serum ( fcs ), l - glutamine and combined antibiotics were purchased from biological industries ltd . ( bet haemek , israel ). hplc solvents were from merck . u - 76 is a murine hybridoma that secretes igg1 antibody against dinitrophenol ( dnp ) and was a kind gift of prof . eshhar ( weizmann institute of science , rehovot , israel ). these cells as well as friend &# 39 ; s leukemia ( fl ) cells were grown in dmem containing 15 % hs , 2 mm l - glutamine and combined antibiotics . human k - 562 cells were grown in rpmi / 15 % hs / glutamine / antibiotics . all cells were maintained at 37 ° c . in a humidified incubator containing 6 % co 2 . 0 . 11 mmole hematoporphyrin hydrochloride was dissolved in 10 ml chloroform and activated by addition of 0 . 173 mmole of nhs and 0 . 11 mmole dcc . the mixture was stirred at room temperature for 2 . 5 hrs . following evaporation with a stream of air , the residue was dissolved in 2 ml of thf and the activated hp was slowly added to a solution of 15 mg transferrin dissolved in 10 ml of 0 . 1m nahco 3 cooled on ice . the solution was allowed to warm to room temperature , adjusted to ph 7 . 5 and stirred vigorously overnight . tubes containing hp were protected from light exposure . the conjugate solution was centrifuged ( 7200 × g , 30 mins , 4 ° c .) and the supernatant was analyzed spectroscopically for the content of protein ( λ = 280 nm ) and hp ( λ = 400 nm ). after dialysis , a small portion of the crude reaction product was chromatographed over sephadex g - 50 equilibrated with 5 mm nahco 3 ( ph 8 . 0 ) or 10 mm pbs ( ph 7 . 2 ). fractions containing materials with absorption peaks at 280 and 400 nm were collected and stored at 4 ° c . hplc : tf , hp and tf - hp were chromatographed over a c - 18 column ( 3 . 9 mm × 300 mm bondclone , particle diameter 10 μm , phenomenex ) using a hplc jasco - 1580 with a jasco 1575 uv / vis detector . the solvent system was composed of acetonitrile - water with 1 % trifluoroacetic acid and compounds were eluted with a linear gradient ( 20 - 100 % acetonitrile ). absorbance spectrum : the absorbance spectra of pbs solutions of hp ( 0 . 02 mg / ml ), tf ( 1 . 4 mg / ml ) and hp - tf ( 1 . 4 mg / ml ) were recorded with a chemusb2 - uv - vis spectrophotometer having optical resolution of 1 nm , grating of 600 lines per mm equipped with ccd array detector . the samples were scanned in the absorbance region of 250 - 500 nm . biological activity : this was assessed by the ability of anti - transferrin or anti - bsa antibodies to inhibit pdt - induced cytotoxicity and was tested using fl cells exposed to tf - hp either alone or together with varying concentrations of each antibody . late log - phase cells were washed with dmem pre - warmed to 37 ° c . and cultured at 0 . 5 - 1 × 10 5 cells / ml either alone or with increasing concentrations of tf - hp ltc for 2 hrs at 37 ° c . in 6 % co 2 . cells were then washed with dmem , exposed to ambient fluorescent light ( fluence rate = 0 . 5 mw / cm 2 ) for 12 - 16 hours and then re - cultured in full medium for 24 hrs . cell viability was determined by trypan blue exclusion . experiments were repeated at least three times . the optimal exposure times of cells to the ps and fluorescent radiation were determined in preliminary time - course experiments . fl cells were grown on glass slides in tissue culture dishes together with hp or tf - hp and the incorporated fluorescence was followed at various time intervals with an ax70 olympus microscope equipped with a high - pressure mercury lamp for excitation and a set of filters for blue violet excitation ( band path 420 - 480 nm ), dichroic mirror ( 455 nm ) and a cut - on red emission barrier filter ( 580 nm ). fluorescence was analyzed with an x60 objective , without addition of any anti bleaching solution , and recorded by a ccd camera . fl cells were washed and cultured for 20 hrs with different concentrations of hp or tf - hp ( 0 . 07 , 0 . 15 or 0 . 3 μm ) together with luminol ( 0 - 10 μm ). manipulations of cells and components were performed with the room lights switched off . culture plates were wrapped in aluminum foil during the culture period . subsequently , experiments aimed to test whether a pdt effect could be obtained by staggering the exposure of the cells to either luminol or tf - hp conjugate . fl cells were cultured for 2 hrs in the dark at 37 ° c . with tf - hp ( 3 μm ), washed and re - suspended in medium at the standard culture concentration . this procedure took approximately 15 minutes . then , the cells were kept at 37 ° c . for an additional 0 , 30 , 60 or 90 minutes , luminol ( 10 μm ) was added and the cultures incubated in the dark for a further 16 hrs . alternatively , cells were first cultured for 24 hrs in the dark in the presence of 10 μm luminol , washed or not - washed and then cultured further for 24 hrs in the presence of tf - hp ( 0 - 3 μm ) at 37 ° c . during washing procedures and cell handling , special care was taken to maintain the cells in a dark environment . while this invention has been described in terms of some specific examples , many modifications and variations are possible . it is therefore understood that within the scope of the appended claims , the invention may be realized otherwise than as specifically described .

a method for destroying harmful cells is provided , applicable in treating proliferative diseases . the cells are destroyed by a combined treatment with a chemiluminescent agent and with a ligand - photosensitizer conjugate . the chemiluminescent agent emits light on reacting with oxygen species present in situ , the conjugate binds to the cell through its ligand and is activated by the emitted light , thereby destroying the cell . the method is demonstrated on a conjugate of transferrin - hematoporphyrin , which destroys cancerous cells in the presence of luminol .

in order to treat human skin for the purpose of effecting a decrease in the transepidermal water loss , there is applied to the surface of the skin a film forming conditioning formulation which can be anhydrous . the alkylmethyl cyclic polysiloxanes are compounds having the formula ## str4 ## in the formula x and y are integers the sum of which is four , five , or six provided that x cannot be zero , and z is an integer which has a value of eleven to about twenty - nine . r is an alkyl group having one to six carbon atoms . typically the r group is methyl although other alkyl radicals may be employed . thus the most preferred compounds have the formula ## str5 ## in which x , y and z are as defined above . thus where x is one y is three , four , or five ; where x is two y is two , three , or four ; where x is three y is one , two or three ; where x is four y is zero , one , or two ; and where x is five y is zero or one . the cyclic alkylmethylpolysiloxanes can be delivered to the skin as an anhydrous formulation which is applied to the skin in the form of a solution of the cyclic alkylmethyl polysiloxane dissolved in a volatile solvent such as an aliphatic hydrocarbon , aliphatic alcohol , aliphatic ester , or a low viscosity cyclic silicone fluid . such volatile solvents are described below . the cyclic alkylmethylsiloxanes of the present invention can be delivered to the skin as a hydrous or as an anhydrous formulation . the cyclic alkylmethyl polysiloxanes of this invention can be produced by the reaction of a linear siloxane having si -- h functionality in the chain such as ( me 3 sio 1 / 2 ) 2 ( osimeh ) x in which me is methyl and x is forty to about one hundred , and a cyclic siloxane having ( me 2 sio ) units of the formula ( me 2 sio ) x in which me is methyl and x is an integer of about three to six preferably four or five . the reaction product is about ninety percent by weight of a linear polymer and ten percent by weight of a cyclic polymer . the reaction product is then contacted with a slight stoichiometric excess of an alkene ch 2 ═ chr in the presence of a platinum on carbon catalyst and a cyclic alkylmethylsiloxane having the structure of formula ( ii ) shown above is produced . the cyclic alkylmethyl polysiloxanes of this invention can also be produced by the direct hydrolysis of methylhydrogen dichlorosilane to form cyclomethylhydrogen polysiloxanes , or by the direct cohydrolysis of methylhydrogen dichlorosilane and dimethyl dichlorosilane to form cyclomethylhydrogensiloxy dimethylsiloxy copolymers . the reaction product is then contacted with a slight stoichiometric excess of an alkene ch 2 ═ chr in the presence of a platinum on carbon catalyst and a cyclic alkylmethylsiloxane having the structure of formula ( ii ) shown above is produced . batch production of the alkylmethyl polysiloxanes is conducted by adding the reaction product to a non - agitated suspension of the catalyst in the alkene at about sixty degrees centigrade . continuous production of the alkylmethyl polysiloxanes is conducted by pumping a preheated solution of a five percent stoichiometric excess of an alkene ch 2 ═ chr and the reaction product through a packed column containing platinum on carbon catalyst chips . the column will require provision for the removal of heat because of the exothermic nature of the reaction . the materials are further processed in accordance with the present invention in order to provide a more cosmetically acceptable product by removing from the product any remaining cyclic siloxane and any residual methylhydrogendimethylsiloxane cocyclics present as ( mehsio )( me 2 sio ) 3 . the alkylmethyl polysiloxanes produced in accordance with the present invention have been found to contain at most about 0 . 5 percent residual alkene and about 99 . 5 percent alkylmethyl polysiloxane product . no measurable residual amount of platinum has been detected . the products are otherwise colorless , odorless , non - volatile , clear and stable materials . the products are particularly adapted to skin care in that the materials have been found to form films on the skin which possess a very low water vapor permeability enabling the materials to form a barrier on the skin which will reduce moisture loss from the stratum corneum . the alkylmethyl polysiloxanes find utility in skin creams and lotions including facial products such as cleaners and moisturizers , hand creams , baby creams and sun care creams and lotions . the water content of the outer layers of the stratum corneum of human skin is a controlling factor in the appearance of dry skin symptoms . when the stratum corneum contains an adequate amount of water within the range of ten to twenty percent the skin remains flexible . however when the water content falls below ten percent the stratum corneum often becomes brittle and rough and can exhibit scaling and cracking . the stratum corneum receives its water from the deep layers of the epidermis by diffusion , from ambient air , or when it is brought into direct contact with water . the diffusion process is controlled by the water content of the skin as well as the concentration gradient . in a very dry environment the water loss from the external skin layers can be significant and often exceeds the rate of replacement by diffusion . an occlusive barrier placed onto the surface of the skin acts to retard the water loss to the environment and allows the skin surface to rehydrate by the diffusion process . due to the effectiveness and safety of the alkylmethyl polysiloxanes they serve as useful skin conditioners , occlusive moisturizers and contribute to dry skin prevention by protection and moisture retention as well as dry skin repair by emolliency , lubricity and moisture restoration . the cyclic alkylmethylsiloxanes of the present invention are provided in an amount sufficient to provide the desired properties ( e . g . occlusivity , substantivity , etc .) to the skin . the total amount of cyclic alkylmethylsiloxane in any formulation will vary depending on the additional components present . generally , the amount of cyclic alkylmethylsiloxane present will comprise between about 1 and about 90 weight percent of the final formulation . volatile solvents which may be employed to deliver the alkylmethyl polysiloxane to the skin include aliphatic hydrocarbons among which are isoparaffins such as a c10 - 11 isoparrafin ( sold by exxon as isopar g ); aliphatic alcohols such as isopropyl alcohol and ethyl alcohol ; aliphatic esters such as isopropyl myristate and ethyl acetate ; and volatile siloxanes . the solvent can also be a linear or cyclic polysiloxane . the solvent must be compatible with and capable of dissolving , dispersing , or suspending the alkylmethyl polysiloxane and any optional component which may be present . volatile siloxanes which may be employed as solvents include the volatile low viscosity cyclic silicone fluids and linear silicones . representative of these materials are polydimethylcyclosiloxane and hexamethyldisiloxane . such fluids have viscosities of 0 . 65 to 5 . 0 centistokes measured at twenty - five degrees centigrade . non - volatile solvents can also be employed in the present invention . non - volatile oils commonly utilized in cosmetic applications are suitable for use as solvents in the present invention . the volatile cyclic silicones conform to the formula ( r 2 sio ) x in which r is an alkyl radical having from one to three carbon atoms or a phenyl group . typically the cyclic siloxanes have the formula ( ch 3 ) 2 sio ! x in which x is an integer from three to ten . volatile cyclic siloxane compounds found to be especially useful in accordance with the present invention are the tetramer compound octamethylcyclotetrasiloxane and the pentamer compound decamethylcyclopentasiloxane . mixtures of the tetramer and pentamer may also be employed . such cyclic siloxanes have viscosities ranging from about 2 . 5 centistokes to about five centistokes . these materials are also known under the cosmetics , toiletries and fragrance association designation as cyclomethicone . volatile low viscosity linear silicone fluids which may be employed as solvents have the formula r 3 sio ( r 2 sio ) n sir 3 in which r is an alkyl radical having one to six carbon atoms and n is an integer of from two to nine . representative of the linear siloxane is hexamethyldisiloxane of the formula ## str6 ## which has a viscosity of 0 . 65 centistokes measured at twenty - five degrees centigrade . the cyclic low viscosity volatile silicones are clear fluids and are essentially odorless , nontoxic , nongreasy and nonstinging . cosmetically they are nonirritating to the skin and possess the properties of good spreadability and ease of rub - out . the materials evaporate leaving behind no residue . in addition to the volatile solvent and the cyclic alkylmethyl polysiloxane , skin care formulations in accordance with this invention may optionally contain other emollients , sunscreens , and adjuvants such as perfumes , fragrances and preservatives . examples of other emollients and moisturizers which may be included in compositions of this invention include straight , branched or cyclic hydroxy compounds such as alcohols containing 1 to 30 carbon atoms ; straight , branched or cyclic carboxylic acids containing 1 to 31 carbon atoms ; acid esters containing c 1 to c 30 carboxylic acids esterfied with c 1 to c 30 alcohols ; alcohol ethers containing 1 to 30 carbon atoms ; and alkanes of the formula h -( ch 2 ) n - h wherein n is 5 to 30 . examples of such materials include 2 - ethylhexyl oxystearate ; arachidyl propionate ; 2 - ethylhexyl adipate ; isopropyl myristate ; stearyl alcohol ; propylene glycol ; propionic acid ; stearic acid ; polyoxypropylene cetyl alcohol ; polyoxypropylene lanolin alcohol ; carbowax &# 34 ; 300 ; petroleum jelly ; mineral oil ; aliphatic hydrocarbons such as mineral spirits ; lanolin and lanolin derivatives such as acetylated lanolin and isopropyl lanolate . sunscreens are evaluated according to their ability to slow the erythema or sunburn resulting from the exposure of skin to ultraviolet light between about 290 - 320 nanometers ( the uv - b region ). this is accomplished by absorbing damaging radiation before the radiation contacts the skin surface . para - aminobenzoic acid derivatives and cinnamates such as octyl methoxycinnamate are examples of preferable and commercially employed categories of sunscreen active compounds . uv - a region agents capable of absorbing ultraviolet light in the range of 320 - 400 nanometers are also useful in accordance with the present invention including benzophenones and materials such butyl methoxy dibenzoylmethane . some additional examples of sunscreen chemicals which may be employed in accordance with the present invention are 2 - ethoxyethyl p - methoxycinnamate ; menthyl anthranilate ; homomenthyl salicylate ; glyceryl p - aminobenzoate ; isobutyl p - aminobenzoate ; isoamyl p - dimethylaminobenzoate ; one compound in accordance with formula ( ii ) is the tetradecylfunctional cyclic alkylmethylpolysiloxane of the formula ( c 14 h 29 omesi ) 4 in which x is four , y is zero and z is thirteen . the durability and substantivity of this material is shown below . in order to illustrate the durability of the cyclic alkylmethyl polysiloxanes of the present invention in comparison to other materials described in the art , data was collected by employing a soap washing procedure that involved the measurement of substantivity on human skin . materials that were tested included ( a ) mink oil , ( b ) a linear alkylmethyl polysiloxane having the formula ## str7 ## where the sum of integers x and y was six and the value of z was seventeen , and ( c ) a cyclic alkylmethylpolysiloxane ( c 14 h 29 omesi ) 4 . sample ( c ) was a material in accordance with the present invention while samples ( a ) and ( b ) were provided for comparative purposes . sample ( b ) was the goldschmidt abil silicone material mentioned in the &# 34 ; background &# 34 ; section . abil silicone is described by the manufacturer as polysiloxane polyalkylene copolymer and the cosmetics , fragrance & amp ; toiletries association adopted name of the material is stearyl dimethicone . abil is a trademark of tho goldschmidt ag chemische fabriken , goldschmidtstrasse 100 , d - 4300 essen 1 . these materials are identified in the table below as samples ( a ), ( b ) and ( c ) respectively . specifically the method was based on attenuated total reflectance / fourier transform infrared spectrophotometric ( atr / ftir ) analysis in which skin studies were conducted and analyzed based on the reflection of energy at the prism / skin interface . instrumentation included a nicolet model 20dx ftir system and a harrick scientific skin analyzer . the atr studies involved contact of the skin sample and prism . a hydration procedure was employed in order to increase the softness and flexibility of the skin surface which resulted in a less variable contact between the skin and prism . this hydration procedure included placing a water soaked towel against the skin test site for one minute prior to actual spectra collection . a skin test site selected was an area of about eighty square centimeters and about eight to ten milligrams of each solution tested was applied to the skin test site area in the form of a thin film using a small paint brush . from the data collected it was possible to calculate percentages of ingredients remaining on the skin following various soap wash sequences . the soap employed was a 0 . 5 weight percent solution of &# 34 ; ivory &# 34 ; bar soap and a soap rub is defined as two passes over the test area with the soap solution cupped in the palm of the hand . one soap wash procedure included fifteen soap rubs and ten rinse rubs under cool running tap water . the test site was the volar forearm . the test solutions were applied to the skin test site on the forearm in the form of a mixture of the test materials dissolved in a hydrocarbon solvent such as isopar g ( a c10 - c11 isoparrafin sold by exxon ) or a volatile silicone fluid of low viscosity such as polydimethylcyclosiloxane which was a mixture of tetramer and pentamer and having a viscosity of about 2 . 5 centistokes measured at twenty - five degrees centigrade . the solution contained ten to twenty percent by weight of the material in the solvent . the solvent was allowed to evaporate from the volar forearm region for fifteen to thirty minutes prior to the institution of the measurement procedures . the site was hydrated as noted above and the initial spectrum was collected . a simplified test procedure is illustrated as follows . a test area on the forearm was marked and the test area was washed with the soap solution using fifteen rubs followed by rinsing with ten rubs under cool running water . excess moisture was blotted from the forearm with a towel . after one minute the skin was hydrated for one minute using a towel saturated with water which was held loosely over the test area . excess moisture was blotted and at the end of about fifteen to thirty seconds a background scan was run . the test mixture was applied to the skin test area and the solvent allowed to evaporate . the skin was again hydrated for one minute and excess moisture was blotted off . after thirty seconds a scan was run of the test area which represented an initial condition . the test area was washed with the soap solution using fifteen rubs followed by ten rinses and the excess moisture was blotted off . after one minute the skin was hydrated for one minute , blotted and at the end of about fifteen to thirty seconds a scan was run of the test area which represented a first soap wash condition . similar steps were repeated for second , third , fourth and fifth soap wash conditions . baselines for infrared bands were defined and band heights were measured . the percent ingredient remaining on the skin was calculated using these data . table i indicates the results obtained by following the preceding procedure and shows that the amount of the cyclic alkylmethyl polysiloxane ( c ) on the skin following the fifth wash was six times the amount of mink oil ( a ) and double the amount of the goldscmidt abil silicone described hereinabove ( b ). thus the substantivity of the cyclic alkylmethyl polysiloxane for skin is substantial and unexpectedly much greater than the compounds described in the art . table i______________________________________percent remaining on skin after washwash no . sample ( a ) sample ( b ) sample ( c ) ______________________________________1 23 43 532 9 37 453 6 24 394 3 22 375 5 17 32______________________________________ the procedure employed to collect the data shown in table i was repeated in order to compare the cyclic alkylmethylsiloxanes of the present invention with u . s . pat . no . 4 , 784 , 844 and u . s . pat . no . 5 , 002 , 762 mentioned in the &# 34 ; background &# 34 ; section . octyl methoxycinnamate ( sold by givaudan as parsol mcx ), a conventional sunscreen , was used for comparative purposes and as a component in a skin care formulation applied to the skin to test the ability of certain alkylmethylsiloxanes to improve the substantivity of the skin care formulation . samples b , c , and d were solutions containing 20 weight percent ( wt %) parsol mcx ( described hereinabove ), 10 wt % silicone , and 70 wt % solvent ( isopar g ( a c10 - c11 isoparrafin sold by exxon )). the specific samples contained : ( a ) parsol mcx ( a cinnimate sunscreen ) at 20 wt % in 80 wt % isopar g , ( b ) a mixture of parsol mcx , isopar g , and an alkylmethylpolysiloxane ( c 6 h 13 mesio ) 4 , ( c ) a mixture of parsol mcx , isopar g , and a cyclic alkylmethylpolysiloxane ( c 14 h 29 mesio ) 4 , and ( d ) a mixture of parsol mcx , isopar g , and a cyclic alkylmethylpolysiloxane ( c 20 h 13 mesio ) 5 . these samples were then tested according to the procedure of example i described hereinabove . samples ( c ) and ( d ) were materials in accordance with the present invention while samples ( a ) and ( b ) were provided for comparative purposes . sample ( a ) contained no alkylmethylpolysiloxane , and the sample ( b ) siloxane was of significantly lower molecular weight than sample ( c ) or ( d ). the sample b silicone is believed to be fairly representative of the compositions taught in both u . s . pat . no . 4 , 784 , 844 and u . s . pat . no . 5 , 002 , 762 mentioned hereinabove . these materials are identified in table ii below as samples ( a ), ( b ), ( c ), and ( d ) respectively . table ii below describes the results obtained by following the procedure of example i and shows that the amount of sunscreen remaining on the skin following the third wash was substantially greater for samples ( c ) and ( d ) when compared to the parsol mcx solution ( sample a ) and the lower molecular weight cyclic alkylmethyl polysiloxane ( sample b ). as table ii below shows , the present invention retained up to 2 . 5 times greater the amount of sunscreen on the skin than the low molecular weight siloxanes described in the &# 39 ; 844 patent or the &# 39 ; 762 patent retained . in fact the lower molecular weight siloxane ( sample b ) appears to have actually had a negative effect on the inherent substantivity of the sunscreen . this negative effect is indicated by sample b having a lower percentage of sunscreen remaining on the skin than does the solution containing the sunscreen alone ( sample a ). thus the cyclic alkylmethyl polysiloxanes of the instant invention are substantivity aids of unexpectedly greater efficacy than the compounds described in the art . table ii______________________________________percent remaining on skin after washwash no . sample ( a ) sample ( b ) sample ( c ) sample ( d ) ______________________________________1 49 23 49 752 29 16 33 573 18 14 22 59______________________________________ the occlusive film forming ability of the present invention was demonstrated by conducting measurements of water loss by using an in vitro water vapor permeability test method . the rate of water loss was measured by charging stainless steel payne permeability cups with 3 milliliters of h 2 o and covering the cups with collagen films spread with a thin coating of the material to be tested . the assembly is then placed in an oven at low humidity and skin temperature . weight loss measurements are taken over time to obtain water loss rates . the results of these tests are set forth in table iii below and indicate that the alkylmethylpolysiloxanes of the present invention decrease the water vapor permeability of a substrate by the formation of an occlusive barrier on a substrate ( such as skin ) which retards the rate of penetration of water vapor from the substrate through the film . samples a , b , and c were all tested at 100 weight percent . experimentation has demonstrated a direct relationship between the ability of materials to decrease water vapor permeability in this test and their ability to reduce transepidermal water loss in vivo . table iii______________________________________in vitro water vapor permeability ( wvp ) of alkylmethyl polysiloxanesmaterial water loss rate ( g / m . sup . 2 / h ) ______________________________________sample a 106sample b 89sample c 84______________________________________ in table iii sample a is a cyclic alkylsiloxane described in u . s . pat . no . 4 , 784 , 844 and u . s . pat . no . 5 , 002 , 762 cited hereinabove and has the formula ( c 6 h 13 mesio ) 4 , sample ( b ) is a cyclic alkylmethylsiloxane of the present invention and has the formula ( c 14 h 29 mesio ) 4 , and sample c is also a cyclic alkylmethylsiloxane of the present invention and has the formula ( c 20 h 41 mesio ) 5 . it can clearly be seen from the data shown in table iii that the compositions of the present invention unexpectedly reduce water loss far more effectively than the compositions described in the above mentioned patents . the occlusive film forming ability of the present invention was again demonstrated by conducting measurements of water loss by using the in vitro water vapor permeability test method described hereinabove . the amounts of cyclic alkylmethylsiloxane and solvent ( a c10 - c11 isoparrafin sold by exxon as isopar g ) utilized in this example along with the results of these tests are set forth in table iv below and indicate that the alkylmethylpolysiloxanes of the present invention decrease the water vapor permeability of a substrate by the formation of an occlusive barrier on a substrate ( such as skin ) which retards the rate of penetration of water vapor from the substrate through the film . table iv______________________________________in vitro water vapor permeability ( wvp ) of alkylmethyl polysiloxanesmaterial siloxane ( wt %) solvent water loss rate ( g / m . sup . 2 / h ) ______________________________________sample a 5 95 132 25 75 135 50 50 133 75 25 133sample b 5 95 138 25 75 137 50 50 134 75 25 124sample c 5 95 142 25 75 134 30 70 120 40 60 47 50 50 54 75 25 45untreated 124collagencontrol 0 100 133 - 145______________________________________ in table iv sample a is a cyclic alkylsiloxane described in u . s . pat . no . 4 , 784 , 844 and u . s . pat . no . 5 , 002 , 762 cited hereinabove and has the formula ( c 6 h 13 mesio ) 4 , sample ( b ) is a cyclic alkylmethylsiloxane of the present invention and has the formula ( c 14 h 29 mesio ) 4 , and sample c is also a cyclic alkylmethylsiloxane of the present invention and has the formula ( c 20 h 41 mesio ) 5 . it can clearly be seen from the data shown in table iii that the compositions of the present invention unexpectedly reduce water loss far more effectively than the compositions described in the above mentioned patents . the procedure employed to collect the data shown in table i and table ii was again repeated in order to show the substantivity of the present invention at varying concentrations . octyl methoxycinnamate ( sold by givaudan as parsol mcx ), a conventional sunscreen , was used for comparative purposes and as a component in a skin care formulation applied to the skin to test the ability of certain alkylmethylsiloxanes to improve the substantivity of the skin care formulation . the materials that were tested were solutions containing parsol mcx ( described hereinabove ), silicone , and solvent ( isopar g ( a c10 - c11 isoparrafin sold by exxon )). the amounts of each component are reported in table v along with the results of the tests performed . the silicone tested in this example was an alkylmethylpolysiloxane ( c 20 h 41 mesio ) 5 . these samples were then tested according to the procedure of example i described hereinabove . all amounts in table v are reported as weight percent ( wt %). table v below describes the results obtained by following the procedure of example i and shows that the amount of sunscreen remaining on the skin following the third wash was substantially greater for samples that contained an alkylmethylsiloxane of the present invention as compared to those that contained no silicone component . table v______________________________________substantivityparsol mcx siloxane solvent % remaining after ( wt %) ( wt %) ( wt %) wash 3______________________________________10 0 90 3920 0 80 20 5 0 95 3320 10 70 5920 5 75 4710 10 80 5610 5 85 4410 2 88 4610 1 89 60 5 1 94 41______________________________________ the following examples illustrate the method of making the cyclic alkylmethylsiloxanes of the present invention . approximately 115 grams ( 1 mole ) of mehsicl 2 dissolved in 120 grams of toluene was added to a flask containing 500 grams of de - ionized water which was rapidly stirred in order to achieve good mixing during the addition . the products of this hydrolysis reaction were two incompatible layers . the upper layer was approximately 180 grams containing 60 grams of ( mehsio ) x cyclosiloxanes with the value of x ranging from 4 to 7 dissolved in toluene ( 33 % silicone ), while the lower layer was approximately 570 grams of 12 % hcl in water . the two layers were separated and the toluene layer was washed to remove residual acid . the toluene layer was then treated with anhydrous calcium carbonate to remove any residual acid as well as water . this material was then distilled to separate the toluene , ( mehsio ) 4 and ( mehsio ) 5 . higher molecular weight cyclosiloxanes were not distilled . these can be recycled in the hydrolysis process . approximately 25 grams ( 83 % total yield ) of each of ( mehsio ) 4 and ( mehsio ) 5 were obtained . the products were identified by analytical comparison ( gas chromatography and mass spectrometry ) with authentic standards . to a mixture of 206 grams ( 1 . 05 mole ) of tetradecene and 1 . 0 gram of 0 . 5 % platinum on carbon heated at 100 ° c . without agitation was added dropwise 60 grams ( 0 . 25 mole ) of pure ( mehsio ) 4 over a period of one hour . after complete addition of the cyclosiloxane hydride , the mixture was heated to 100 ° c . for two hours , cooled to 40 ° c . and filtered . the product ( c 14 h 29 mesio ) 4 was allowed to cool to room temperature . the product was a wax with a softening point of 27 ° c . approximately 115 grams ( 1 mole ) of mehsicl 2 and 1161 grams ( 9 moles ) of me 2 sicl 2 dissolved in 1500 grams of toluene were added to a flask containing 5000 grams of de - ionized water , which was rapidly stirred in order to achieve good mixing during the addition . the products of this hydrolysis reaction were two incompatible layers . the upper layer was approximately 2225 grams containing 725 grams of cyclosiloxanes dissolved in toluene ( 33 % silicone ), while the lower layer was approximately 5700 grams of 13 % hcl in water . the two layers were separated and the toluene layer was washed to remove residual acid . the toluene layer was then treated with anhydrous calcium carbonate to remove any residual acid as well as water . this material was then distilled to separate the toluene and the cyclosiloxanes . after removal of the toluene , the cyclosiloxanes were seperated by distillation in the following order : ______________________________________a ) ( me . sub . 2 sio ). sub . 3 ( mehsio ). sub . 1 -- 100 grams ( 0 . 35 mole ) b ) ( me . sub . 2 sio ). sub . 4 -- 160 grams ( 0 . 54 mole ) c ) ( me . sub . 2 sio ). sub . 4 ( mehsio ). sub . 1 -- 144 grams ( 0 . 40 mole ) d ) ( me . sub . 2 sio ). sub . 5 -- 150 grams ( 0 . 40 mole ) e ) ( me . sub . 2 sio ). sub . 5 ( mehsio ). sub . 1 -- 60 grams ( 0 . 14 mole ) f ) ( me . sub . 2 sio ). sub . 6 -- 40 grams ( 0 . 09 mole ) ______________________________________ no further materials were distilled and the siloxane residue was 75 grams . this material can be recycled in the hydrolysis process . the above materials were identified by gas chromatography and mass spectrometry . to a mixture of 80 grams ( 0 . 315 mole ) of 1 - octadecene and 1 . 0 gram of 0 . 5 % platinum on carbon heated at 100 ° c . without agitation was added dropwise a mixture of 100 grams ( 0 . 30 equivalents of si -- h ) of 40 wt . % ( me 2 sio ) 3 ( mehsio ) 1 , 45 wt . % ( me 2 sio ) 4 ( mehsio ) 1 and 15 wt . % ( me 2 sio ) 5 ( mehsio ) 1 over a period of one hour . after complete addition of the cyclosiloxane hydride mixture , the resultant mixture was heated at 100 ° c . for an additional two hours , cooled and filtered . the product , a mixture of ( c 18 h 37 mesio ) 1 ( me 2 sio ) 3 - 5 cyclosiloxanes was a clear , colorless , odorless liquid . the method described in example iv - a hereinabove was used to produce the cyclosiloxanes in this example . to a mixture of 155 grams ( 0 . 615 mole ) of 1 - octadecene and 1 gram of 0 . 5 % platinum on carbon heated to 100 ° c . without agitation was added dropwise a mixture of 100 grams ( 0 . 585 equivalents of si -- h ) of an average composition of ( mehsio ) 2 ( me 2 sio ) 2 - 4 cyclosiloxanes over a period of one hour . after complete addition of the cyclosiloxane hydride mixture , the mixture was heated at 100 ° c . for an additional two hours , cooled and filtered . the product , a mixture of an average composition of ( c 18 h 37 mesio ) 2 ( me 2 sio ) 2 - 4 cyclosiloxanes was a white , odorless wax with a softening point of approximately 25 ° c . it should be apparent from the foregoing that many other variations and modifications may be made in the compounds , compositions and methods described herein without departing substantially from the essential features and concepts of the present invention . accordingly it should be clearly understood that the forms of the invention described herein are exemplary only and are not intended as limitations on the scope of the present invention as defined in the appended claims .

a method of treating human skin to decrease transepidermal water loss . a method of enhancing the substantivity of conditioning compounds applied to the skin . a film forming conditioning formulation which includes as an ingredient thereof an organosilicon compound is applied to the skin . the improvement resides in the utilization of a formulation which includes as the organosilicon compound a cyclic alkylmethyl polysiloxane .

in its preferred form the support system ( 10 ) of the invention comprises three basic components : 1 ) the molded high impact resistant plastic base member ( 12 ) which serves both as a platform for stationary holding of a light source and as a shaped wrist or forearm mount for portable use of a light source ; 2 ) an adjustable diameter ring ( 14 ) which attaches the light source to the high - impact resistant plastic carrier ( 15 ) that is attached to the base ( 12 ) with an adjustable pivot mounting ; 3 ) the attachment straps ( 18 ) which preferably utilize hook and loop fastener material , at the front and rear of the base to encircle the wrist , forearm or other similar shaped object . the base ( 12 ) is preferably molded in a u shape ( cross - section ) with the radius of curvature being preferably smaller at the front end ( 12a ) and tapering to a larger radius at the rear end ( 12b ), consistent with the taper of a person &# 39 ; s forearm . the lower edges ( 12c and 12d ) of the base provide the platform on which the base sits when the device is used for stationary horizontal lighting applications . the rear end ( 12b ) of the base ( larger radius of the u shape ) is preferably perpendicular to the long axis of the base and the long axis of the flashlight , thereby forming the platform for the placement of the unit on a surface for stationary vertical lighting . in the center of the top of the base member , a semi - circular tab ( 13 ) projects upwardly , perpendicular to the base member thereby forming a mounting point for the flashlight &# 34 ; ring &# 34 ; carrier ( 15 ). as illustrated in fig1 the tab ( 13 ) may be formed by cutting a semi - circular arc through the base material and then folding or bending the tab upwardly . alternatively , the tab may be formed of separate material which is fastened to the base member ( e . g . by means of adhesive , snaps , screws , etc .). the tab ( 13 ) preferably includes an opening ( 13a ) through which bolt ( 16 ) may extend as well as through corresponding opening ( 15a ) in the lower end of carrier ( 15 ) for pivotal mounting of the carrier to the tab . by tightening nut ( 17 ) on bolt ( 16 ) the orientation of carrier ( 15 ) on tab ( 13 ) can be maintained in a desired fixed position . loosening nut ( 17 ) enables the carrier to be tilted to any desired angle relative to the tab ( 13 ). the carrier ( 15 ) is preferably molded from plastic material identical to the base and is the means of flashlight ring attachment and angular adjustment of the light . the adjustable ring ( 14 ) defines a round opening for slidably receiving the barrel of a flashlight . the carrier ( 15 ) preferably comprises two matching platforms containing slotted openings ( 15b ) to hold the ring ( 14 ). the carrier may include two tabs or legs extending downward as shown . these tabs have openings ( 15a ) allowing attachment thereof to tab ( 13 ) on the base with bolt ( 16 ) providing an attachment and pivot point between the base and the carrier . this arrangement allows tool - free adjustment of the angle of light relative to the long axis of the base member ( 12 ). the ring ( 14 ) in preferred form comprises an adjustable metal band which attaches to carrier ( 15 ) through slotted openings ( 15a ) in the carrier . the ring ( 14 ) diameter is adjusted by tightening a thumb - turn bolt ( 14a ) to obtain desired tension around a flashlight barrel . this type of ring may be , for example , a hose clamp . on the interior surface of the body ( 12 ) at the front and rear are preferably located foam rubber padding strips ( 19 ) to provide user comfort when the unit is attached to the wrist or forearm . the flexible attachment straps ( 18 ), which preferably include hook and loop materials encircle the &# 34 ; u &# 34 ; shaped base at the front and the rear ends . in detail the straps at the front and rear of the unit are identical in design and function with the only difference being that the rear strap is slightly longer to accommodate the larger circumference at the rear of the base . each strap has a slotted ring ( 20 ) stitched thereto to define one end of the strap . the opposite end of the strap passes through the slotted ring , and folds back on itself . end ( 18a ) includes a strip of fastening material ( 18b ) which secures to the mating fastening material which the strap is constructed . preferred mating fastening materials are hook and loop fastener material . preferably each strap includes a strip ( 18c ) of fastener material on the inside radius of the strap for fastening to strips ( 21a and 21b at the rear end , 21c and 21d at the front end ) of mating fastener material which are secured ( e . g . by means of adhesive ) to the outer surface of body member ( 12 ) ( one patch on each side near the front and one patch on each side near the rear end of the body member ). this arrangement assures that each of the straps ( 18 ) will not slide off the body member during use . the straps are preferably non - elastic . the slotted ring ( 20 ) is preferably designed to break away for emergency release of the base from the arm of the user . the break away occurs by the straightening or deflection of the ends ( 20a ) of the slotted rings when excessive forces exist on strap ( 18 ), as depicted in fig4 and fig5 . because the end portions ( 20a ) of ring ( 20 ) are deflectable and resilient , they will deflect outwardly when a large force is applied to the strap . the length of the base or body member ( 12 ) may vary , e . g . from about three inches to about six inches . the preferred material for the body member ( 12 ) is impact - resistant plastic which is tough , durable and light in weight . if desired , the base member could be made from metal ( e . g . aluminum ), fiberglass or composite materials . the thickness of the material may also vary , depending upon the strength required and also depending upon any weight limitations which might exist .

a flashlight stand and wrist mount comprising a molded high - impact resistant plastic base shaped to facilitate the hands - free positioning of a flashlight in any desired direction . the device additionally comprises straps which can encircle the forearm of a person or similarly sized object allowing an attached flashlight to be carried or mounted on the arm or other object . a flashlight can be attached to the base utilizing one or more rings attached to a pivot point on the base , allowing for directional adjustment of the flashlight .

with reference to fig1 , radiation treatment device 1 incorporates a multi - leaf collimator ( not shown ) within the treatment head 3 . the head 3 is fixed to a gantry 5 that swivels about a horizontal axis around a patient couch 7 . a linear accelerator is located within the gantry 5 for generated high - energy radiation for therapeutic treatment . suitable orientation of the beam is achieved relative to the patient by selecting appropriate gantry and couch angles of rotation . the phantom 9 of the present invention is shown positioned on the couch 7 for receiving radiation from a conventional radiation treatment device 1 ( i . e . a linear accelerator with a 100 cm source axis distance ( 100 cm from source to isocenter 33 )). although the device 1 is shown as a linear accelerator in fig1 , the phantom of the present invention may be used to equal advantage to assess qa of an mri . as shown in fig2 and 3 , the phantom 9 includes a rotatable component 11 that is fixed in a yoke 13 . yoke 13 is fixed to a platter 16 , which is in turn rotatably mounted to a base 15 . the component 11 is free to rotate within yoke 13 , and platter 13 is free to rotate on base 15 , thereby providing two degrees of rotational freedom , corresponding to gantry 5 and couch 7 rotations . the beam display is assessed by creating a beam with isocenter 33 ( see fig6 ) at the center of the rotatable component 11 , with gantry and couch rotations corresponding to the orientation of the component 11 when the phantom is scanned . the rotational component 11 includes a tapered cubic outer portion 17 that , in transverse cross - section through the isocenter 33 , is characterized by outer wall length and width of approximately 150 mm and inner wall length and width of approximately 100 mm ( i . e . wall thickness of approximately 25 mm ). a pyramid - shaped portion 19 is disposed within the portion 17 . in transverse cross - section through the isocenter 33 , the pyramid - shaped portion 19 is characterized by a step - shaped outer wall with rise and run of each step being approximately 10 mm , and a step - shaped inner wall with the rise of each step being approximately 4 mm and the run of each step being approximately 3 mm . a solid internally tapered cube portion 21 is disposed within the pyramid - shaped portion 19 . the portion 21 is characterized by a rectangular shape in transverse cross - section through the isocenter 33 , with a length of 20 mm and a width of approximately 10 mm . each of the components is preferably made of acrylic such that a plurality of air - to - acrylic interfaces are visible on ct images . other appropriate plastics having near - tem ( tissue equivalent material ) properties , such as polystyrene , may be used . in addition , the component 11 may be fabricated from tissue equivalent materials or may include oil ( in place of air ) with magnetic resonance properties . portion 21 has a tiny metal ball ( not shown ) embedded at the isocenter 33 of the phantom 9 , and base 15 has a metal z - line wire embedded therein . the metal components shown in the ct images as high contrast points , which are used as reference markers during calibration . the base 15 has adjustable leveling feet 23 and a level indicator 25 to ensure the phantom 9 is properly leveled prior to use . turning to the schematic representation of fig4 , the phantom 9 is shown being irradiated by a beam 27 that has been shaped by a multi - leaf collimator 29 . because the geometry of the phantom 9 is known , the fidelity of the images obtained from radiation treatment device 1 can be assessed . the beam 27 is directed at the isocenter 33 of the rotatable component 11 , with gantry and couch rotations corresponding to the orientation of the rotatable component 11 when it is scanned . the divergence of the air - to - acrylic phantom surfaces aligns with the 100 cm source axis distance of a conventional linear accelerator . by comparing the images of the irradiated phantom 9 against the known phantom geometry , information on image distortions , orientation , image slice and thickness are easily obtained . for proper qa , the beam display should agree with the phantom geometry in all available views , including transverse slices , multiplanar image reconstructions , drrs , etc . in operation , to assess qa of the radiation treatment installation , the following general steps are executed : ( a ) set the desired phantom rotations ; ( b ) acquire a ct data set for the phantom ; ( c ) transfer the ct data to the planning software ; and ( d ) compare the beam or anatomy display / data measured by the planning software with the known values for the phantom 9 ( e . g . geometry , volumes , electron densities ). more particularly , the first step in assessing qa of the device 1 is to acquire a ct data set . this requires precise positioning of the phantom 9 on the ct scanner couch 7 , and acquiring scans with the phantom rotated to correspond to the desired beam orientations . as shown in the flow chart of fig5 , flat couch top inserts are first placed on the ct scanner couch 7 ( step a ). next , according to step b , the phantom 9 is then placed on the couch 7 , with the rounded end of the base 15 closest to the ct gantry 5 . in step c , lasers or ct scanner lasers ( not shown ) are then used to align with the laser alignment marks 31 on the phantom 9 . the phantom 9 is then leveled ( step d ), using the leveling feet 23 in the base 15 . at step e , a pilot scan for use in locating the phantom in the subsequently acquired ct image set is acquired . a transverse image is then obtained near the superior end of the phantom 9 ( step f ). using the ct scanner cursor function , the coordinates of the two outer z - wire points 35 are recorded on the left and the right side of the base 15 ( step g ). a transverse ct image is next acquired near the inferior end of the phantom 9 and the coordinates of these points are also recorded ( step h ). the horizontal and vertical coordinates should agree within ± 1 mm ( high contrast points are shown in the ct scan of fig6 embedded in base 15 ). if the coordinates do not agree , the position of the phantom 9 is adjusted and steps c — h are repeated . at step 1 , the rotatable component 11 is rotated to the orientation corresponding to a gantry rotation of 0 degrees on a couch rotation of 0 degrees , and a pilot scan is acquired for the entire length of the phantom ( step j ). at step k , transverse ct images are acquired for the entire length of the rotatable component 11 . for best results , it is recommended that slice thickness and spacing do not exceed 3 mm . steps i through k are then repeated for two other rotatable component orientations . at least one other scan set should be performed with either the gantry 5 or couch 7 rotated to a multiple of 90 degrees , and one scan set at an oblique angle with neither the gantry nor couch rotated to a multiple of 90 degrees . finally , at step m , the images are transferred to the 3 - d radiation treatment planning system and / or ct simulator work station . registration of the treatment planning coordinate system with the coordinate system of the phantom 9 is an important process . this is necessary because the image slice thickness and spacing is generally much greater than the pixel size in transverse ct images . there are two methods for performing coordinate system registration . the first is most appropriate when the ct slices are relatively thick compared to the transverse ct pixel size . this method involves measuring the high contrast points in the base and fitting a straight line to find the coordinate of isocenter 33 along the scanning axis . the second method is most appropriate when the ct slice thickness is relatively small , the treatment planning software does not allow for easy measurements of the required data , or if software to perform a linear regression is not available . according to the first coordinate system registration method , the technician initially determines the slice that is closest to the centre of the z - line marker 35 on the base of the phantom ( fig6 ). this is the slice where the distance from either side wire to the central wire is 10 cm . using the ruler function of the software ( fig7 ) the distance from one of the outer wires to the central wire is measured , and the couch index of the central wire is recorded . this measurement is repeated for four slices superior and four slices inferior to the central slice . next , a linear regression fit of the couch index is performed versus the distance between the wires . using the fit equation , the axial coordinate of the phantom &# 39 ; s origin is determined ( where the distance between the wires is 10 cm finally , the horizontal origin coordinate is determined by calculating the mid - point of the horizontal coordinates of the left and right wires of the z - line . the origin for the vertical axis is at the height of the metal ball 33 in the centre of the phantom 9 ( the position of the metal ball at isocenter 33 is indicated in fig3 , though because of its small size , the ball itself is not visible in the figure ). according to the second method which , as discussed above , may be more appropriate when software tools for determining the coordinates are insufficient , the technician scans through the transverse ct images and finds the slice or slices where the high contrast point corresponding to the metal ball at isocenter 33 appears . the origin can be assumed to be the position of the high contrast point . if the high contrast point appears on multiple images , then the coordinate along the axis of scanning must be approximated as well as possible . image acquisition and transfer tests are designed to quickly assess a few aspects of the ct images to ensure that they have been correctly acquired by the scanner and correctly transferred to the treatment planning software . failure of any of these tests may indicate errors in image acquisition and transfer . first , the technician verifies that the central and right z - line wires intersect at the inferior end of the z - line to confirm the orientation of the image set . a z - line regression may then be formed to ensure that the scope of the regression equation is 1 . 00 ± 0 . 05 . deviation from this may indicate either poor measurement of the z - line geometry or an error in the image slice thickness and / or spacing . beam display tests may also be conducted to permit assessment of the display of radiation beam geometry in the treatment planning software . these allow the testing of multiple field apertures on transverse , sagittal , coronal , and oblique ct images , beam &# 39 ; s eye views , digitally reconstructed radiographs ( drrs ), and 3 - d views for any combination of gantry and couch rotations . fig8 is a flow chart showing the steps for conducting a beam display test . at step a , the ct images of the rotatable component 11 are contoured , identifying the edges of all tapered surfaces . since the contours may obscure the phantom geometry in some views , step a may be performed later . at step b , a beam is created with its isocenter at the isocenter 33 of the rotatable component 11 , with a 10 × 10 cm 2 field size , and with gantry and couch rotations corresponding to the orientation of the rotatable component . at step c , the source - to - surface distance and depth are checked for correctness . as indicated above , the phantom geometry is correct for a 100 cm source - to - axis geometry , according to the preferred embodiment . at step d , the technician ensures that the graphical beam display and the interface of the air and inner acrylic shape 21 agree to within ± 2 mm on transverse ct images . step d is repeated for 1 × 2 cm 2 , and 15 × 15 cm 2 field sizes , as well as different mlc leaf arrangements . fig9 shows a 2 × 1 cm 2 radiation field superimposed on the phantom for a gantry rotation of 0 degrees and couch rotation of 90 degrees ( fig9 a ), and a gantry rotation of 323 degrees and couch rotation of 204 degrees ( fig9 b ). the beam edges align with the outer dimensions of the inner acrylic shape 21 , indicating that the beam is displayed correctly . at step e , sagittal , coronal , and ( if possible ) oblique reconstructed ct images are created . the technician should ensure that the beam graphics and phantom geometry agreed to within ± 3 mm for all field sizes . this accuracy may vary with slice thickness and spacing , wherein very coarse slices exhibit worse agreement , while very fine slices exhibit better agreement . fig1 shows a 10 × 10 cm 2 radiation field superimposed on a sagittal reconstructed ct image for a gantry rotation of 0 degrees and a couch rotation of 90 degrees ( fig1 a ), and a gantry rotation of 323 degrees and a couch rotation of 204 degrees ( fig1 b ). the beam edges align with the outer dimensions of the air cavity adjacent the inner wall of cubic element 17 , indicating that the beam is correctly displayed . fig1 shows a 10 × 10 cm 2 radiation field superimposed on a coronal reconstructed ct image for a gantry rotation of 0 degrees and a couch rotation of 90 degrees ( fig1 a ), and a gantry rotation of 323 degrees and a couch rotation of 204 degrees ( fig1 b ). the beam edges align with the outer dimensions of the air cavity adjacent the inner wall of cubic component 17 , indicating that the beam is correctly displayed . fig1 shows a 10 × 10 cm 2 radiation field superimposed on an oblique ( normal to the central beam axis ) reconstructed ct image for a gantry rotation of 0 degrees and a couch rotation of 90 degrees ( fig1 a ), and a gantry rotation of 323 degrees and a couch rotation of 204 degrees ( fig1 b ). the beam edges align with the outer dimensions of the air cavity adjacent the inner wall of component 17 , indicating that the beam is correctly displayed . at step f , a beam &# 39 ; s eye view is created to ensure that the field sizes correspond to the contoured materials within ± 4 mm . at step g , a digitally reconstructed radiograph is created ( fig1 ) to ensure that the field sizes correspond to the phantom geometry within ± 3 mm . specifically , fig1 shows an mlc shaped radiation field superimposed on a digitally reconstructed radiograph for a gantry rotation of 0 degrees and a couch rotation of 90 degrees ( fig1 a ), and a gantry rotation of 323 degrees and a couch rotation of 204 degrees ( fig1 b ). the beam edges align with the dimensions of the inner acrylic shape 19 , indicating that the beam is displayed correctly . at step h , a 3d surface view is created of the rotatable component geometry to ensure that the beam geometry agrees within ± 4 mm for all available 3d views . finally , at step 1 , steps a - h are repeated for the remaining scan sets . multiplanar ct image reconstruction tests may be used to assess the accuracy of the anatomy displayed on multiplanar ct image reconstructions ( i . e . to test general image quality and geometric accuracy ). the software ruler function is used to measure the dimensions of the shapes . firstly , a sagittal ct image is constructed . next , for east of the materials , the technician ensure that the geometry displayed is consistent with the known phantom geometry within ± 4 mm ( this limit depends on the scan parameters ) by measuring the imaged dimensions of the components 17 , 19 and 21 using the software ruler function . the inner acrylic rectangle 21 should measure 1 × 2 cm 2 , the air square adjacent inner wall of component 17 should measure 10 × 10 cm 2 , and the outer wall of acrylic square 17 should measure 15 × 15 cm 2 . these steps are repeated for a coronal ct image ( fig1 ), and an oblique image , if possible . the multiplanar ct image reconstructions are then repeated for all ct scan sets . tests may also be performed to check the geometric accuracy of digitally reconstructed radiograph ( drr ) images , as well as contoured anatomy superimposed on the images . at step a of fig1 , a drr is produced with gantry and couch orientations that correspond to the orientation of the rotatable component 11 , and a source axis distance of 100 cm . at step b , the technician checks that the drr image displays three squares of different contrast and ensures that the height and width of each square corresponds to the phantom geometry ( i . e . the size that the isocentre multiplied by any magnification factor ). at the isocentre , the inner acrylic rectangle 17 is 1 × 2 cm 2 , the air square is 10 × 10 cm 2 , and the outer wall of acrylic square 17 is 15 × 15 cm 2 . at step c , the technician ensures that the interfaces between the materials are sharp and not significantly blurred , and that the penumbra between materials is no larger than 4 mm . blurring can indicate errors in the ray line divergence of the drr . finally , at step d , the technician ensures that the displays of any contoured tapered cubes are superimposed on the edge of the appropriate material . fig1 shows a digitally reconstructed radiograph of the phantom 9 . the software ruler function is used to measure the dimensions of the shapes . as seen in fig1 , the outer dimensions of the air cavity measure 10 cm across , indicating that it is correctly displayed . in addition to the qa of radiation treatment planning software as set forth in detail above , the phantom 9 according to the present invention can also be used to implement a qa program for film or electronic portal imaging in order to verify the imaging geometry for any combination of gantry and couch angles . the steps for performing portal imaging tests are set forth in fig1 . at step a , the technician positions the rotatable component 11 on the linear accelerator couch 7 . using the treatment room lasers and the linear accelerator light field ( not shown ), the phantom 9 is aligned ( step b ) such that the reference marker in the centre of the rotatable component is at the isocenter 33 . at step c , the gantry and couch are rotated to the desired orientations and the field size is set to 15 × 15 cm 2 . at step d , the portal image is acquired . the size of each square is measured on the portal image ( step e ), wherein each square should be the size defined at the isocenter 33 , multiplied by the portal image magnification . at the isocentre 33 , the inner acrylic rectangle 21 is 1 × 2 cm 2 , the air square is 10 × 10 cm 2 , and the outer wall of acrylic square 17 is 15 × 15 cm 2 . finally , at step f , the sharpness of the square edges are inspected on the image portal . these edges should appear sharp . blurred edges may indicate misalignment of the gantry and the imager . an intensity profile through the image may be conducted to determine this more quantitatively , if available . the many features and advantages of the invention are apparent from the detailed specification and , thus , it is intended by the appended claims to cover all such features and advantages of the invention that fall within the true spirit and scope of the invention . further , since numerous modifications and changes will readily occur to those skilled in the art , it is not desired to limit the invention to the exact construction and operation illustrated and described , and accordingly all suitable modifications and equivalents may be resorted to , falling within the purpose and scope of the invention .

a phantom for evaluating nondosimetric functions in radiation therapy installation having a patient couch and a gantry with a head thereon for generating a multi - leaf collimated beam , wherein the beam is directed toward the couch at an orientation dictated by relative orientations of the couch and gantry . the phantom comprises a base adapted for disposition on the couch , and a component mounted to the base for rotation in accordance with the relative orientations of the couch and gantry . the component incorporates a plurality of known geometrical structures corresponding in shape to the multi - leaf collimated beam . upon imaging the component , nondosimetric functions may be evaluated by comparing the known geometrical structures with images of the structures and identifying discrepancies therebetween .

fig1 shows a framing device 10 of the present invention . the upper left hand corner of the framing device 10 is shown curled forward to reveal the adhesive backing 12 . in addition , the framing device 10 is shown with a photograph 14 positioned therein and indicia 16 on the border area . it will be appreciated by persons skilled in the art that the indicia 16 may be preprinted on the framing device 10 or , alternatively , can be printed on by the consumer or user of the device . additionally , it will be appreciated that the framing device 10 of the present invention can be used for the display of photographs , certificates , artwork , and / or any other item a person may desire to display in a frame . with reference to fig3 , there is shown a cross - sectional view of the portion of fig1 taken along lines 3 - 3 thereof . what is shown is a cross - section of the frame with the face stock material 18 and the adhesive backing 12 thereon . also shown is the outer perimeter 15 of photograph 14 which is being displayed . the thickness of each layer 12 , 15 and 18 are exaggerated fro the sake of illustration . the temporary adhesive 12 allows the outer perimeter of the picture or other item being displayed to be releasably secured to the frame 10 . this is also shown in phantom in fig1 . thus , the frame can be reused with a number of different pictures or other items to be displayed until such time as the temporary adhesive loses sufficient tackiness to perform its intended purpose . fig2 shows an exemplary sheet 21 of the frame material die cut to provide several different frame sizes from a single sheet of stock material . in the particular example shown , the sheet can provide a frame for an 8 × 10 item 20 , a 4 × 6 item 22 , a 2 × 4 item 24 and a coupon 26 or other solid piece in the center . other combinations of frames , etc ., are also contemplated . with this manner of die cutting the stock material , a very efficient use is achieved with little or no waste . also advantageous is the fact that various sized framing devices of the present invention can be provided using a single sheet of stock material . while the sheet material 21 is shown die cut in a rectangular fashion with various sized framing devices cut therein , it should be appreciated that other shapes of framing devices can be die cut from a sheet material , including , circular , oval , diamond or other shapes . fig4 shows a side edge view of the sheet stock material of fig2 . fig4 shows a surface sheet 28 and a backing / release sheet 30 separated by the releasable temporary adhesive 12 . the thickness of each layer 12 , 28 and 30 are exaggerated for the sake of illustration . sheets of this stock material ( uncut ) are available from dcm of cincinnati , ohio . alternatively , the stock material may be in roll form prior to die cutting . one suitable temporary adhesive is available from dcm under the trade name magikstick . the face stock material may be of any desired thickness , but is advantageously an 8 - point material . moreover , the face stock may be high gloss , semi - gloss , coated or uncoated , direct thermal , edp , latex impregnated , or thermal transfer material . it may also be paper , plastic or tag stock . these are all well known in the art and are advantageous for different purposes and uses of the framing device of the present invention . although specific reference has been made to the magikstick temporary adhesive product of dcm , and the various face stock materials that can be utilized with such an adhesive , those details are not intended to limit the scope of the present invention to such specifics . moreover , it is contemplated that the present invention encompasses various face stock materials and temporary adhesive products that , together , result in a temporary , re - positionable , removable framing device . while the present invention has been illustrated by a description of various preferred embodiments and while these embodiments has been described in some 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 will readily appear to those skilled in the art . the various features of the invention may be used alone or in numerous combinations depending on the needs and preferences of the user . this has been a description of the present invention , along with the preferred methods of practicing the present invention as currently known .

a framing device having a face sheet with a temporary adhesive on one surface thereof to facilitate removing and re - positioning the framing device . the device may include pre - printed graphics or graphics may be applied by the user .

the purpose of the invention is easiest clarified by first a brief comparison to prior art . fig1 ( prior art ) shows a male patient being prepared by antibacterial swab before a urological procedure according to prior art . the whole exposed genital area must be treated . it is noted that exposed body hair and skin folds will create crevices that may harbor particles and bacteria that is difficult to fully reach with the swab . fig2 ( prior art ) shows a catherization or similar urology procedure performed according to prior art . it is noted that hair or particles in the genital area may become dislodged during the process and reach the meatus , or the operator &# 39 ; s sterile gloves , or insertable urology instruments . it is also noted that the usually flaccid penis must be supported by hand during the process , or it may fall down and reach contamination . furthermore , the need for one hand providing support during most of the process makes it inconvenient for the operator to do other duties during the procedure . it is also noted that due to the open path to the pubic area , liquids emerging from the patient or from treatment may flow down under the drapes and onto the patient and operating table . the invention drape system is shown in fig3 and includes a drape 1 with a fenestration 2 and a split line 20 . the drape 1 may be made of a transparent material , for instance clear plastics , or by a thin elastic film , for instance latex . the purpose of the fenestration and the split line will be explained in subsequent paragraphs . the shape of the drape can be planar and rectangular as shown , but may he cut to any shape or formed to fit the patient and also include additional features known from prior art . thus , the shape of the drape can be non - rectangular , such as circular . in fig4 is shown a variation of the design where the drape 1 is attached in a sealed fashion to a surrounding larger drape sheet 3 that is made of a different material , for instance textile , non - wovens , or opaque plastics . the drape 1 , preferably translucent , can be transparent . in the embodiment of fig4 , surrounding sheet 3 , for example formed of standard medical non - woven disposable material , can be more opaque than central translucent sheet 1 , providing a feeling of privacy for the patient . the translucent sheet 1 is constructed from readily available plastic film used in the medical field , for example , vinyl ( such as polyvinyl chloride ), polyethylene , polypropylene , polycarbonate , polyester , silicone elastomer , acetate and so forth film materials . in selecting a film material for use as sheet 1 , factors such as the softness of the film , the ease of application of the film when used as a male drape , adaptability of the film to body contour , patient comfort and wrinkle stiffening properties of the film can be evaluated . for example , a 3 mil ( 0 . 070 mm ) soft grade vinyl film can be used for construction of sheet 1 . sheet 1 may be constructed of plastic film used in forming prior art drape materials , for example , plastic film of about 1 to 5 mil ( 0 . 025 to 0 . 125 mm ) in thickness . a sheet made of soft material may need to be made thicker than a drape made of a harder grade material in order to provide similar stiffening effects . the male drape of the present invention must be sterile as packaged and remains sterile until use . the inventive drape can be uncoated or completely or partially coated or impregnated with agents known in the art , such as antibacterial , adhesive and sealing compounds . fig5 is an enlarged and more detailed description of the fenestration 2 with a planar view on the top side away from the patient , while fig6 shows a cross section . the drape 1 includes a generally circular aperture 4 that is initially covered by a pull - away capable cover 5 . this is preferably made of a transparent thin material for operator see - through , or it may be made of stretchable thin film like latex . the cover 5 may be attached and sealed to the drape 1 by means of a temporary adhesive , and shaped with a finger tab for manual removal . additionally , the aperture 4 in the drape 1 may also have a seal ring 6 or 16 attached around the aperture 1 to provide seal to the male body parts as will be explained later , and also for reinforcement of the aperture . the inside diameter of the aperture 4 and the seal ring 6 or 16 are chosen to be smaller than the diameter of the male glans such that it will rest on the glans without full penetration . the sealing ring 6 or sealing ring 16 that is attached to the drape 1 can be formed of a material which possess the same degree of flexibility and rigidity as , or be softer or more rigid than the film material used for sheet 1 . for example , sealing ring 6 or sealing ring 16 may be die cut from a soft sheet material or molded as a more rigid plastic material . soft sealing ring materials may provide better patient comfort while still functioning as an adaptable gasket . on the other hand , harder sealing ring materials provide a greater dimensional stability . routine experimentation will provide a sealing ring possessing a balance of desired properties . for example , the sealing ring 6 or sealing ring 16 may be constructed of a silicone elastomer , or could be made of a soft sponge - like material . it may furthermore be made of a homogeneous material or coated or infused with antibacterial or liquid sealing agents . the degree of partial penetration of the male glans by drape aperture 4 and by sealing ring 6 as depicted in fig6 in which the diameter of aperture 4 and inside diameter of sealing ring 6 are substantially identical , can vary with the diameter of the patient &# 39 ; s glans . fig1 depicts an embodiment of the invention distinct from the embodiment of fig6 . in fig1 , the sealing ring 16 has a smaller inside diameter than the diameter of drape aperture 4 . by selecting a soft and elastic material for construction of sealing ring 16 in the fig1 arrangement , a flexible seal is provided that will accommodate a wide range of glans diameters , because the sealing ring 16 will elastically deform to the glans contour . in fig5 is also shown a marking 7 that can be printed or attached on the drape 1 to enable the operator to quickly locate the fenestration 2 on the drape , which will be of particular value if both the drape 1 and the cover 5 are made of translucent materials . now referring to fig7 , 9 , 10 and 11 , these show a suitable sequence in applying the drape 1 onto a patient and prepare the patient for the urological procedure . fig7 shows the drape 1 that is laid over the patient with the cover 2 away from the patient . the drape 1 will from now on isolate the non - sterile patient area on the bottom side from the sterile and sealed top side of the drape 1 . fig8 shows the drape 1 being positioned around the penis in an initially tent like shape such that the cover 5 and the sealed aperture 4 are approximately centered over the urethral meatus . this can be done by vision through a translucent drape or cover , or via tactile feel through a thin elastic and less translucent drape . by this procedure , the drape 1 will form wrinkles 10 that are essentially longitudinal to the penis . these wrinkles will be most evident and hard if the material in the drape 1 is of moderate thickness , and smaller in effect if the material in drape 1 is very thin and elastic . the presence of these wrinkles provides an unexpected and simple means of penile positioning that will be further explained in later paragraphs . fig9 shows the removal of the cover 5 from the drape 1 , exposing the urethral meatus approximately in center of the aperture 4 . the diameter of the aperture 4 is less than the diameter of the patient &# 39 ; s glans , making the seal ring 6 resting and sealing against the glans tip surrounding the meatus . the use of seal ring 6 is optional depending on the softness and edge characteristics of drape 1 to perform the sealing task . in fig1 , a sponge with antibacterial agents is applied to wipe and sterilize the meatus and small exposed portion of the glans tip . it is remarked that the area requiring treatment is very small compared to prior art , and all accessible areas from the top side of drape including the active urology area are now sterile and safely sealed from the bottom side . fig1 shows a clamp 10 applied around the exterior of the penile portion of the drape 1 . the clamp 10 is a sterile device that may utilize a velcro ® loop , elastic bands , or a molded medical clamp preferably made in two halves , and is applied with light pressure to not constrict the urethra . this clamp locks the drape in place to the penis , aids in sealing between above and below the drape , and generates further stiffness and position control of the shaped drape portion including longitudinal wrinkles . this allows the operator to not have to support the penis with one hand most of the time for a typical urological procedure . in order to best secure the drape 1 , the clamp 10 is preferably applied right below the glans . the clamp 10 may also allow a second clamp where one clamp is positioning the penis and a second clamp may be temporary applied to close the urethra to retain medications or other purposes . the clamp 10 , in a preferred embodiment of the invention , is packaged together with the inventive drape in a convenient , single - use surgical drape system . the sealed separation of a top side from a bottom side provided by this drape can now preferably also be utilized to create an improved liquid waste collection system that reduces liquids reaching the patient , the operating table or the floor . fig1 shows one possible shape of a liquid absorbing pad 21 with a penile notch 22 that may be positioned on top of the drape of the invention . the illustrated shape is just one example , other shapes may include as example a ring like shape with a slit for easy removal , or one or more of rectangular shape individual pads . the pad can be made of conventional fibrous materials but may preferably utilize superabsorbent materials that allow large liquid absorption without seeping out . antibacterial agents may be incorporated in this pad . it may also include a special exterior layer for dryness and internal gelling chemicals that convert liquid waste to semi - solid waste . handling semi - solid medical waste is usually easier and safer than handling liquid waste that may involve open tanks , plastic bags , containers with lid , tubing and pumps , and risk for spills , leaks and personnel exposure . in fig1 is shown a complete drape system in conjunction with a urological procedure . the drape 1 is placed on the patient , a clamp 10 is applied around the penile area of the drape 1 , and the cleaned meatus is exposed in the drape aperture 4 . the operator may initially use one hand holding the penile section of the drape 1 or clamp 10 but once the critical meatus entry of urology instruments is completed , this hand can be free . on top of the drape 1 is placed one or more absorbing pads 21 with a penile notch 22 in suitable positions to collect liquids emerging during the procedure . the sealed aperture 4 reduces chance for liquids reaching the rest of the patient body and operating table . upon completion of the urology procedure shown in fig1 a catheter or other instruments may need to be left in place in the patient for extended time . this is simplified by the split line 20 in the drape 1 allowing it to be torn apart , and made practical due to the simple flat shape of drape 1 with no protruding molded shapes . while the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof , those of ordinary skill will understand and appreciate the existence of variations , combinations , and equivalents of the specific embodiment , method , and examples herein . the invention should therefore not be limited by the above described embodiment , method , and examples , but by all embodiments and methods within the scope and spirit of the invention as claimed .

a simple surgical drape system of generally flat shape for male urology procedures that provides full isolation of top versus bottom surface by a sealing fenestration surrounding the meatus area . it is achieved by manually forming the flat drape to a tent - like shape around the penis with a fenestration aperture smaller than glans diameter , supported by and sealing to the glans tip , and then attaching a penile clamp to hold the drape . this allows a simplified safer antibacterial preparation and less chance of infection complications . the sealed design permits better management of urology liquids , and can use absorption pad on drape top side . the drape wrinkles act as a penile position stabilizer , reducing need for extended use of the one operator hand for penile support . drape is removable with catheter in place .

the game comprises a board having a continuous playing path , which is divided into a plurality of playing positions . each position contains images of polyhedral dice and mathematical operator symbols , which instruct players in the combinations of dice to be rolled in order to obtain a score for each individual turn . upon calculating the score for each turn the player increases or decreases their overall score by that point total . the game is ended when a player achieves a predetermined total amount of points . to start the game , each player rolls two standard six - sided dice . typically , the player with the highest number begins . the order of the remaining players &# 39 ; turns may be determined by their rolled numbers or other agreed order , e . g ., rotating toward the right of the starting player . the starting player rolls the two standard six - sided dice again , moving the number of spaces required by that roll along the game board ( 10 ). the player then follows the instructions pictured on the space they arrive at and rolls the combination of polyhedral dice pictured on that space and performs the mathematical operations needed to calculate the amount of points they achieve for that turn . the player then adds or deducts the amount of point from their overall score . examples of instructions on the individual spaces may included but are not limited to , the following : 1 . roll the four - sided die ( 12 ) and the six - sided die ( 14 ) and add ( 26 ) the sum of these dice to overall score . 2 . roll the eight - sided die ( 16 ) and the ten - sided die ( 18 ) and add the sum of these dice to overall score . 3 . roll the twelve - sided die ( 20 ) and add the result to overall score . 4 . roll the four - sided die , six - sided die and the ten - sided die and add the sum of these dice to overall score . 5 . roll the twenty - sided die ( 22 ) and add the result to overall score . 6 . roll the four - sided die , six - sided die and the eight - sided die and add the sum of these dice to overall score . 7 . roll the six - sided die twice and the eight - sided die and add the sum of these dice to overall score . 8 . roll the four - sided die twice and the twelve - sided die and add the sum of these dice from the overall score . 9 . roll the ten - sided die and subtract ( 28 ) the result from overall score . 10 . roll the four - sided die twice and the ten - sided die and add the sum of these dice from the overall score . 11 . roll the four - sided die twice and the eight - sided die and add the sum of these dice from the overall score . 12 . roll the four - sided die and the eight - sided die twice and add the sum of these dice from the overall score . 13 . roll the four - sided die and the six - sided die twice and add the sum of these dice from the overall score . 14 . roll the twelve - sided die and subtract the result from overall score . 15 . roll the six - sided die and the eight - sided die and add the together and subtract the result from overall score . the game board ( 10 ) shall have four ‘ random chance ’ spaces ( 24 ) symbolized by a large question mark . upon landing on one of these spaces , a player will roll the twelve - sided die and will take action ( 30 ) based on the result . if a player rolls the number one , they will have to move forward one space . if a player rolls the number two , they will have to move back one space . if a player rolls the number three , they will have to move forward two spaces . if a player rolls the number four , they will have to move back two spaces . if a player rolls the number five , they will roll the four - sided die twice and the six - sided die then add those results together and add the amount to their overall score . if a player rolls the number six , they will roll the four - sided die twice and the eight - sided die then add those results together and add the amount to their overall score . if a player rolls the number seven , they will roll the four - sided die and the six - sided die twice then add those results together and add the amount to their overall score . if a player rolls the number eight , they will roll the four - sided die , the six - sided die and eight - sided die then add those results together and add the amount to their overall score . if a player rolls the number nine , they will roll the six - sided die twice then add those results together and add the amount to their overall score . if a player rolls the number ten , they will roll the eight - sided die twice then add those results together and add the amount to their overall score . if a player rolls the number eleven , they will roll the ten - sided die twice then add those results together and add the amount to their overall score . if a player rolls the number twelve they will roll the twenty - sided die and add the result to their overall score . each turn players will add or deduct points from their overall score based on each turn they take until a predetermined score of three hundred points is achieved . however , players can choose the final tally they desire for a target amount of points to achieve in order to win the game before the game begins . in summary , the present board game will be seen to provide a most enjoyable means of teaching children and others who have poor arithmetic and basic numerical skills , the rudiments of such skills . the game enable players of virtually any skill level to sharpen their arithmetic and mathematical skills , while still enjoying a pleasant , competitive board game . while the present invention has been described in detail with reference to the preferred embodiment thereof , it should be understood to those skilled in the art that various changes , substitutions and alterations can be made hereto without departing from the scope of the invention as defined by the appended claims . accordingly , the scope should be determined not by the embodiment illustrated , but by the appended claims and their legal equivalents .

the present invention comprises a board game for teaching basic arithmetic and mathematical operations to children in need of such skills . the game board includes a continuous playing path having a series of playing positions there along , with each of the positions requiring a player to roll combinations of polyhedral dice and using mathematical operations to achieve a score for each turn along the playing path . play proceeds as described above until a predetermined total amount of points is achieved .

referring to fig1 the portable anesthesia administrating system is shown which includes upper and lower plates 41 and 42 respectively which are held in essentially parallel spaced relationship by supporting posts 43 defining a container space 44 there between . upper plate 41 includes a number of orifices each of which accepts an operating element of the unit therein with the element then projecting into the container space . the following is an index identifying each operating element by number for ease of identification and location in the drawings . 15 . adjustable pressure limiter ( apl ) valve with 19 mm connector 17 . pressure gauge , breathing system , − 40 to + 80 cmh 2 o 23 . hose , fresh gas , key index and locking on both ends 31 . secondary ( spare ) thermh 2 osorb ™ co 2 canister with seal caps in practice it can be seen that what is presented is a simple straightforward portable anesthesia administration system having application wherever anesthesia is required . the system can best be described by describing its function in actual use . the first step is to connect a mask not shown and inhalation and exhalation conduits 46 and 47 respectively to inhalation and exhalation valves 13 and 12 respectively . the inhalation and exhalation conduits can be of the typical corrugated variety commonly in use in such medical applications . however , most preferably they are of the variety which are the subject of u . s . pat . nos . 5 , 377 , 670 ; 5 , 623 , 922 and 5 , 735 , 286 which patents are herein incorporated by reference . having thus connected the conduits , the next step is to flush the system with oxygen purging residual gasses therefrom . activation of the oxygen flush valve 10 charges the patient breathing system with 100 % oxygen . the oxygen is forced at 50 liters per minute through the fresh gas outlet ii into the breathing bag 21 and then through the thermh 2 osorb ™ absorber / humidifier 18 . the preferred absorber / humidifier for use in this invention is described and claimed in u . s . pat . nos . 5 , 143 , 060 ; 5 , 228 , 435 ; 5 , 360 , 002 ; and 5 , 558 , 088 all of which are incorporated herein by reference . it contains sufficient co 2 absorbing material such as soda lime to accommodate a single patient and is referred to as a single patient use disposable carbon dioxide absorber . the oxygen continues to flow through the open inspiratory valve 13 to the patient mask . the oxygen sensor 14 will signal 100 % oxygen concentration to the oxygen monitor ( optional ). at this stage , all gasses from a previous exhalation present in the breathing circuit will be flushed out by the 100 % oxygen gas flow and all carbon dioxide will be removed by the thermh 2 osorb ™ absorber / humidifier 18 . the oxygen flush will have been completed at this stage . the patient is then connected to the system . when the patient initiates an inhalation he creates a sub - atmospheric pressure in the system . this sub - atmospheric pressure opens the inspiratory or inhalation valve 13 while at - the same time the subatmospheric pressure keeps the expiratory or exhalation valve 12 closed . since the fresh gas which is 100 % oxygen will continue to flow from the fresh gas common gas outlet 11 , excess gas will be evacuated from the breathing system through the adjustable pressure limiter valve 15 . it should be noted that the common gas outlet has a key index with a locking device . this prevents tampering or unauthorized use of the anesthesia system by those not properly trained to do so . similarly , it should be noted that the adjustable pressure limiter valve has a 19 mm connector while the exhalation and inhalation valves 12 and 13 have 22 mm connectors . this difference in size prevents any possibility of improperly connecting hoses in the system . downstream of the pressure limiter valve 15 gas is removed through an active suction or charcoal filter scavenger system 25 . the filter scavenger system contains an absorber for waste anesthesia gas which is preferably comprised of various halogenated agents . as the patient begins to exhale , a positive pressure opens the exhalation or expiratory valve 12 but keeps the inhalation valve 13 closed . the patient exhales into the breathing bag 21 where the exhaled gas is mixed with fresh gas coming through manifold block 27 from fresh gas connection 32 . the exhaled gas contains carbon dioxide and an anesthetic agent may be added from the vaporizer 48 to the completely dry 100 % oxygen of the system . as the exhalation continues the breathing bag 21 expands with a dry fresh gas mixture and with the exhaled patient gas containing co 2 . the extent of the expansion depends on the adjustment of the adjustable pressure limiter valve 15 . any excess fresh gas mixture from the manifold block is directed through the thermh 2 osorb ™ absorber / humidifier 18 to the adjustable pressure limiter valve 15 and from there the gas will be removed through an active suction or charcoal scavenger system 25 delivered through hose 24 . the breathing bag is held in position and in fluid connection with the manifold block by virtue of the breathing bag elbow 20 inserted within the bag elbow connection port 22 . assisted ventilation is initiated by squeezing the breathing bag 21 . this creates a pressure which is registered on the patient system pressure gauge 17 which is calibrated to measure pressure between − 40 to + 80 centimeters of water . this is generally a sufficient operating range to meet the requirements of the patient . upon exhalation the gas which contains co 2 and the completely dry fresh gas mixture which may contain an anesthetic agent are transferred from the breathing bag 21 to the absorber / humidifier 18 . the absorber removes the co 2 from the exhaled gas . the foam granule barriers 19 prevent absorbent dust from entering the patient &# 39 ; s breathing circuit as well as facilitate the humidifying of the gas before it is delivered to the patient . humidification occurs by virtue of water vapor from the patient &# 39 ; s previous exhalation being condensed in the foam granule barriers and water vapor which is now reintroduced to the gas mixture as co 2 is removed . very typically the absorber is filled with soda lime which upon contact with co 2 reacts to produce heat during the co 2 removal process . the heat warms the gas now being returned to the patient . the inhalation and exhalation breathing conduits previously described can be insulated to preserve the heat so generated . the gas once replenished with anesthetic agent and oxygen flows through the inhalation valve 13 to the patient in this closed system . the inspiratory oxygen concentration is recorded via the oxygen sensor 14 . advantageously , there is provided oxygen flow control valve 5 a fine and coarse oxygen flow meter 6 and 7 . typically the coarse flow meter permits adjustment between 0 and 10 liters per minute while the fine adjustment flow meter permits adjustment between 0 and 4 liters per minute . the pressure in the system as registered on the patient system pressure gauge 17 will depend on the adjustment of the adjustable pressure limiter valve and the patient &# 39 ; s lung compliance . all excess gas will flow through the pressure limiter valve and will be removed through the scavenger charcoal system 25 . at this stage the cycle may be repeated by once again applying pressure to the breathing bag 21 . advantageously , there is provided a test plug 30 for breathing circuit pressure testing and a spare or secondary thermh 2 osorb ™ canister 31 which can be readied for use by simply removing the seal caps thereon and positioning manifold block 27 in flow communication therewith . also it is advantageous to provide lifting handles 34 to the structure between plates 41 and 42 to provide for the easy movement and placement of the anesthesia system of this invention . also , it should be noted that exhalation and inhalation valves 12 and 13 include a very dependable valve design for directional gas flow comprising a simple disk which is flat and retained on seating with a circular seat . this type valve is universally used in anesthesia machines for gas flow directional control . the valve opens with low pressure and low flow rates and depending on the weight of the disk creates negligible back pressure . the valve is virtually free of the possibility of reverse flow when in the closed position as long as complete contact is maintained between the disk and the total circumference of the seat . when used with low flows and pressure such as in anesthesia equipment , the valve operates quickly , precisely and dependably due to the low mass of the valve disk which reduces inertia of the disk to a minimum . the valve is normally in the closed position due to gravity acting on the disk when no flow is present . valves of this type are limited to vertical flow positioning with flow pressure being applied to the bottom or top of the disk to open it . this disk is attached at one point on the circumference of the shell of the unit and tips up to allow gas flow . as can be seen from fig2 there are a plurality of orifices 51 though 56 in the upper plate 41 which receive and contain various of the operating elements . as best seen in fig2 orifice 51 receives and contains the carbon dioxide absorber 18 . orifice 52 receives and contains the charcoal absorber 25 . orifice 53 receives and contains oxygen sensor 14 . orifice 54 receives and contains the oxygen flush control actuator and valve 10 . orifice 55 receives and contains an airway for oxygen pressure supply gauge 3 and lastly , orifice 56 receives and contains fresh or common gas outlet 11 . lastly , with respect to the manifold block 27 , it can be seen that there are a plurality of conduits which provide for the attachment of anesthesia regulating and control elements . these conduits are best seen in fig4 designated by the numbers 61 through 68 . conduit 61 provides flow communication with the airway pressure gauge 3 while conduit 62 provides flow communication with breathing bag 21 through the elbow for the breathing bag 20 and the bag elbow connection port 22 . conduit 63 provides flow communication with the airway pressure limiting valve 15 while conduit 64 permits flow communication with the oxygen pressure sensor 3 . conduits 65 and 66 are in flow communication with inlet and outlet airway control valves 13 and 12 . lastly conduits 67 and 68 are in flow communication with the inlet and outlet terminals of the carbon dioxide absorber 18 . as can be seen , the manifold block provides an important function in addition to that of a manifold by virtue of it serving in conjunction with the breathing bag at least in part as a mixing chamber . the manifold block is easily sterilizable upon removal of the appartences thereto . except for the manifold block all of these elements are neatly positioned within the container space 44 . as can be seen and realized from the foregoing figures and description there are many advantageous features to the portable anesthesia system of this invention . for example , it is smaller than the typical co 2 absorber system by at least 90 % and significantly lighter perhaps as by as much as ten times lighter . the operating parts exposed to the patient &# 39 ; s exhalant breath are totally cleanable or autoclavable . the unit can be located remotely from an anesthesia machine if it is used in conjunction therewith where the anesthesia machine would provide the breathing function in place of a breathing bag . moreover , the design , size and weight promotes portable application for military and emergency rescue situations . the low cost directional valves provide for positive gas control and they are either cleanable or disposable . the absence of ferrous metal parts allows use in the vicinity of mri procedures . the system is equipped with a positive locking means to hold the manifold block 27 to the co 2 absorber in an aligned and indexed fashion . also the connections to and from the manifold block incorporate size specific quick disconnect or tapered fit connections to eliminate leaks and o - rings used where applicable to insure a leak free system . no tools are thus required for preparation to clean , autoclave , set up or disassemble the unit . also the reduced surface area of the compact unit makes it easier to clean and lower in cost than a typical anesthesia system . the unit accommodates any type circle or closed circuit breathing system and yet is easily integrated into those systems when advantageous to do so . also it is evident that it is much quicker to change co 2 absorbent canisters which can be stored for long periods of time since they are airtight . it is also possible to provide a fold - down shelf 70 shown in fig7 attached to either upper plate 41 or support structure 43 for supporting various surgical or anesthesia items . fig8 shows another embodiment of the invention which is preferred and which uses both oxygen and air as carrier gases for the anesthesia gas . air and oxygen lines 71 and 72 respectively are shown entering the unit while flow meters 73 and 74 control their flow . fig8 also shows a hose 75 for alternatively connecting the system of this invention to a commercial ventilator .

a portable anesthesia administering system which includes a compact , lightweight unit that does not require a source of electrical power to provide regulated pressurized anesthesia gas to a patient . the operating elements include a disposable carbon dioxide absorber , a charcoal scavenger absorber , an oxygen pressure sensor and alarm for detecting a drop in the oxygen pressure below a pre - selected level . the unit utilizes an anesthesia vaporizer and regulator , an airway pressure limiting valve and airway inlet and outlet control valves to provide a gaseous anesthesia agent in pre - selected amounts . attached to the disposable carbon dioxide absorber is a manifold block which provides for a plurality of anesthesia regulating and control elements to facilitate the administration of the anesthesia . connected to the manifold block is an external breathing bag for assisting in the breathing of the patient .

as background , we describe an earlier prototype of an automated sprayer generally referred to in the figures by reference number 20 . with particular reference to fig1 – 2b , the sprayer 20 includes as main components a bottle 22 , a housing 24 with an adjustable hanger 26 , a pump 28 , a drive mechanism 30 , a spray head 32 and a control circuit 34 . the sprayer is typically suspended via the hanger from a shower spout or the like and then activated via a button 35 at the front of the sprayer to rotate a spray head and pump cleanser from the bottle out of the spray head during a spray cycle of a prescribed time period , after which dispensing is automatically terminated . the exterior of the sprayer is defined by the housing 24 , which can be molded from , for example , plastic by any suitable technique and consists primarily of two pieces , a receptacle 36 and a hanger tower 38 that easily snaps into a pocket in the receptacle . this allows the sprayer to be shipped and stored in a compact package with minimal assembly by the consumer . the hanger tower 38 is an upright member defining a cavity in which the elongated body of the hanger 26 fits through an opening 40 at its upper end . the upper end of the hanger tower 38 has two oval openings 42 vertically spaced apart . a deflectable tab 44 formed in the lower end of the hanger can snap into one of the openings to lock the hanger at either of two extended positions . the hanger is extended and locked in the lower opening by simply pulling it away from the hanger tower . in this position , the sprayer 20 will hang from standard shower spouts at an appropriate height for spraying down the shower walls . the height can be adjusted by depressing the tab inwardly and sliding the hanger up or down . the hanger itself has two ears 46 at its upper end for mounting a rubber strap 48 . the ears can be tapered to ease connection of the strap , which can have a series of holes at one end for adjustment purposes so that the strap fits tightly around a shower spout or the like . the back side of the hanger tower is closed by a back plate 50 . the hanger tower connects to the receptacle at its lower end , which fits into a pocket 52 and has two latches 54 ( one shown ) that snap into two slots in the back of the receptacle . the receptacle defines an upwardly opening bottle tray 56 above a compartment 58 ( see fig4 ) containing the pump and drive mechanism which is closed at the bottom by a cover 60 . the cover has a circular skirted opening 62 for the spray head and a wall stand - off 64 extending backward the distance of the pocket to brace the lower end of the receptacle against the wall and keep it plumb . the back side of the receptacle defines a battery compartment 66 with a lid 68 and the front side has an oval switch opening 70 for the control button 35 . the tray 56 is formed to mate with a specially contoured upper end of the bottle . the bottle and tray are generally oval and have mating seating surfaces 72 and 74 and sloped shoulders 76 and 78 with complementary v - shaped features 80 and 82 , respectively . these features and the contour of the shoulders fix the orientation of the bottle in the tray and make conventional cleanser bottles incompatible with proper operation of the sprayer . referring next to fig9 – 12 , the tray defines a circular well 84 at the center of the seating surface 74 accommodating a special cap 86 screwed onto the mouth of the bottle . the well is formed with a shoulder portion 88 , a vent nipple 90 and a recess 92 with a discharge nipple 94 . the well supports a valve plate 96 ( see fig2 a ) fastened thereto by two screws 97 ( see fig3 ). the valve plate has a piercing post 98 projecting up from the valve plate . the post has a slanted top end defining a sharp point and defines a vent passageway 100 and three radial ribs 102 . the vent passageway extends into a recess 104 at the underside of the valve plate accommodating a small o - ring 106 surrounding the vent passageway and the opening in the vent nipple 94 . the valve plate also defines a valve recess 108 with a discharge passageway 110 through which a valve stem 112 extends . the upper end of the valve stem has a cross - shaped plunger 114 that is biased away from the well by a coil spring 116 fit into the valve recess . the lower end of the valve stem mounts a disc - shaped rubber gasket 118 retained by an enlarged end 120 of the valve stem . as shown in fig1 , the plunger is biased upward by the spring so that the gasket seals against the underside of the valve plate so as to close off the discharge orifice when the sprayer is not being used . the valve plate also defines arcuate stand - offs 124 spaced in slightly from its periphery . the valve plate and the well are designed to cooperate with the specially designed bottle cap ( described below ) to discourage use of unaffiliated cleanser and thereby promote proper operation of the sprayer . referring next to fig8 – 11 , the cap is generally circular with a serrated periphery 126 and a tapered sealing flange ( or web ) 128 that seals against the tray well above its shoulder . the top of the cap has an outer surface 130 with a recessed thinned area 132 at its center around which is a raised ring surface 134 extending to a plane spaced from surface 130 . the thinned area 132 is located so that as the bottle is seated in the tray the piercing post will puncture the cap in this area to permit discharge of the cleanser and venting of the bottle . the raised ring is located to contact the plunger of the valve and push the valve downward to unseat the gasket from the plate and open the discharge orifice . the flat surface 130 of the cap rests on the stand - offs 124 to space the punctured area from the floor of the well . this arrangement thus provides a no - mess means of opening and inserting the bottle , but also further inhibits uses of improper cleanser containers . it does this for several reasons . first , if a conventional bottle and cap were inserted into the tray , the piercing post would not puncture a conventional cap lacking the weakened area . even if the cap was removed so that the mouth was opened , the sprayer still would not operate because the valve is located radially inward of the place where a conventional thin - walled bottle mouth would normally extend so that the valve would not be opened . another feature that serves this purpose is the conforming sloping of the bottle shape and receiving well . a bottle not having a complementary shape would not be received sufficiently low to activate the outlet valve . also , while the cap has conventional internal threads 136 at its upper end that mate with threads 138 on the mouth of the bottle , and it also has a ring of one - way ratchet teeth 140 that engage corresponding ratchet teeth 142 on the bottle ( see fig1 ). the ratchets allow the cap to be turned in a tightening direction but resist untightening rotation to prevent non - destructive removal of the cap and thus refilling of the bottle . fig2 b – 6 show the pump , controller , and drive mechanism contained inside the receptacle compartment beneath the bottle tray . these components will now be described working from the bottle - tray interface to the spray head . a short vent tube 144 couples to the vent nipple 90 defining the vent orifice in the tray well . a small check valve 148 fits into the end of the vent tube . the check valve is normally closed so that cleanser does not leak out via that path . the valve opens by negative pressure that develops as cleanser is withdrawn from the bottle . the opened check valve aspirates the air to the bottle to allow the cleanser to flow from the bottle in a consistent manner , without introducing air in a manner that would cause foaming or gurgling . the check valve remains open until the pressure in the bottle has equalized sufficiently to alleviate the negative pressure and then it closes . from the discharge nipple defining the discharge orifice of the tray well a first tube 152 of a dispenser line 154 extends to an inlet barb 156 of the pump 28 , which snaps into a support 158 mounted to the underside of the bottle tray . the pump can be any conventional pump , such as a diaphragm pump , a piston pump , a peristaltic pump , or even a gear pump as shown . the inlet defines a passageway leading between intermeshing drive gear 160 and idler gear 162 ( see fig2 c ). the drive gear is connected to an upper shaft 164 ( surrounded by o - ring 165 ) of a direct current motor 166 mounted through an opening in a gear plate 167 mounted to the lower cover of the receptacle . operation of the motor rotates the drive gear which meshes with and turns the idler gear as conventional to draw cleanser from the bottle and through to an outlet barb 168 . a second tube 170 connects the outlet barb to a filter 172 . the filter accumulates cleanser within its housing and aids in priming the pump . a short tube 174 of the dispenser line connects the filter 172 to another check valve 176 which is connected by another short tube 178 continuing a spring 179 for support to an inlet barb 180 of a shaft junction 182 . referring to fig2 b and 5 , the stationary portion of the junction 182 is a chamber formed in part by the gear plate at a circular wall 184 having an inner shoulder 185 and covered at one end by a cap 186 . the cap includes the inlet barb 180 and a raised annular ring 188 extending downwardly within the circular wall to press an o - ring 190 against the shoulder . the o - ring seals against the upper end of a rotating spray head drive shaft 192 , which forms the rotating portion of the function . the drive shaft is an inverted y - shaped structure with a cylindrical stem 194 defining a passageway 198 and a forked end 196 extending down through an opening in the receptacle cover and defining a gap 200 accommodating a spray nozzle 202 . the forked end has lateral mounting posts 204 onto which snaps a dome - shaped cover 206 concealing the spray nozzle 202 . the spray nozzle is preferably a fluidic oscillator providing oscillating spray ( in this case up and down ), however , any other suitable nozzle could be used . see e . g . u . s . pat . no . 4 , 562 , 867 which shows examples of known fluidic oscillators . such a fluid oscillator can be any suitably sized oscillator including a housing 208 with an inlet 210 and an outlet 212 on opposite sides . a barrier member ( not shown ) in the interior of the housing defines a passage between the inlet and the outlet so that cleanser entering the inlet passes through and around the barrier member to the outlet . the fluidic oscillator operates , as known in the art , by creating areas of low pressure at alternate sides of the passage through the barrier member to convert the straight flow entering the housing to an oscillating pattern . the nozzle is coupled to an outlet barb 214 extending from the stem by another tube 216 . the nozzle is mounted so that its outlet end extends through the opening in the cover pointed downwardly at approximately a 30 degree angle . a drive gear 220 is press fit onto the stem of the drive shaft and meshes with a first reducer gear 222 which is rotated by another smaller diameter reducer gear 224 driven by a pinion 226 at the end of lower motor shaft 228 . the gear train couples to the motor to the spray head at a reduced revolution per minute rate than the motor shaft . this arrangement provides a revolving , oscillating spray pattern . also mounted to the support within the receptacle compartment is the control circuitry 34 which is electrically coupled to a direct current power supply via battery terminals 230 ( see fig2 a and 7 ) in the battery compartment and to the push - button switch 35 , which is mounted through the opening 70 in the front of the receptacle through a lighted watertight , flexible membrane 232 . the circuitry includes timing circuitry 234 and a speaker 236 that functions as described below . the electrical arrangement as well as the dispensing line and bottle venting flow paths are shown in fig7 and the sprayer is operated as follows . when a bottle is loaded into the sprayer ( that is , the bottle is inverted and set into the receptacle tray ), the thinned area of the bottle cap is punctured by the piercing post , the cap sealing flange seals against the tray well and the annular ring contacts and depresses the plunger of the discharge valve to open the valve . cleanser pours out of the bottle between and around the ribs of the piercing post and is replaced by an equal volume of air through the vent tube . because air is lighter than the cleanser , it is displaced to the top of the bottle where it is trapped . cleanser pours out of the bottle and drains through the valve plate and into the dispenser line , through the pump , past the filter until it reaches valve 176 . until the sprayer is operated , the sprayer remains in this state of equilibrium in which no cleanser flows from the bottle . when a user wishes to spray the enclosure walls with cleanser , he or she simply depresses the switch at the front of the sprayer . this signals timing circuitry to begin a countdown delaying spraying for a predetermined time , such as 20 seconds . this affords the user time to exit the shower enclosure and close the doors or curtains . it also may provide the user time to abort the spray cycle by depressing the switch a second time . initially depressing the switch may also send a pulsed tone to the speaker and flashes the lighted ring around the switch for warning the user of the impending operation of the sprayer . unless cancelled by the user , the spray cycle begins automatically at the expiration of the countdown . the motor is then energized which simultaneously rotates the drive gear of the pump and turns the gear train to rotate the drive shaft and the spray head . at the same time , the pump draws cleanser from the bottle through the dispenser line and opens valve 176 so that cleanser can flow through the junction and be expelled through the nozzle as the spray head is rotated , thereby providing a circular , oscillating spray pattern . this reduces the level of cleanser in the bottle , creating a negative pressure in the bottle , which opens the check valve in the vent tube to aspirate the bottle and allow more cleanser to be drawn from the bottle during the spray cycle . the motor continues to be energized until the expiration of a second countdown performed by the timing circuit , preferably another 20 second interval , automatically initiated by the timer . at that point the motor is deenergized which shuts down the pump causing valve 176 to close . closing the valve prevents cleanser from leaking out of the dispenser line and also keeps the cleanser in the line upstream from the valve so that the pump remains primed . the sprayer thus returns to stand - by mode without further intervention from the user , ready for another spray cycle at the demand of the user . fig1 – 16 depict a modified bottle cap and an adapter suitable for use with the dispenser of fig1 – 13 . a flat top cap 86 a is provided with a bottle 22 . an adapter 300 is employed between the bottle cap and tray 56 to bridge the action of loading the bottle into the tray and the opening of the discharge orifice . in fig1 , bottle cap 86 a has a generally flat transverse outer surface 130 a with a recessed thinned area 132 a at its center . adapter 300 has a flat ring 302 with an opening in the middle and a ring 134 a protruding from the ring 302 but with a smaller outer circle . the ring 302 of the adapter 300 may have the same serrated periphery 306 as the bottle cap 86 a , and the outer circles of the ring 302 and the bottle cap 86 a , including the serrated peripheries , typically have the same diameter . when the bottle 22 is seated in the tray 56 , piercing post 98 will go through the opening in the middle of the adapter 300 and puncture the cap 86 a in the thinned area 132 a to permit discharge of the cleanser and venting of the bottle . meanwhile , the bottle cap 86 a presses against the ring 302 of the adapter 300 so that the ring 134 a of the adapter , which is located to contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . the ring 302 of the adapter 300 rests on the stand - offs 124 to space the punctured area from the floor of the well 84 . what has been described thus far with respect to fig1 – 16 provides context for the use of the present invention claimed herein . turning now to fig1 – 19 , there are shown embodiments of a cap and the bottle - tray interface according to the invention that may used to deliver cleanser from the bottle 22 to the tube 152 of the dispenser line 154 that extends to the inlet barb 156 of the pump 28 as described above . in fig1 – 19 , the cap 86 b is as described above with references to fig8 – 11 except that the cap 86 b has four equally spaced segmented ridges 134 b extending to a plane spaced from the surface 130 . the segmented ridges 134 b are separated by slots 434 . the segmented ridges 134 b are located to contact a valve actuator to deliver cleanser from the bottle 22 to the first tube 152 of the dispenser line 154 that extends to the inlet barb 156 of the pump 28 as described below . referring now to fig1 , the embodiment of a bottle - tray interface is shown just before the bottle 22 is placed in the reservoir tray . the reservoir tray has a well 480 including a circular upper section 484 with a floor 485 and a circular lower chamber 490 extending downwardly from a portion of the floor 485 . a spout 491 extends downwardly from the lower chamber 490 and defines an outlet orifice 492 . a circular piercing post 420 extends upwardly from the floor 485 of the circular upper section 484 of the well 480 . the piercing post 420 has an outer wall 421 , and an inner wall 427 that defines an air vent path 425 and a cleanser conduit 428 in the piercing post 420 . the cleanser conduit 428 provides a fluid flow path to the lower chamber 490 of the well 480 . an air hole 426 passes through the outer wall 421 into the air vent path 425 , and an opening 429 passes through the outer wall 421 into the cleanser conduit 428 . the piercing post terminates in an obliquely truncated upper end 422 to facilitate puncturing the cap 86 a in the thinned area 132 a to permit discharge of the cleanser . the lower chamber 490 of the well 480 contains a valve 438 that controls cleanser flow from the bottle 22 as will be described below . the valve 438 includes a valve actuator 440 and a valve stem 448 . the valve actuator 440 includes a plunger 441 , a valve cover 443 and a rocker 444 . the plunger 441 is biased in the upward direction against the valve cover 443 by a spring 442 as shown in fig1 . the rocker 444 includes a pivot pin 446 , an upper arm 445 and a lower forked arm 447 . the forked arm 447 is seated in a groove 450 in the valve stem 448 . a spring 449 biases the valve stem 448 against the entry to the outlet orifice 492 as shown by the arrow in fig1 . by spring - biasing the valve stem 448 into a normally closed seated position that seals the outlet orifice 492 of the lower chamber 490 of the well 480 , any downward pressure exerted on the valve stem 448 ( such as sucking by the pump , downward fluid pressure , or gravity ) merely keeps the valve stem 448 seated ( absent downward movement of the plunger 441 as described below ). turning now to fig1 , the embodiment of a bottle - tray interface is shown after the bottle 22 has been placed in the reservoir tray . when the bottle 22 is placed in the tray , at least a portion of one or more of the segmented ridges 134 b of the cap 86 b contacts the valve cover 433 thereby moving the plunger 441 downward in the direction shown in fig1 . the slots 434 between the segmented ridges 134 b of the cap 86 b have a width smaller than the diameter of the plunger 441 to insure movement of the plunger 441 . when the plunger 441 moves downward , the upper arm 445 of the rocker 444 pivots the lower forked arm 447 in an upward direction thereby moving the valve stem 448 in the upward direction shown in fig1 . this unseats the valve stem 448 from the entry to the outlet orifice 492 as shown in fig1 . a cleanser flow path is then created from the bottle 22 , through the cleanser conduit 428 of the piercing post 420 , into the lower chamber 490 of the well 480 , through the outlet orifice 492 , and into the first tube 152 of the dispenser line 154 that extends to the inlet barb 156 of the pump 28 as described above . delivery of the cleanser from the spray nozzle 202 then occurs using the mechanisms , circuits , and processes described above . still referring to fig1 , when the bottle 22 is placed in the tray , an air passage 460 is created between the bottle 22 and an inner surface 482 of the well 480 . an air flow path is thereby created from the air passage 460 , through the slots 434 ( best shown in fig1 ) between the segmented ridges 134 b of the cap 86 b , through the air hole 426 in the outer wall 421 of the piecing post 420 , through the air vent path 425 of the piercing post 420 , and into the bottle 22 . the arrangement of fig1 – 19 also provides a no - mess means of opening and inserting the bottle and also further inhibits uses of improper cleanser containers . it does this for several reasons . first , if a conventional bottle and cap were inserted into the tray , the piercing post 420 would not puncture a conventional cap lacking the weakened area . even if the cap was removed so that the mouth was opened , the sprayer still would not operate because the valve actuator 440 is located radially inward of the place where a conventional thin - walled bottle mouth would normally extend so that the valve would not be opened . in addition , the floor 485 of the well may also include arcuate upwardly extending ribs ( such as arcuate stand - offs 124 in fig1 ) of a thickness or spaced inward sufficiently such that bottles with a narrower neck cannot contact the valve while a cap with narrow segmented ridges can contact the valve by way of thin , high segmented ridges . also , while the cap 86 b has conventional internal threads 136 at its upper end that mate with threads 138 on the mouth of the bottle , and it also has a ring of one - way ratchet teeth 140 that engage corresponding ratchet teeth 142 on the bottle as in fig1 . the ratchets allow the cap to be turned in a tightening direction but resist untightening rotation to prevent non - destructive removal of the cap and thus refilling of the bottle . fig2 – 22 depict an embodiment of a modified cap and adapter that may be used with the present invention . a flat top cap 86 c is provided for the bottle 22 and an adapter 500 is employed between the bottle cap 86 c and tray 56 to bridge the action of loading the bottle into the tray and the opening of the discharge orifice . other aspects of this embodiment are the same as those described in fig1 – 19 above . in this embodiment , bottle cap 86 c has a generally flat transverse outer surface 130 c with a recessed thinned area 132 c at its center . adapter 500 has a flat ring 502 with an opening in the middle and four segmented annular ridges 134 c protruding from the ring 502 . the ring 502 of the adapter 500 may have the same serrated periphery 506 as the bottle cap 86 c and the outer circles of the adapter ring and the bottle cap , including the serrated peripheries , typically have the same diameter . when the bottle 22 is seated in the tray 56 , piercing post 420 will go through the opening in the middle of the adapter 500 and puncture the cap 86 c in the thinned area 132 c to permit discharge of the cleanser and venting of the bottle . meanwhile , the bottle cap 86 c presses against the ring 502 of the adapter 500 so that at least a portion of one of the segmented ridges 134 c , which is located to contact valve cover 443 , pushes the valve actuator 440 downward to unseat valve stem 448 from outlet orifice 492 and open the outlet orifice 492 . fig2 depicts a modified bottle cap and an adapter suitable for use with the dispenser of fig1 – 13 . a flat top cap 86 d and a cap liner or gasket 333 are provided with a bottle 22 . other aspects of this embodiment are the same as those described in fig1 – 16 above . in this embodiment , bottle cap 86 d has a generally flat transverse outer surface 130 d with a central hole 132 d at its center . the cap liner 333 , which may be any piercable material such as a soft closed cell polyethylene foam or foil , seals the opening of the bottle 22 and also seals the central hole 132 d of the bottle cap 86 d . in one version of the invention , the cap liner 333 is sealed to the bottle 22 by way of conventional methods such as ultrasonic welding , radio frequency welding or heat sealing . in another version of the invention , the cap liner 333 is positioned between the bottle 22 and the bottle cap 86 d but is not attached to the bottle 22 or the bottle cap 86 d . still referring to fig2 , when the bottle 22 is seated in the tray 56 by movement in direction ‘ d ’, piercing post 98 will go through the opening in the middle of the adapter 300 , through the central hole 132 d of the bottle cap 86 d , and puncture the cap liner 333 to permit discharge of the cleanser and venting of the bottle . the cap liner 333 can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . meanwhile , the bottle cap 86 d presses against the ring 302 of the adapter 300 so that the ring 134 a of the adapter 300 , which is located to contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . fig2 depicts a modified bottle cap and an adapter suitable for use with the dispenser of fig1 – 22 . a flat top cap 86 d and a cap liner or gasket 333 are provided with a bottle 22 as described in fig2 above . other aspects of this embodiment are the same as those described in fig1 – 22 above . in this embodiment , when the bottle 22 is seated in the tray 56 by movement in direction ‘ e ’, the piercing post 420 will go through the opening in the middle of the adapter 500 , through the central hole 132 d of the bottle cap 86 d , and puncture the cap liner 333 to permit discharge of the cleanser and venting of the bottle . the cap liner 333 can provide a compliant seal around the piercing post 420 . this prevents leakage down the sides of the piercing post 420 . meanwhile , the bottle cap 86 d presses against the ring 502 of the adapter 500 so that at least a portion of one of the segmented ridges 134 c , which is located to contact valve cover 443 , pushes the valve actuator 440 downward to unseat valve stem 448 from outlet orifice 492 and open the outlet orifice 492 . fig2 depicts another modified bottle cap and an adapter suitable for use with the dispenser of fig1 – 13 . a cap closure 833 is provided with a bottle 22 . other aspects of this embodiment are the same as those described in fig1 – 16 above . the cap closure 833 , which may be any piercable material such as a closed cell polyethylene foam or foil , seals the opening of the bottle 22 . the cap closure - 833 may be sealed to the bottle 22 by way of conventional methods such as ultrasonic welding , radio frequency welding or heat sealing . optionally , the bottle 22 may be provided with a removable cap ( similar to cap 86 d with no central hole 132 d ) for shipping purposes . when the bottle 22 is seated in the tray 56 by movement in direction ‘ f ’, piercing post 98 will puncture the cap closure 833 to permit discharge of the cleanser and venting of the bottle . the cap closure 833 can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . meanwhile , the cap closure 833 presses against the ring 302 of the adapter 300 so that the ring 134 a of the adapter 300 , which is located to contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . fig2 depicts a modified bottle cap and an adapter suitable for use with the dispenser of fig1 – 22 . a cap closure 833 provided with a bottle 22 as described in fig2 above . other aspects of this embodiment are the same as those described in fig1 – 22 above . the cap closure 833 , which may be any piercable material such as a closed cell polyethylene foam or foil , seals the opening of the bottle 22 . optionally , the bottle 22 may be provided with a removable cap ( similar to cap 86 d with no central hole 132 d ) for shipping purposes . in this embodiment , when the bottle 22 is seated in the tray 56 by movement in direction ‘ g ’, the piercing post 420 will puncture the cap closure 833 to permit discharge of the cleanser and venting of the bottle . the cap closure 833 can provide a compliant seal around the piercing post 420 . this prevents leakage down the sides of the piercing post 420 . meanwhile , the cap closure 833 presses against the ring 502 of the adapter 500 so that at least a portion of one of the segmented ridges 134 c , which is located to contact valve cover 443 , pushes the valve actuator 440 downward to unseat valve stem 448 from outlet orifice 492 and open the outlet orifice 492 . what has been described with respect to fig1 – 13 also provides context for the use of another modified cap and adapter that may be used with the present invention as depicted in fig2 and 28 . a flat top cap 86 d is provided with a bottle 22 . an adapter 800 is employed between the bottle cap and tray 56 to bridge the action of loading the bottle into the tray and the opening of the discharge orifice . other aspects of this embodiment are the same as those described in fig1 – 13 and 23 above . in this fig2 embodiment , bottle cap 86 d has a generally flat transverse outer surface 130 d with a hole 132 d at its center . adapter 800 is a flat annular ring with an opening in the middle and has a square or rectangular vertical cross - section . when the bottle 22 is seated in the tray 56 by movement in direction ‘ i ’, piercing post 98 will go through the opening in the middle of the adapter 800 , through the central hole 132 d of the bottle cap 86 d , and puncture the cap liner 333 to permit discharge of the cleanser and venting of the bottle . the cap liner 333 can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . meanwhile , the bottle cap 86 d presses against the adapter 800 so that the adapter 800 , which is located to contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . the adapter 800 rests on the floor of the well inward of the stand - offs 124 . the vertical height of the adapter 800 is preferably greater than the height of the stand - offs 124 above the floor of the well 84 . however , the vertical height of the adapter 800 must not be so great as to prevent the piercing post 98 from puncturing the cap liner 333 to permit discharge of the cleanser and venting of the bottle . what has been described with respect to fig1 – 13 also provides context for the use of another modified cap and adapter that may be used with the present invention as depicted in fig2 and 29 . a cap closure 833 is provided with a bottle 22 . an adapter 800 is employed between the bottle cap and tray 56 to bridge the action of loading the bottle into the tray and the opening of the discharge orifice . other aspects of this embodiment are the same as those described in fig1 – 13 and 25 above . the cap closure 833 , which may be any piercable material such as a closed cell polyethylene foam or foil , seals the opening of the bottle 22 . optionally , the bottle 22 may be provided with a removable cap ( similar to cap 86 d with no central hole 132 d ) for shipping purposes . when the bottle 22 is seated in the tray 56 by movement in direction ‘ j ’, piercing post 98 will puncture the cap closure 833 to permit discharge of the cleanser and venting of the bottle . the cap closure 833 can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . meanwhile , the cap closure 833 presses against the adapter 800 so that the adapter 800 , which is located to contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . the adapter 800 rests on the floor of the well inward of the stand - offs 124 . the vertical height of the adapter 800 is preferably greater than the height of the stand - offs 124 above the floor of the well 84 . however , the vertical height of the adapter 800 must not be so great as to prevent the piercing post 98 from puncturing the cap closure 833 to permit discharge of the cleanser and venting of the bottle . what has been described with respect to fig1 – 19 provides context for the use of another embodiment the present invention claimed herein . turning now to fig3 , there is shown another bottle - tray interface according to the invention that may used to deliver cleanser from the bottle 22 to the tube 152 of the dispenser line 154 that extends to the inlet barb 156 of the pump 28 as described above . in fig3 , the cap 86 is as described above with references to fig8 – 11 . referring still to fig3 , the embodiment of a bottle - tray interface is shown after the bottle 22 has been placed in the reservoir tray . the reservoir tray has a well 480 including a circular upper section 484 with a floor 485 and a circular lower chamber 490 extending downwardly from a portion of the floor 485 . the circular upper section 484 of the well 480 has a downwardly extending vent nipple 90 a . a spout 491 extends downwardly from the lower chamber 490 and defines an outlet orifice 492 . a circular piercing post 420 a , which is formed as part of a valve plate 496 , extends upwardly from the floor 485 of the circular upper section 484 of the well 480 . valve plate 496 is secured to the well 480 with screws as described above with reference to valve plate 96 . the piercing post 420 a has an outer wall 421 a , and an inner wall 427 a that defines an air vent path 425 a and a cleanser conduit 428 a in the piercing post 420 a . the air vent path 425 a extends from the top end of the piercing post 420 a to the vent nipple 90 a . the cleanser conduit 428 a provides a fluid flow path to the lower chamber 490 of the well 480 . optionally , an air hole may pass through the outer wall 421 a into the air vent path 425 a , and an opening may pass through the outer wall 421 a into the cleanser conduit 428 a . the piercing post 420 a terminates in an obliquely truncated upper end to facilitate puncturing the cap 86 in the thinned area 132 to permit discharge of the cleanser . the lower chamber 490 of the well 480 contains a valve 438 that controls cleanser flow from the bottle 22 as will be described below . the valve 438 includes a valve actuator 440 and a valve stem 448 . the valve actuator 440 includes a plunger 441 , a valve cover 443 and a rocker 444 . the plunger 441 is biased in the upward direction against the valve cover 443 by a spring 442 as shown in fig1 . the rocker 444 includes a pivot pin 446 , an upper arm 445 and a lower forked arm 447 . the forked arm 447 is seated in a groove 450 in the valve stem 448 . a spring 449 biases the valve stem 448 against the entry to the outlet orifice 492 as shown by the arrow in fig1 . by spring - biasing the valve stem 448 into a normally closed seated position that seals the outlet orifice 492 of the lower chamber 490 of the well 480 , any downward pressure exerted on the valve stem 448 ( such as sucking by the pump , downward fluid pressure , or gravity ) merely keeps the valve stem 448 seated ( absent downward movement of the plunger 441 as described below ). still referring to fig3 , the bottle - tray interface is shown after the bottle 22 has been placed in the reservoir tray . when the bottle 22 is placed in the tray , circular gasket 577 ( which may be formed from suitable conventional gasket materials ) provides a seal between the piercing post 420 a and the surface 130 of the cap 86 . this prevents leakage down the sides of the piercing post 420 a . also , when the bottle 22 is placed in the tray , raised ring surface 134 of the cap 86 contacts the valve cover 433 thereby moving the plunger 441 downward in the direction shown in fig3 . when the plunger 441 moves downward , the upper arm 445 of the rocker 444 pivots the lower forked arm 447 in an upward direction thereby moving the valve stem 448 in the upward direction shown in fig3 . this unseats the valve stem 448 from the entry to the outlet orifice 492 as shown in fig3 . a cleanser flow path is then created from the bottle 22 , through the cleanser conduit 428 a of the piercing post 420 a , into the lower chamber 490 of the well 480 , through the outlet orifice 492 , and into the first tube 152 of the dispenser line 154 that extends to the inlet barb 156 of the pump 28 as described above . delivery of the cleanser from the spray nozzle 202 then occurs using the mechanisms , circuits , and processes described above . still referring to fig3 , the short vent tube 144 described above with reference to fig2 b – 6 couples to the vent nipple 90 a defining the vent orifice in the tray well . a small check valve 148 fits into the end of the vent tube 144 as described above . the check valve 148 is normally closed so that cleanser does not leak out via the air vent path 425 a , the vent nipple 90 a and the vent tube 144 . the check valve 148 opens by negative pressure that develops as cleanser is withdrawn from the bottle via cleanser conduit 428 a . the opened check valve 148 aspirates the air to the bottle through the vent tube 144 , the vent nipple 90 a and the air vent path 425 a to allow the cleanser to flow from the bottle in a consistent manner , without introducing air in a manner that would cause foaming or gurgling . the check valve 148 remains open until the pressure in the bottle has equalized sufficiently to alleviate the negative pressure and then it closes . fig3 depicts a modified bottle cap 86 e suitable for use with the dispenser of fig1 – 13 and 30 . a bottle cap 86 e and a cap liner or gasket 333 are provided with a bottle 22 . other aspects of this embodiment are the same as those described in fig1 – 16 above . the top of the bottle cap 86 e has an outer surface 130 e with a central hole 132 e at its center around which is a raised ring surface 134 e extending to a plane spaced from surface 130 e . the central hole 132 e is located so that as the bottle is seated in the tray the piercing post will go through this area to permit discharge of the cleanser and venting of the bottle . the raised ring 134 e is located to contact the plunger of the valve and push the valve downward to unseat the gasket from the plate and open the discharge orifice . still referring to fig3 , the flat surface 130 e of the cap rests on the stand - offs 124 to space the punctured area from the floor of the well . the cap liner 333 , which may be any piercable material such as a closed cell polyethylene foam or foil , seals the opening of the bottle 22 and also seals the central hole 132 e of the bottle cap 86 e . in one version of the invention , the cap liner 333 is sealed to the bottle 22 by way of conventional methods such as ultrasonic welding , radio frequency welding or heat sealing . in another version of the invention , the cap liner 333 is positioned between the bottle 22 and the bottle cap 86 e but is not attached to the bottle 22 or the bottle cap 86 e . still referring to fig3 , when the bottle 22 is seated in the tray 56 by movement in direction ‘ r ’, piercing post 98 will go through the central hole 132 e of the bottle cap 86 e , and puncture the cap liner 333 to permit discharge of the cleanser and venting of the bottle . the cap liner 333 can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . meanwhile , the raised ring 134 e of the bottle cap 86 e presses the contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . in order to facilitate movement of the piercing post 98 through the central hole 132 e of the bottle cap 86 e , the central hole 132 e has a chamfered inner surface 133 . in this configuration , the central hole 132 e is frustoconical with a larger diameter near the surface 130 e of the bottle cap 86 e as shown in fig3 . accordingly , the central hole 132 e has a smaller diameter near the cap liner 333 . the larger diameter near the surface 130 e of the bottle cap 86 e provides a guide means for ensuring that the piercing post 98 will go through the central hole 132 e of the bottle cap 86 e in the event that the piercing post 98 is off center with respect to the central hole 132 e when the bottle 22 is being placed in the tray . this central hole configuration may be used with any bottle cap described herein . fig3 depicts another modified bottle cap 86 f suitable for use with the dispenser of fig1 – 13 and 30 . a bottle cap 86 f and a cap liner or gasket 333 are provided with a bottle 22 . other aspects of this embodiment are the same as those described in fig1 – 16 above . the bottle cap 86 f has a raised cylindrical inlet conduit 133 f having a piercable area 132 f at its center around which is a raised ring surface 134 f extending to a plane spaced from surface 130 f . the piercable area 132 f is located so that as the bottle is seated in the tray the piercing post 98 will puncture the cap 96 f in this area to permit discharge of the cleanser and venting of the bottle . the raised ring 134 f is located to contact the plunger of the valve and push the valve downward to unseat the gasket from the plate and open the discharge orifice . still referring to fig3 , the flat surface 130 f of the cap rests on the stand - offs 124 to space the punctured area from the floor of the well . the cap liner 333 , which may be any piercable material such as a closed cell polyethylene foam or foil , seals the opening of the bottle 22 and also seals the cylindrical inlet conduit 133 f of the bottle cap 86 f . in one version of the invention , the cap liner 333 is sealed to the bottle 22 by way of conventional methods such as ultrasonic welding , radio frequency welding or heat sealing . in another version of the invention , the cap liner 333 is positioned between the bottle 22 and the bottle cap 86 e but is not attached to the bottle 22 or the bottle cap 86 f . still referring to fig3 , when the bottle 22 is seated in the tray 56 by movement in direction ‘ s ’, piercing post 98 will puncture the piercable area 132 f of the bottle cap 86 f , and puncture the cap liner 333 to permit discharge of the cleanser and venting of the bottle . the cap liner 333 can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . the cylindrical inlet conduit 133 f is configured in a raised arrangement from the bottle cap surface 130 f as described above in order to provide clearance for the chad 299 ( drawn in phantom in fig3 ) that may remain attached to the cylindrical inlet conduit 133 f after puncturing the piercable area 132 f . meanwhile , the raised ring 134 f of the bottle cap 86 f presses the contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . fig3 depicts another modified bottle cap 86 g suitable for use with the dispenser of fig1 – 13 and 30 . a bottle cap 86 g and a cap liner or gasket 333 a are provided with a bottle 22 . other aspects of this embodiment are the same as those described in fig1 – 16 above . the bottle cap 86 g has a raised cylindrical inlet conduit 133 g having a piercable area 132 g at its center around which is a raised ring surface 134 g extending to a plane spaced from surface 130 g . the piercable area 132 g is located so that as the bottle is seated in the tray the piercing post 98 will puncture the cap 96 g in this area to permit discharge of the cleanser and venting of the bottle . the raised ring 134 g is located to contact the plunger of the valve and push the valve downward to unseat the gasket from the plate and open the discharge orifice . the flat surface 130 g of the cap rests on the stand - offs 124 to space the punctured area from the floor of the well . still referring to fig3 , the cap liner 333 a , which may be any piercable material such as a closed cell polyethylene foam or foil , includes a central opening 399 spaced away from the cap liner surface 599 by frustoconical wall 499 . in one version of the invention , the cap liner 333 a is sealed to the bottle 22 by way of conventional methods such as ultrasonic welding , radio frequency welding or heat sealing . in another version of the invention , the cap liner 333 a is positioned between the bottle 22 and the bottle cap 86 g but is not attached to the bottle 22 or the bottle cap 86 g . still referring to fig3 , when the bottle 22 is seated in the tray 56 by movement in direction ‘ t ’, piercing post 98 will puncture the piercable area 132 g of the bottle cap 86 g , and go through the central opening 399 of the cap liner 333 a to permit discharge of the cleanser and venting of the bottle . the cap liner 333 a can provide a compliant seal around the piercing post 98 . this prevents leakage down the sides of the piercing post 98 . the cylindrical inlet conduit 133 g is configured in a raised arrangement from the bottle cap surface 130 g as described above in order to provide clearance for the chad 299 a ( drawn in phantom in fig3 ) that may remain attached to the cylindrical inlet conduit 133 g after puncturing the piercable area 132 g . meanwhile , the raised ring 134 g of the bottle cap 86 g presses - the contact plunger 114 , pushes the valve downward to unseat gasket 118 from valve plate 96 and open the discharge orifice . turning now to fig3 a , there is shown an alternative valve plate 496 a suitable for use with the invention of fig3 . the valve plate 496 a includes a circular piercing post 511 a ( which extends upwardly from the floor 485 of the circular upper section 484 of the well 480 when installed in the well 480 in the manner shown in fig3 ). the valve plate 496 a is secured to the well 480 with screws as described above with reference to valve plate 96 . in particular , mounting holes 515 a are provided to accept screws that attach the valve plate 496 a to the well 480 as shown in fig3 and described above with reference to screws 97 in fig3 . access hole 517 a is also provided to accept plunger 441 and valve cover 443 as shown in fig3 . the piercing post 511 a has an outer wall 521 a , and an inner wall 527 a that defines an air vent path 525 a and a cleanser conduit 528 a in the piercing post 511 a . the air vent path 525 a extends from the top end of the piercing post 511 a to the vent nipple 90 a which is shown in fig3 . the cleanser conduit 528 a provides a fluid flow path to the lower chamber 490 of the well 480 as shown in fig3 . still referring to fig3 a , the cleanser conduit 528 a terminates at an opening 541 a of the piercing post 511 a , and the air vent path 525 a terminates at another opening 543 a of the piercing post 511 a . the opening 543 a of the air vent path 525 a is at a position above the opening 541 a of the cleanser conduit 528 a . in particular , the outer wall 521 a of the piercing post 511 a is lower at the side of the piercing post 511 a nearest the cleanser conduit 528 a . because of this arrangement , the opening 543 a of the air vent path 525 a is at a position further into the bottle than the opening 541 a of the cleanser conduit 528 a when the bottle is installed in the inverted orientation in the tray . as a result , the mixing of the air flow from the air vent path 525 a into the liquid cleanser flow in the cleanser conduit 528 a is controlled to avoid levels of mixing of the air flow into the liquid flow that prevents appropriate dispensing of the liquid cleanser . in other words , the short circuiting of vent air into the liquid flow is reduced . turning now to fig3 b , there is shown an alternative valve plate 496 b suitable for use with the invention of fig3 . the valve plate 496 b includes a circular piercing post 511 b ( which extends upwardly from the floor 485 of the circular upper section 484 of the well 480 when installed in the well 480 in the manner shown in fig3 ). the valve plate 496 b is secured to the well 480 with screws as described above with reference to valve plate 96 . in particular , mounting holes 515 b are provided to accept screws that attach the valve plate 496 b to the well 480 as shown in fig3 and described above with reference to screws 97 in fig3 . access hole 517 b is also provided to accept plunger 441 and valve cover 443 as shown in fig3 . the piercing post 511 b has an outer wall 521 b , and an inner wall 527 b that defines an air vent path 525 b and a cleanser conduit 528 b in the piercing post 511 b . the air vent path 525 b extends from the top end of the piercing post 511 b to the vent nipple 90 a which is shown in fig3 . the cleanser conduit 528 b provides a fluid flow path to the lower chamber 490 of the well 480 as shown in fig3 . referring still to fig3 b , the cleanser conduit 528 b terminates at an opening 541 b of the piercing post 511 b , and the air vent path 525 b terminates at another opening 543 b of the piercing post 511 b . the opening 543 b of the air vent path 525 b is at a position above the opening 541 b of the cleanser conduit 528 b . also , the opening 541 b of the cleanser conduit 528 b extends into the outer wall 521 b of the piercing post 511 b at the side of the piercing post 511 b nearest the cleanser conduit 528 b . because of this arrangement , the opening 543 b of the air vent path 525 b is at a position further into the bottle than the opening 541 b of the cleanser conduit 528 b when the bottle is installed in the inverted orientation in the tray . as a result , the mixing of the air flow from the air vent path 525 b into the liquid cleanser flow in the cleanser conduit 528 b is controlled to avoid levels of mixing of the air flow into the liquid flow that prevents appropriate dispensing of the liquid cleanser . in other words , the short circuiting of vent air into the liquid flow is reduced . turning now to fig3 c , there is shown an alternative valve plate 496 c suitable for use with the invention of fig3 . the valve plate 496 c includes a circular piercing post 511 c ( which extends upwardly from the floor 485 of the circular upper section 484 of the well 480 when installed in the well 480 in the manner shown in fig3 ). the valve plate 496 c is secured to the well 480 with screws as described above with reference to valve plate 96 . in particular , mounting holes 515 c are provided to accept screws that attach the valve plate 496 c to the well 480 as shown in fig3 and described above with reference to screws 97 in fig3 . access hole 517 c is also provided to accept plunger 441 and valve cover 443 as shown in fig3 . the piercing post 511 c has an outer wall 521 c , and an inner wall 527 c that defines an air vent path 525 c and a cleanser conduit 528 c in the piercing post 511 c . the air vent path 525 c extends from the top end of the piercing post 511 c to the vent nipple 90 a which is shown in fig3 . the cleanser conduit 528 c provides a fluid flow path to the lower chamber 490 of the well 480 as shown in fig3 . still referring to fig3 c , the cleanser conduit 528 c terminates at an opening 541 c of the piercing post 511 c , and the air vent path 525 c terminates at another opening 543 c of the piercing post 511 c . the opening 543 c of the air vent path 525 c is at a position above the opening 541 c of the cleanser conduit 528 c . also , the opening 541 c of the cleanser conduit 528 c extends into the outer wall 521 c of the piercing post 511 b at the side of the piercing post 511 c nearest the cleanser conduit 528 c . furthermore , the inner wall 527 c in the piercing post 511 c extends outward from the piercing post 511 c between the opening 543 c of the air vent path 525 c and the opening 541 c of the cleanser conduit 528 c . because of this arrangement , the opening 543 c of the air vent path 525 c is at a position further into the bottle than the opening 541 c of the cleanser conduit 528 c when the bottle is installed in the inverted orientation in the tray . as a result , the mixing of the air flow from the air vent path 525 c into the liquid cleanser flow in the cleanser conduit 528 c is controlled to avoid levels of mixing of the air flow into the liquid flow that prevents appropriate dispensing of the liquid cleanser . also , the extended inner wall 527 c in the piercing post 511 c between the opening 543 c of the air vent path 525 c and the opening 541 c of the cleanser conduit 528 c further serves to block the mixing of the air flow into the liquid cleanser flow . in other words , the short circuiting of vent air into the liquid flow is reduced . turning now to fig3 d , there is shown an alternative valve plate 496 d suitable for use with the invention of fig3 . the valve plate 496 d includes a circular piercing post 511 d ( which extends upwardly from the floor 485 of the circular upper section 484 of the well 480 when installed in the well 480 in the manner shown in fig3 ). the valve plate 496 d is secured to the well 480 with screws as described above with reference to valve plate 96 . in particular , mounting holes 515 d are provided to accept screws that attach the valve plate 496 d to the well 480 as shown in fig3 and described above with reference to screws 97 in fig3 . access hole 517 d is also provided to accept plunger 441 and valve cover 443 as shown in fig3 . the piercing post 511 d has an outer wall 521 d , and an inner wall 527 d that defines an air vent path 525 d and a cleanser conduit 528 d in the piercing post 511 d . the air vent path 525 d extends from the top end of the piercing post 511 d to the vent nipple 90 a which is shown in fig3 . the cleanser conduit 528 d provides a fluid flow path to the lower chamber 490 of the well 480 as shown in fig3 . referring still to fig3 d , the cleanser conduit 528 d terminates at an opening 541 d of the piercing post 511 d , and the air vent path 525 d terminates at another opening 543 d of the piercing post 511 d . the opening 543 d of the air vent path 525 d is at a position above the opening 541 d of the cleanser conduit 528 d when the bottle is installed in the inverted orientation in the tray as described above . also , the opening 541 d of the cleanser conduit 528 d extends into the outer wall 521 d of the piercing post 511 d at the side of the piercing post 511 d nearest the cleanser conduit 528 d . because of this arrangement , the opening 543 d of the air vent path 525 d is at a position further into the bottle than the opening 541 d of the cleanser conduit 528 d when the bottle is installed in the inverted orientation in the tray . as a result , the mixing of the air flow from the air vent path 525 d into the liquid cleanser flow in the cleanser conduit 528 d is controlled to avoid levels of mixing of the air flow into the liquid flow that prevents appropriate dispensing of the liquid cleanser . in other words , the short circuiting of vent air into the liquid flow is reduced . turning now to fig3 e , there is shown an alternative valve plate 496 e suitable for use with the invention of fig3 . the valve plate 496 e includes a circular piercing post 511 e ( which extends upwardly from the floor 485 of the circular upper section 484 of the well 480 when installed in the well 480 in the manner shown in fig3 ). the valve plate 496 e is secured to the well 480 with screws as described above with reference to valve plate 96 . in particular , mounting holes 515 e are provided to accept screws that attach the valve plate 496 e to the well 480 as shown in fig3 and described above with reference to screws 97 in fig3 . access hole 517 e is also provided to accept plunger 441 and valve cover 443 as shown in fig3 . the piercing post 511 e has an outer wall 521 e , and an inner wall 527 e that defines an air vent path 525 e and a cleanser conduit 528 e in the piercing post 511 e . the air vent path 525 e extends from the top end of the piercing post 511 e to the vent nipple 90 a which is shown in fig3 . the cleanser conduit 528 e provides a fluid flow path to the lower chamber 490 of the well 480 as shown in fig3 . still referring to fig3 e , the cleanser conduit 528 e terminates at an opening 541 e of the piercing post 511 e , and the air vent path 525 e terminates at another opening 543 e of the piercing post 511 e . the opening 543 e of the air vent path 525 e is at a position above the opening 541 e of the cleanser conduit 528 e . also , the opening 541 e of the cleanser conduit 528 e extends into the outer wall 521 e of the piercing post 511 e at the side of the piercing post 511 e nearest the cleanser conduit 528 e . furthermore , the inner wall 527 e in the piercing post 511 e extends outward from the piercing post 511 e between the opening 543 e of the air vent path 525 e and the opening 541 e of the cleanser conduit 528 e . the inner wall 527 e terminates in a curved chisel top . because of this arrangement , the opening 543 e of the air vent path 525 e is at a position further into the bottle than the opening 541 e of the cleanser conduit 528 e when the bottle is installed in the inverted orientation in the tray . as a result , the mixing of the air flow from the air vent path 525 e into the liquid cleanser flow in the cleanser conduit 528 e is controlled to avoid levels of mixing of the air flow into the liquid flow that prevents appropriate dispensing of the liquid cleanser . also , the extended inner wall 527 e in the piercing post 511 e between the opening 543 e of the air vent path 525 e and the opening 541 e of the cleanser conduit 528 e further serves to block the mixing of the air flow into the liquid cleanser flow . in other words , the short circuiting of vent air into the liquid flow is reduced . the invention thus provides an automated dispenser that can accept inverted bottles of cleaning fluid and can deliver the fluid from the bottle with improved fluid flow characteristics . in particular , the invention provides for improved air venting of the inverted bottle ( by way of , among other things , the air vent path in the piercing post , the slots in the segmented ridges of the cap , and the air passage created between the bottle and an inner surface of the well ) and provides for improved control of delivery of cleaning fluid from the dispenser ( by way of , among other things , the cleanser conduit in the piercing post and the valve ). it should also be noted that the inventive aspects of the invention could be used to dispense a cleaning or disinfecting solution in applications other than a tub / shower surround . in this regard , u . s . pat . no . 4 , 183 , 105 depicts how one type of automated cleansing equipment could be installed to clean the bowl . the inventors envision an embodiment of their invention designed to mount to the underside of a toilet bowl cover with the supply cleaning fluid being delivered from a reservoir near the tank , and the chemical being sprayed in the bowl . such a structure should be considered to be an “ enclosure ” for purposes of this application . preferred embodiments of the invention have been described in considerable detail above . many modifications and variations to the preferred embodiments will be apparent to those skilled in the art , which will be within the spirit and scope of the invention . therefore , the invention should not be limited to the described embodiments . to ascertain the full scope of the invention , reference should be made to the following claims . the invention provides a sprayer for automatically spraying the walls of bath and shower enclosures and the like .

an automated sprayer for spraying the walls of a shower enclosure with a liquid cleanser dispenses the cleanser using a pump and rotatable spray head . a motor drives the pump and rotates the spray head . the sprayer has a showerhead mountable housing with a hanger . the housing supports a bottle of cleanser in an inverted fashion . cleanser is delivered from the bottle through a cleanser conduit in the piercing post into a well of the housing . the bottle is vented from the well through an air vent path in the piercing post or from a well vent outlet through the air vent path in the piercing post . an outlet valve in the well permits outflow of cleanser from the well . various bottle caps and bottle closures are also provided to improve venting and / or limit cleanser leakage from the bottle when the bottle is installed in the housing .

in the following description , certain terms will be used for brevity , clarity , and understanding , but no unnecessary limitations are to be implied therefrom beyond the requirements of the prior art , because such words are used for description purposes herein and are intended to be broadly construed . furthermore , the embodiments of the system illustrated and described herein are by way of example , and the scope of the invention is not limited to the exact details of construction and use . many other variations are possible with the teachings of the various embodiments . one embodiment of the container holder is illustrated in fig1 - a thru 8 - b . fig2 - a thru 3 - b show the holder as a single structure comprised of a connecting bar ( 44 ) at the opposite ends of which are solid but flexible holder band eye brackets ( 31 ). the bands encircle the container they hold , fig1 - a . depending upon the materials used to create the holder and the material of the container , the interior surface of the holder bands may be coated or of a coarse texture to create sufficient friction to retain the container within the holder ; fig8 - b . in the alternative , such as shown in instant embodiment fig1 - b and 8 - a , inner retaining bands ( 34 ) may be sandwiched between the holder band and the container to create sufficient friction and pressure to retain the container within the holder . to allow for adjustments in the diameter of the container and additional or variable thickness of the inner retaining bands ( 34 ), the holder bands may be cross cut at one location on each band ( 43 ) to allow for contraction and expansion of the bands and or container . in order to create additional contracting pressure of the holder bands around and against the container , an outer retaining band ( 33 ) may be attached around the outer circumference of the holder bands . in certain applications , the bands may be used as additional attachment points for hoses or other devices connected to the container . a connector bar ( 44 ) may , or it may not be utilized ( fig2 - e ), to communicate with or predetermine the distance between the holder bands ( 31 ), as predetermined by the dimensions of the container it is intended to hold . attachment of the holder to a host device or user is by the use of multiple fasteners . a plurality of fasteners ( 36 , 37 , 38 ) are incorporated to attach and control the mobility of the holder and container . although a variety of fasteners may be used , depending upon the intended use and design of the host device or attachment points on the user , the embodiment shown in fig1 - a and b by way of example , shows alternative embodiments of fasteners : fastener “ a ” ( 36 ) and fastener “ b 2 ” ( 37 ). alternatively , fig1 - d shows fasteners “ a ” ( 36 ) and b 1 ( 37 ). fig5 - a and fig6 - a thru c show in detail how fasteners “ a ” ( 36 ) are connected to the holder by a flexible fastener strap ( 35 ). the strap is looped at the point of attachment to the holder around the strap bolt ( 40 ), which is inserted between the eye brackets ( 31 ) and held in place by the strap bold open head ( 41 ) and strap bolt nut ( 42 ). at the opposite end of the strap , connecting fastener “ a ” ( 36 ) to the container holder , the strap is fed directly on to the strap adjuster ( 53 ) component of fastener “ a ” ( 36 ). this is accomplished fig1 - a thru f by threading the fastener strap ( 35 ) through the spaces ( 54 ) and over the cross bars ( 55 ) of each strap adjuster ( 53 ) component of each fastener “ a ” ( 36 ) fasteners “ b 1 ” ( 37 ) or “ b 2 ” ( 38 ), when utilized , are similarly attached to the container holder ( 31 ) as fastener “ a ” ( 36 ), with one modification . inserted between the fastener strap ( 35 ) and the fastener “ b 1 ” ( 37 ) or “ b 2 ” ( 38 ) is a release buckle ( 39 ). fig5 - b & amp ; c detail the method of attachment between the fastener strap ( 35 ) and the respective fastener . the strap ( 35 ) is thread at the appropriate location of the release buckle male component ( 45 ), which is inserted into the release buckle female ( 46 ) component , to which either fastener “ b 1 ” or “ b 2 ” is connected . fig7 a thru 7 f detail the release buckle male ( 45 ) and female ( 46 ) components in both the connected and disconnected configuration . operation : container holder hard embodiment —[ fig1 - a thru 8 - b ] one manner of using the hard embodiment , by way of example only , is for the use of holding a container of backup gas for emergency use by a scuba diver , or to assist a distress diver who has lost access to his own main gas supply . in this example , the diver would install a container of compressed gas within the holder . the containers are available in various sizes , typically for this application : 13 c . ft . or 19 c . ft . the first stage of a gas delivery regulator is attached to the on / of valve of the container . a small pressure gauge may also be attached to allow the diver to monitor the internal gas pressure of the container . located properly , this gauge may be read by the diver / user , while the holder is attached and in use . a hose connects the first stage to the second stage regulator / mouthpiece from which the diver may breath . said hose would be coiled and inserted between the outer retaining bands ( 34 ) bands and the holder band ( 31 ) encircling the container . the second stage regulator and mouthpiece may be attached to the holder , via a mouthpiece holder , attached to a split ring , fed through the strap bolt open head ( 41 ) in this example application , the holder would be situated on the front torso of the diver . fasteners “ a ” ( 36 ) would be attached to commonly found “ d - rings ” on the buoyancy control vest worn by the diver . the elevation of the holder relative to the user &# 39 ; s torso , would be adjusted by straps that are threaded through strap adjuster ( 53 ) component of the fastener “ a ”. if the diver is in a vertical position , fasteners “ b ” would extend from below the holder , connected via the fastener strap ( 35 ), through the quick release buckle ( 39 ). which ever is used , fasteners “ b 1 ” or “ b 2 ” would connect , by straddling waistline belt of the buoyancy control vest of the diver , at locations separated by a distance approximately equal to the length of the connector bar ( 44 ). because of the plurality of attachment points , the holder and container remain in a relatively fixed location on the torso of the diver , regardless of his orientation relative to gravity . with the holder located in front of the diver , emergency use greatly is simplified compared to traditional systems of redundant gas deployment . in the event of loss of gas , the diver simply pulls the second stage regulator from the outer bands and inserts into his mouth , and begins a safe ascent . in the event a distressed diver requires use of the gas supply , the same process is used to hand the regulator to the distress diver , who would be located directly in front . the regulator hose would automatically extend by pulling it from under the outer retaining bands ( 33 ). once stabilized , the safe diver has the option of removing the gas container and holder system , and deploying it on the distressed diver , to allow his unencumbered ascent . this is accomplished by first squeezing the release buckles ( 39 ) to free the lower portion of the holder . thereafter the safe diver disengages fasteners “ a ” from his own “ d - ring ” attachment points to allow their attachment of the holder / container system to the distressed diver . fasteners “ b ” remain with the safe diver as they are not needed by the distressed diver , whose immediate intent would be to surface in the vertical position . a group of alternative embodiment of the container holder is illustrated in fig9 - a thru 11 - d . fig9 - a shows one embodiment , that incorporates fastener straps ( 35 ) that attach to either end and encircle a connecting sleeve , ( 47 ) that may be made of flexible synthetic or fabric - like material . if required to create additional contracting pressure around the container , outer retaining bands ( 33 ) may be employed around the outer circumference of the sleeve ( 47 ). in certain applications , the bands may be used as additional attachment points for hoses or other devices connected to the container . the length of the sleeve and the distance between the stretch bands is predetermined by the dimensions of the container the holder is intended to hold . attachment of the holder to a host device or user is by the use of a plurality of fasteners , similar to the hard embodiment described hereinabove , and illustrated in fig1 thru 8 - a . therein a plurality of fasteners is used to attach and control the mobility of the holder and container relative to the user or host . furthermore , based upon the soft embodiment configuration , a variety of alternative embodiments are conceived , the suitability of which is determined by the intended application . by way of example , fig1 - c & amp ; d shows the soft embodiment without the use of the outer retaining bands . alternatively , fig1 - e & amp ; f shows the soft embodiment with the outer retaining bands ( 33 ), but without the sleeve . alternatively , fig1 - g & amp ; h show the soft embodiment incorporating use of the fastener bands ( 35 ) only , eliminating both the outer retaining bands ( 33 ) and the sleeve ( 47 ). additional alternative embodiments are shown in fig1 - a and c wherein a connector band ( 48 ) is utilized in embodiments using outer retaining bands fig1 - a and do not fig1 - c . the manner of using the alternate embodiments , by way of example only , may be for holding a container of refreshment fluids for a hiker , back packer , climber or cyclist . the beneficial attributes of the soft embodiment are many and include light weight , low manufacturing cost and compressibility of size for storage or transport , while retaining all the functional attributes of the hard embodiment . one example application of the soft embodiment is the backpacker or hiker where drinking fluids that add considerable weight to the backpackers load carrying requirements . carrying the fluids , hands free in the area of the front torso , where it is more readily accessed would offer better distribution of the total carrying weight . reduced weight together with its superior distribution increases hiker safety , as does increased control of the container mobility while climbing or traversing spaces that place the hiker in positions other that upright . cyclists would receive similar benefits from the soft embodiments , where drinking fluids may be easily configured from the torso , with hands free use and instant accessibility , as opposed to “ one armed cycling ” while accessing and drinking from a container attached to the cycle . the instant soft embodiment provides all these attributes , including a highly compact , and storable configuration when not it use . because of the plurality of attachment points and options , the holder and container is fixable in a variety of locations suitable to the user for his intended purpose . in the following description , certain terms will be used for brevity , clarity , and understanding , but no unnecessary limitations are to be implied therefrom beyond the requirements of the prior art , because such words are used for description purposes herein and are intended to be broadly construed . furthermore , the embodiments of the system illustrated and described herein are by way of example , and the scope of the invention is not limited to the exact details of construction and use . many other variations are possible with the teachings of the various embodiments . each embodiment of fastener “ a ” is comprised of connecting components ( 51 , 53 ) and a point of free or limited articulation ( 52 ) between them . the snap / clip / hook / bolt assembly ( 51 ) is connected to the strap connector adjuster ( 53 ), through a variety of articulation types ( 52 ) as determined by the intended use or application . similarly , the materials of which each component is made are determined by the intended use and are not limited to metals , plastics , carbons , synthetics or any other suitable material . the materials chosen for each element may , but need not be , the same . each may be chosen for the specific qualities required by the intended use . the first aspect of fastener “ a ” is the snap / clip / hook / bolt assembly ( 51 ) is commonly the point of attachment to a user or host device . this assembly may be any appropriate design , as dictated by the intended use . types commonly used , by way of example and without limitation include , slide bolts , spring clips , pin clips and butterfly snaps the instant embodiment incorporates the use of a “ butterfly slide bolt ” ( 51 ). the second aspect of fastener “ a ” is the strap connector adjuster ( 53 ), wherein a flexible strap may be attached . the spaces ( 54 ) of the strap connector adjuster ( 53 ) are rectangular , as created by the straightness of the cross bars ( 55 ). a flexible strap is attached fig4 - a and 5 - a by threading it through the spaces ( 54 ) and over and or under the cross bars ( 55 ), the shape of the cross bars ( 55 ) and remaining structure of the strap connector adjuster ( 53 ) may be anything suitable to the task , included circular fig1 - a thru c or rectangular fig1 - d thru f or any other shaped desired . customarily , the spaces ( 54 ) would be large enough to accommodate a double passing of the webbing or strap . the straight cross bar ( 55 ) and rectangular shape of the space ( 54 ) distributes the strap load across the full width of each cross bar ( 55 ). this decreases wear and slippage , increases durability and security of the attachment the third aspect of fastener “ a ” is the point of articulation ( 52 ) between the snap / clip / hook / bolt assembly ( 51 ) and the strap connector adjuster ( 53 ). said articulation may be pivotal / rotational fig1 - a , b , d , e , swingable fig1 - g , or fixed fig1 - c , as dictated by the intended use of the device . the following manner of using fastener “ a ” is by way of example only , with no intended limitation . fastener “ a ” increases reliability and simplicity of use wherever a strap or web must be attached to a snap , clip , hook or bolt . the design decreases wear and tear on the strap or webbing to which it is attached . it increases the ease and security of the attachment and adjustment of the strap to the snap , clip , hook or bolt . it eliminates the purchase and use of a separate strap adjuster . fasteners of this typed include but are not limited to snap devices that terminate on the “ strap ” end with a “ u ” shaped point of attachment , often called an “ eye ”. in the event the material attached is a rope , this “ eye ” may be satisfactory . but where the material to be attached is flat , i . e . ; a strap or webbing , the webbing becomes bunched at the bottom of the “ u ” shape . the bunching up of the material increases the rate of wear and likelihood of failure . this occurs in part because the surface pressure of the strap material upon the snap device is not evenly distributed . this not only increase wear and decreases reliability , it also requires the use of a second device , a “ strap adjuster ” to secure and adjust the strap relative to the snap device and prevent its slippage , mal - adjustment or release . the strap adjuster is a separate , second device that is required by the deficiency of common fastener design . it requires additional cost to the use , is more complex to use and more prone to mal - adjustment and slippage . operation of the instant embodiment demonstrates the superiority of the applicant &# 39 ; s design . the design of the fastener , at the point of its attachment to the strap , is optimized for the wear and stress loads of the strap or webbing in all the following ways . first , by assuring the strap distributes its load evenly over the entire surface of the fastener , the pressure per square inch is significantly reduced . wear is distributed evenly across all surfaces . secondly , by distributing the load over three or more cross bar ( 55 ) surfaces , the load per square inch is reduced proportionally . in contrast , where the strap adjuster is separate from the snap device , said adjuster cannot carry any of the load of the strap or help transfer that load directly to the snap device . in this common arrangement , its work is limited to adjustment and not to transferring the load from the strap to the snap device . wherein , fastener “ a ”, the material strength of the strap adjuster works not only to adjust the strap length , but also to transfer the entire strap load directly to the fastener . in the following description of fasteners “ b 1 ” and “ b 2 ”, certain terms will be used for brevity , clarity , and understanding , but no unnecessary limitations are to be implied therefrom beyond the requirements of the prior art , because such words are used for description purposes herein and are intended to be broadly construed . furthermore , the embodiments of the system illustrated and described herein are by way of example , and the scope of the invention is not limited to the exact details of construction and use . many other variations are possible with the teachings of the various embodiments . fastener “ b 1 ” is one “ b ” embodiment , expressed in this application , as shown in fig1 a thru f . fastener “ b 1 ” has a plurality of points of attachment for hooks , snap devices , clips and bolts : the d - ring ( 61 ), g - ring ( 62 ), and one point of attachment for webbing ; the space between the clam shell top ( 72 ) and the clam shell bottom ( 73 ) and the teeth ( 74 ) that protrude from each interior side of clam shell halves . fastener “ b 1 ” is easily attached to webbing by feeding it through the space between the clam shell top ( 72 ) and the thumb latch ( 68 ), until the webbing is seated flat , between the respective teeth ( 74 ) of the upper and lower half of the clam shell ( 72 , 73 ). once seated , the clam shell may be closed , by engaging the following simultaneous actions . the thumb latch ( 68 ) must be depressed and pulled backward by applying thumb pressure to the thumb latch ridges ( 71 ). the user must simultaneously squeeze the clam shell halves together until the open end lip of the clam shell top ( 42 ) is situated under the thumb latch lip ( 69 ). fig1 - a shows fastener “ b 1 ” in the open position . fig1 - b shows fastener “ b 1 ” in the closed position . to open fastener “ b 1 ” and release the webbing , the above procedure is reversed . the thumb latch ( 68 ) rises from its base , situated between the clam shell halves ( 72 , 73 ), which includes the d - ring ( 61 ) that extends from the clam shell top ( 72 ) and g - ring ( 62 ) attachment points , over which it curves . the thumb latch ( 68 ) provides three important functions . a ) to facilitate the closing of the clam shell ; b ) to facilitate the opening of the same , and c ) to create protection and cover for the g - ring ( 62 ) under adverse conditions . the d - ring ( 61 ) extends perpendicular to the direction of threading of the host webbing and serves a similar function as commonly used “ d - rings ”. this half circle extension allows for the attachment of additional devices via use of commonly designed snap devices . the g - ring ( 62 ) also extends perpendicular to the direction of the threading of the host webbing . unlike the commonly designed d - ring , the g - ring ( 62 ) provides a unique point for the direct attachment of snap devices , buckles , slides , glides , strap adjuster and similar devices that are customarily attach via webbing , that must in turn attached to a snap device in order for it to attach to a d - ring . the unique function of the g - ring ( 62 ) provides a direct attachment of said snap device , but without the need for an intermediary strap or additional connecting hardware . every additional strap or connecting device is a potential point of failure . it is also an additional cost in economics and complexity . the g - ring eliminates all that , by facilitating the direct attachment at the point customarily dedicated to a strap or web . the g - ring ( 62 ) has a connective shape extends that is roughly the equivalent of an upside down letter “ g ” and extends from the clam shell bottom ( 73 ). it includes three g - ring flex points ( 63 , 64 , 65 ), an access point ( 66 ) through which an appropriately designed snap device may pass , to become connected . the access point corners ( 67 ) are rounded to facilitated the insertion and removal of any connected device , as described herein . the upper and lower teeth ( 74 ) of fastener “ b 1 ” are of varying length and width , to accommodate both the insertion of the webbing within the fastener , and to facilitate its secure attachment to the webbing . alternative embodiments of the teeth , within the fastener “ b ” may facilitate movement or adjustment of fastener “ b ” along the length of the inserted webbing , pursuant to the intended use . operation : fastener “ b 1 ” [ fig1 - a thru f ] the manner of using fastener “ b 1 ” is multiple and varied . the “ d ” attachment point may be utilized , with our without the “ g ” attachment point and vice versa fig1 - a & amp ; b . furthermore , snap devices of standard design are attachable to the d - ring attachment point of the fastener “ b 1 ” the manner of using the g - ring attachment point is diverse with many creative options . fig1 - a thru e show a variety of standard snap devices that were originally designed to attach to webbing , but are instead attached directly to fastener “ b 1 ”. in the current embodiment , a form of quick release is shown as part of the design . attached to the g - ring of fastener “ b 1 ” is side release buckle fig7 - a thru f . fig5 - b shows fastener “ b 1 ” ( 37 ) attached directly to the female component ( 46 ) via the g - ring ( 62 ). the male component ( 45 ) of the side release buckle is attached to the fastener strap ( 35 ) arriving from the holder . in use , this arrangement allows for the immediate release and removal of the container holder from the waistline webbing / belt of the user , in the example embodiment given hereinabove . use of the d - ring ( 61 ) and g - ring ( 62 ) is independent . some devices may utilize both attachment points simultaneously together . one example of this dual use utilization incorporates a coiled lanyard , with one end attached to the “ d ” via snap device for permanence , with the opposite end of the lanyard attached both to the tool or accessory , and to the male component of side release buckle , the female component is attached directly to the g - ring . this configuration allows for the quick release of the tool from the fastener , while the lanyard , still attached firmly to the “ d ” is stretched during tool use . the tool is immediately useable , but if dropped , is not lost because of its continued attachment to the d - ring via the lanyard . the application of fastener “ b 2 ” is identical in all aspects described hereinabove to “ b 1 ” as they pertain to the d - ring ( 61 ) and g - ring ( 62 ). however , fastener “ b 2 ” provides an alternate method of attaching the fastener to the host web or belt . unlike the “ b 1 ” where the host web is fed between the halves of the clam shell , the “ b 2 ” incorporates an “ over , under , over ” threading of the host webbing across the base platform of the fastener . fig1 - a thru e show outer fingers ( 81 ) bracketing a center strut ( 80 ) above which extends the d - ring ( 61 ) and to which at one end is attached the g - ring ( 62 ). at the opposite end of the center strut ( 80 ) are to outer finger flex points ( 82 ). located at the opposite end of the outer fingers ( 81 ) is a outer finger insertion point ( 83 ). the space separates the outer fingers ( 81 ) from the g - ring ( 62 ) and allows for the insertion of the webbing so that it arrives over the top of each outer finger ( 81 ) and extends under the center strut ( 80 ). the center strut ( 80 ) includes small teeth ( 84 ) on the underside . when the host webbing or belt is thread through the fastener using the “ over , under , over ” configuration , the teeth will prove additional grip , to inhibit movement along the length of the webbing . an alternative embodiment may allow the teeth to be eliminated . this will facilitate movement of the fastener along the length of the webbing , if the intended use requires . while the description herein contains many specificities , these should not be construed as limitations on the scope of any embodiment , but as exemplifications of alternative embodiments thereof . many other ramifications and variations are possible with the teachings of the various embodiments . operation : fastener “ b 2 ” [ fig1 a thru g ] the operation of alternative embodiment fastener “ b 2 ” resembles all those described about the “ b 1 ” embodiment , herein . both embodiments are equally applicable , with no preference except that which is indicated by the needs and requirements of the intended use . many other variations are possible with the teachings of the various embodiments as each offers an alternative set of advantages and anticipated uses . some embodiments present greater structural strength , to accommodate holding greater weight or reliability under extreme environmental conditions . other embodiments reduce structural strength to reap a lighter weight , a more pliable shape or other important configuration options . by varying the types of fasteners used , whether “ a and a ”, “ b and b ” or “ a and b ” the variety of uses and types of attachment options to host devices or users , expands greatly . additional considerations include a ) the weight of the container b ) the weight of its contents , c ) the viscosity of the contents d ) the environment or special user conditions ( such as the user being in motion ) in which the container contents may be accessed . from the description and illustration of each embodiment of each component hereinabove , numerous advantages become evident : a . is scalable to accommodate containers of different sizes and shapes b . is adaptable in structure and the materials from which it is manufactured — from minimally to highly flexible materials , as dictated by the requirements of its application . c . may be fabricated from a vast array of materials including metals , plastics , synthetics , rubbers , carbons , composites as well as an array of natural and synthetic fabrics . d . in both its hard and soft embodiments , is functional without the use of latches , buckles or other devices that may fail and are costly to manufacturer , in order to retain the container within the holder . e . its soft embodiments offer the advantage of lighter weight , reduced manufacturing costs , easy adaptability to a variety of shapes and sizes and the ability to fold or role the holder with it fasteners into a compact size for storage . f . depending upon the fasteners chosen , may be utilized in any position , relative to gravity , with and without the option of fast release and redeployment . a . provides the choice of snap device assembly , pursuant to the needs and specifications of the intended use . b . provides a strap connector adjuster that is scalable and incorporable into every choice of snap device assembly . c . is scalable to any dimension , size and load bearing capacity . d . is scalable in the number of “ spaces and cross bars ”. e . may be fabricated from a vast array of materials either uniformly throughout or in mixed combination . a . in either embodiment , “ b 1 ” or “ b2 ” is installable upon the host webbing at the location of use , by simple threading “ over and under ”, or “ through ” as required and does not require disassembly and or reassembly of the web or strap for installation . b . integrated d - ring attachment point provides all the benefits of a standard d - ring , but with greater ease of installation . c . integrated g - ring provides a direct point of attachment for a vast array of both standard and customized snap devices , without the need for any intermediary strap , web , or additional attachment device . d . integrated g - ring and d - ring attachment points may be utilized independently or jointly as determined by the intended use , effectively doubling the opportunities for utilization . e . the clam shell arrangement of embodiment “ b 1 ” i . incorporates a thumb latch to provide three functions ; 1 ) the opening and 2 ) closing of the upper half of the clam shell to secure the host webbing within the fastener , and 3 ) create a protective cover for the “ g - ring attachment point under adverse conditions . ii . provides strength and reliability and secure attachment to the host webbing pursuant to the clam shell top and bottom contiguous material design . f . the over , under , over arrangement of embodiment “ b 2 ” i . provides a simpler , lighter weight design that is ii . easier to install on host webbing of greater variation in thickness . accordingly the reader will see that , many variations are possible with the teachings of the various embodiments . each offers an alternative set of advantages and anticipated uses . some embodiments present greater structural strength and usefulness in extreme environments . other embodiments reap lighter weight , a more pliable shape , greater options in configuration and more compact storage . similarly , fastener configuration expands the variety of uses and types of attachments to which the container holder system by be attached , used , transported and redeployed . in accordance with each embodiment of each component ; container holder , fasteners “ a ” and “ b ”, the applicant provides a quantum improvement in the design of holders and fasteners for attaching , using and deploying containers and / or other accessories , that is simple , inexpensive and easy to use . while the above description contains many specificities , these should not be construed as limitations on the scope of any embodiment , but as exemplifications of the embodiments described thereof . many other ramifications and variations are possible with the teachings of the various embodiments . thus the scope of the invention should be determined by the appended claims and their legal equivalents , and not by the examples given .

one design embodiment of a holder for a container comprising : one or more bands each capable of retaining a container inside the band , with straps attached to and extending away from the exterior of the band ; with fasteners on the ends of each strap such that container within the band or bands are held in a stable position relative to a harness to be worn by a user . the design embodiment allows easy attachment , use and deployment of containers in a variety of environmental conditions and situational uses , including but not limited to the carrying of gas supplies for underwater divers .

referring to fig1 through 5 , wherein like reference numerals refer to like components in the various views , there is illustrated therein a new and improved apparatus for destemming and vegetative shredding referred to a destemmer hereafter ), generally denominated 100 herein . fig1 illustrates a first preferred embodiment of the inventive destemmer 100 . this view shows that the inventive apparatus generally comprises a cabinet 110 with a waste chute 125 and a cylindrical shredding drum 130 . the cabinet is a substantially cuboid box , having a front side 112 , a left side 114 , a right side 116 , a bottom side 118 ( or base ) for placement on a floor or ground , a top side 120 , and a back side 122 . the waste chute 125 may empty on any side of the cabinet . the top of the cabinet is open , with the tops of the left and right sides each having a semicircular or arcuate cutout 140 to accommodate the curved surface of the shredding drum 130 . the shredding drum is preferably fabricated from a sheet metal , stainless steel , ideally , and having a plurality of axially oriented perforations or slots 150 formed during manufacture by a process of laser cutting . these laser cut slots 150 allow the vegetative portion of a crop 160 to protrude through the slots 150 as the drum is rolled and centrifugal force acts on the crop material to pull it outwardly from the axis of rotation . as an alternative , the slots may be circumferentially oriented , or they may comprise the opening formed in a mesh or wire screen - type cylindrical shredding drum ( as shown in fig4 a ), and the wire or mesh pattern may consist of any of a number of suitable forms , including wires disposed principally circumferentially and thereby defining the outside wall of the cylinder with a suitable number of wires running transversely ( i . e ., from one end of the drum to the other ) and welded to the circumferentially disposed wires in a sufficiently sturdy configuration ; or wires disposed principally transversely ( i . e ., from one end of the cylinder to the other ) with a suitable number of wires running circumferentially and welded to the transversely disposed wires in a sufficiently sturdy configuration . it will be noted that the cabinet 110 includes spindle or axle holes 170 cut into the cabinet sides and through which roller spindles or axles protrude . fig2 is a cross - sectional right side view in elevation of the destemmer 100 . in this view , the shredding drum 130 shows a solid end cap 200 that serves to contain the crop 160 being processed within the shredding drum 130 . an electric or otherwise powered motor 210 provides a rotational motive force to a plurality of brush rollers 220 , a drive spindle ( axle ) 230 , and a drive roller 240 . a freely rotating support roller 250 , shown disposed pictured at the front of the destemmer , acts simply as a support for the shredding drum . the motor 210 includes a drive pulley 255 mounted on a drive shaft 257 , and the drive pulley is connected to the brush rollers 220 through a primary drive belt 260 b . one primary drive belt interacts with the brush rollers 220 by winding through the brush roller pulleys 265 . the brush roller pulleys 265 preferably have a smaller diameter than the drive pulley 255 so as to produce a faster rotation of the brush roller pulleys 265 relative to the drive pulley 255 . in the preferred embodiment , the primary drive belt 260 b interacts with at least three brush rollers , two outside ( or outboard ) and one inside , middle ( or inboard ) brush roller , each having a brush roller pulley 265 , and the primary drive belt is wound through the brush roller pulleys 265 in an “ over - under - over ” pattern , causing the outside brush rollers 220 to rotate in a direction opposite the middle or interior brush roller . this fast , counter rotational action by the brush rollers 220 initiates a grabbing action by the brush rollers 220 , which have bristles that extend at least partially into the slots 150 in the shredding drum 130 . this grabbing action pulls vegetative material through the slots 150 and directs the separated material into the waste chute 125 . a second primary drive belt 260 a is connected to a spindle pulley 275 , which is approximately the same diameter as the drive pulley 255 , thus delivering a rotational force to the spindle 230 , which in turn provides rotational force to the drive roller 240 through a secondary drive belt 280 . the drive roller 240 is constructed of metal , with a rubber or other suitable coating for providing a traction surface to the shredding drum , the latter of which has an outer circumferential surface that rides upon the drive roller 240 . as used herein , “ belt ” means any kind of belt or chain employed to transfer power smoothly from an engine to a pulley . it is intended to encompass belts that are flat , vee shapped , round , reinforced , non - reinforced , toothed , notch , or cog , or any suitable combination thereof , and it is further intended to include the operationally equivalent kinds of chain . accordingly , as used herein , the term “ pulley ” be understood to encompass apparatus suitable for use with complementary power transfer apparatus , such as the belts and chain described above . thus , it will be understood to mean a toothed gear , a splined wheel or pulley , a smooth grooved pulley , and so forth . spindle pulley 275 may be removed , and the brush rollers and drive rollers independently actuated by separate motors . further , both rollers may be provided with reversible operation so that the brushing action relative to the rolling action of the drum can be altered and tailored to optimize the destemming and shredding action . thus , in a second preferred embodiment , two motors are provided : a first gear motor rotating at 60 rpm and driving the drive roller , and a second brush motor rotating at 3500 rpm and driving the brush rollers . the purpose of the segregated operation is to permit operation of the drive rollers and rotation of the drum even after the brush motor is shut off . accordingly , the rotating drum will continue to aerate product and thereby prevents the product from settling in piles that can heat up and cause mold . fig3 and 3a provide a left side view of the destemmer 100 showing the orientation of the shredding drum 130 in relation to the drive roller 240 , the brush rollers 220 and the support roller 250 . the bristles 270 of the brush rollers 220 protrude through the slots 150 ( fig . 1 ) in the shredding drum 130 . a hinged access door 300 is disposed in the end cap 200 to provide access to the interior of the shredding drum 130 . fig4 is partial cross - sectional rear view of the destemmer 100 , with a cut away of the cabinet 110 exposing the motor 210 , the brush rollers 220 , the drive roller 240 , and the spindle 230 . mounted upon the spindle 230 are final drive pulleys 400 evenly spaced along the length of the spindle 230 , which employ tertiary drive belts 410 engaged on the final drive pulleys 400 and operatively connected to the drive roller 240 via belt grooves 420 . the belt grooves 420 align with the final drive pulleys 400 to provide the rotational force to the drive roller 240 , and thereby transferring rotational force to the shredding drum 130 . fig4 a shows an alternative shredding drum 135 employed on the cabinet and motor drive unit . the drum is essentially a cylindrical wire basket comprising a plurality of circumferentially disposed circular wires or rods connected by a plurality of spaced apart transverse rods welded to the circumferential rods , in a manner well known in the art . this construction maximizes the available openings for presenting plant material to the brush rollers and provides rounded edges that reduce wear and tear on the roller bristles . fig5 is a top plan view of the destemmer 100 showing the parallel orientation of the drive roller 240 , brush rollers 220 and support roller 250 in the cabinet 110 . also pictured is the waste chute 125 . tertiary drive belts 410 are pictured in the belt grooves 420 on the drive roller 240 . the above disclosure is sufficient to enable one of ordinary skill in the art to practice the invention , and provides the best mode of practicing the invention presently contemplated by the inventor . while there is provided herein a full and complete disclosure of the preferred embodiments of this invention , it is not desired to limit the invention to the exact construction , dimensional relationships , and operation shown and described . various modifications , alternative constructions , changes and equivalents will readily occur to those skilled in the art and may be employed , as suitable , without departing from the true spirit and scope of the invention . such changes might involve alternative materials , components , structural arrangements , sizes , shapes , forms , functions , operational features or the like . it will be appreciated , for instance , that the entire inventive apparatus could be mounted on casters or rollers and thus made fully transportable . it will be further appreciated that the inventive apparatus need not be powered by a plurality of motor driven rollers disposed atop a cabinet of the kind described in the preferred embodiment . as an alternative , the shredding drum may be constructed around a central axle journaled in bearings supported in vertical supports . in such a configuration the axle is operatively connected to the motor through belts or may actually be an extension of the motor drive shaft itself . the brush rollers may be disposed at the sides of the shredding drum and driven by gears or belts operative connected to the drum axle . accordingly , it will be appreciated that the essence of the invention is the combination of the inventive motorized shredding drum and motorized brush rollers configured to share a single power source and utilizing centrifugal force to expose plant material for mechanical shredding and destemming . therefore , the above description and illustrations should not be construed as limiting the scope of the invention , which shall be defined by claims when and as filed .

a vegetative shredder and destemming apparatus that includes a shredding drum having a interior volume into which a harvested plant crop may be placed for processing . the drum includes a substantially cylindrical side with a plurality of openings and at least one brush roller disposed proximate the cylindrical side . a motor rotates the shredding drum and the brush rollers simultaneously . the apparatus employs centrifugal force to urge portions of the plant material into engagement with the drum &# 39 ; s cylindrical side and the openings therethrough so as to allow bring the brush rollers to mechanically shred and destem the plant material .

the invention described herein is a system of a primary absorbent article with secondary enhancement products . such a system allows a consumer to customize the primary absorbent article to meet the consumer &# 39 ; s individual needs . [ 0016 ] fig1 illustrates an example of an absorbent article system 10 of the present invention . the system 10 includes a primary absorbent article or chassis 15 and a number of secondary or enhancement products 20 . the absorbent article system 10 may include any type of absorbent article at its core , including , but not limited to , a diaper , a training pant , a swim pant , a youth pant , a feminine hygiene product , an incontinence product , or the like . for purposes of illustration , and not for purposes of limitation , the absorbent article system 10 is described as it would apply to a diaper . the same system , however , may be described using another suitable absorbent article . the absorbent article system 10 includes a chassis 15 that may be very similar or identical to absorbent article products available to consumers . the chassis 15 is used to treat a base condition , typically the need for absorbency . the base function performed by the chassis 15 is typically waste collection and absorption . in the case of a diaper , the chassis 15 is a diaper that may be used on its own as a standard diaper . again in the case of a diaper , the chassis 15 or basic diaper component of the absorbent article system 10 is preferably a more premium - level disposable diaper , but may also be a lower - end , non - premium diaper , or any other suitable disposable diaper . the term “ basic ” in this instance implies that the diaper performs the typical and expected duties of a disposable diaper including a certain level of urine and fecal absorbency and containment , along with an acceptable level of comfort , fit , and skin health . for example , a diaper fitting the basic classification may include a breathable cloth - like outer cover , mechanical fasteners , superabsorbent material and / or fluff absorbents , stretch ears , surge , feces or bowel movement ( bm ) containment flaps , gentle leg elastics , and a back waist elastic system . this type of product is generally sold as a premium diaper . the chassis or basic diaper 15 will meet the needs of most consumers , and performs better than , or at least as well as , other premium disposable diapers . the absorbent article system 10 also includes a variety of secondary or enhancement products 20 . each of these enhancement products 20 performs at least one primary function such as humidity or odor control . enhancement products 20 are designed to complement the chassis 15 by being disposed within or around the chassis 15 , or otherwise coupled to the chassis 15 , as described in more detail herein . the enhancement products 20 deliver benefits that allow the consumer to customize the chassis 15 to the consumer &# 39 ; s needs . while the enhancement products 20 may take any suitable form or function , a variety of examples are described herein for use in a diaper - based system . similar enhancement products 20 may be used in systems based on other absorbent articles . the following enhancement products 20 are among those that may be used in a diaper - based system : an extra absorbency liner 50 is an absorbent - containing liner sized to fit within the diaper , between the diaper and a wearer of the diaper . as used herein , the term “ liner ” implies that the enhancement product 20 is put on the inside of the product . the liner does not need to extend over the entire width or length of the product . the extra absorbency liner 50 supplements the absorbent capacity of the chassis 15 . the extra absorbency liner 50 may be inserted for overnight use of the chassis , for long car trips , or whenever extra absorbency is desired . a bm liner 55 is designed to quickly separate bm from skin contact with the wearer to limit the exposure of the skin . the bm liner 55 is sized to fit within the diaper , between the diaper and the wearer of the diaper . a lotion liner 60 is a liner coated , impregnated , or otherwise treated with a lotion designed to promote skin health . the lotion may be applied in stripes or other patterns to help to maintain the absorbency of the diaper . in the diaper example , the lotion may prevent or treat diaper rash . a lotion liner 60 such as this may be used consistently , or , more likely , it may be used only on occasions when diaper rash is anticipated based on stool consistency , the wearer &# 39 ; s health , etc . diaper rash lotions may be difficult to remove from the applier &# 39 ; s fingers ; simply inserting a lotion liner 60 would avoid such a mess . in alternate embodiments , any other suitable lotion may be used in conjunction with the lotion liner 60 . further examples include petrolatum , zinc oxide , and cornstarch . an odor tab 65 is designed to be inserted in or attached to the chassis 15 to reduce or eliminate odors emanating from the diaper . the odor tab 65 may include baking soda and / or activated charcoal to absorb urine or bm odor . while some consumers may prefer to have some odor remain as indicator of the need to change the diaper , a reduction in odor may still be desirable for those consumers . multiple odor tabs 65 may be used for additional odor reduction or elimination . similarly , an aromatherapy tab 70 is designed to be inserted in or attached to the chassis 15 to produce beneficial aromas such as lavender or chamomile to soothe and relax or peppermint to refresh the wearer , similar to the aromas produced by aromatherapy candles and bathing products . a humidity tab 72 may be a small packet that sticks to the inside of the wasteband to help control humidity inside the diaper and keep the wearer &# 39 ; s skin dryer . a health screen 75 may be inserted into or attached to the chassis 15 to screen for one or more health conditions . a health screen 75 may test for one or multiple conditions . in addition , one or more health screens 75 may be used . examples of health screens 75 include , but are not limited to , a dehydration sensor , a rash screen , a urinary tract infection screen , and medical diagnostic screens such as indicators of sugar content in urine and urine ph . health screens for elderly incontinent adults who are often institutionalized with a variety of medical conditions present a large opportunity for a variety of enhancement products . health screens 75 may not be typically used on a daily basis , but may be purchased to be ready in case a health condition is suspected . a wetness monitor 80 is designed to indicate to a caregiver when the absorbent article has been made wet . such an indication is particularly useful in newborn &# 39 ; s whose wet diapers are difficult to detect . the wetness monitor 80 may generate a light or sound in the presence of wetness , may transmit a signal to a monitor , may change colors or cause a graphic to appear or disappear in the presence of wetness , or may provide any other suitable indication of wetness . an air dry liner 85 is a liner that provides additional air circulation between the chassis and the wearer &# 39 ; s skin to promote skin health and dryness . a bio tissue 90 is designed to be folded into a diaper prior to disposal to promote biodegradation of the diaper to minimize environmental loading due to disposable diapers . a diaper cover 100 is worn by the wearer over and outside of the diaper and is designed to improve the fit of the diaper and to promote leakage protection . the diaper cover 100 may be a mesh cover , and the diaper cover 100 may be decorative . suspenders 105 may be used to help keep diapers up on babies who have a hard time keeping clothes up . the suspenders 105 may be made from a soft , stretchy material , and soft fasteners may be used to fasten the suspenders 105 to the diaper without harming the skin of the wearer . in addition to enhancement products 20 , the absorbent article system 10 may also include tertiary or associated products 140 . associated products 140 are products that would likely be used by those who use the chassis 15 and enhancement products 20 . associated products 140 may be used to enhance the use of the absorbent article system 10 , to assist in the education provided by the absorbent article system 10 , or for any other suitable use . in the diaper example , associated products 140 may include infant bathing products , infant toys , infant powders and ointments , changing pads , specialty wipes , and the like . in an example of a specific application of the absorbent article system 10 , a toilet training system 150 of products related to toilet training may be provided . the chassis 15 as described herein for a toilet training system 150 may be either a diaper or a training pant . a useful enhancement product 20 in the toilet training system 150 may be a disposable shell designed to be worn over the chassis 15 . another useful enhancement product in the toilet training system 150 is one that would provide notification to the wearer of wetness , allowing the wearing to associate the notification with certain body signals that indicate that wetness is imminent . a wetness notification liner or insert 155 may include a bicomponent spunbond web that includes a water absorbing component , a bonded carded web containing a hydrophilic material such as cotton or rayon , or a hydrophobic spunbond web that is treated with a durable wettable treatment such as a surfactant . the wetness notification liner 155 may function by cooling , warming , releasing a gas , releasing an astringent , changing texture , reducing porosity such that any liquid is absorbed more slowly into an absorbent core , releasing a scent , or changing in the z - dimension ( towards the wearer ) when wet , or some combination thereof . the wetness notification liner 155 may also function by including items that attach to the liner 155 or chassis 15 and produce noise or light to alert both the wearer and a caregiver of the wetness . in another embodiment , in the toilet training system 150 example , associated products 140 may include graphics activated by oxygen or electricity that appear with time to signal how long the chassis 15 has been on the child ; attachments to the wetness notification liner 155 or other liner or the chassis 15 that cause graphics to appear or disappear with wetness , stickers ; progress charts ; toilet training educational materials such as videos , books , and hint sheets ; coloring books and / or crayons and markers ; urine targets ; and graphics on the shell that disappear when wet . other associated products 140 may include bibs , changing pads , onesies , and medicated or other specialty wipes . the absorbent article system 10 described herein may also employ as a chassis 15 a feminine hygiene product , an adult incontinence product , or other similar absorbent product . each type of chassis 15 may be supplemented with suitable enhancement products 20 and associated products 140 , including products similar to those described herein for use in conjunction with a diaper . the absorbent article system 10 described herein allows a manufacturer to produce a chassis 15 , enhancement products 20 , and associated products 140 and package these separately . each separate package of enhancement product 20 and associated product 160 may include a description of the condition intended to be addressed by that enhanced or associated product 20 , 160 , a description of the primary function of that enhancement or associated product 20 , 160 , a description of the entire absorbent article system 10 , or some combination thereof . the descriptions may be placed on the packaging , in the packaging , or some combination of both . the descriptions may allow a consumer to become educated as to the conditions that typically dictate the use of an absorbent article , and the further conditions that may be associated with or experienced in conjunction with the use of an absorbent article . such education allow a consumer to make informed decisions as to which enhancement and associated products 20 , 160 to purchase such that the consumer may assemble a customized absorbent article to address to various conditions . consumer education may be further enhanced by providing indicia on the packaging to indicate various different but associated components of the absorbent article system . the indicia may include graphic design features , text , branding , or any other suitable indicia . for example , all of the packages may exhibit similar graphic design components and branding to identify their association , yet have different coloring and illustrations to identify their differences . these indicia may help a consumer to quickly discern which products may be needed for a particular purpose . in other words , the absorbent article system 10 described herein allows a consumer to customize an absorbent article on an as - needed basis to address whatever conditions the wearer may be experiencing without spending more every day for an absorbent article that contains every enhancement . consumers desire a high quality , consistent product at a good price with the ability to upgrade for certain circumstances . the various components of the absorbent article system 10 may be sold through any retailer , including internet retailers . various distributors , wholesalers , hospitals , doctors &# 39 ; offices , and other suitable parties may also be involved . a retailer , for example , locates the various components of the absorbent article system 10 , including packages of the chassis 15 , packages of enhancement products 20 , and packages of associated products 140 , in general proximity to each other on one or more store shelves . additionally , targeted enhancement devices allow for opportunities for advertising systems . for example , a health screen device could be co - marketed with the appropriate remedy for the health condition . this proximity allows a consumer to see the components of the absorbent article system 10 in one place , allows the consumer to read the packaging to learn about the absorbent article system 10 , and allows the consumer to select those components that will address the consumer &# 39 ; s needs . as an example , a consumer wishes to prevent diaper rash in a baby susceptible to diaper rash because of periodic illness . the consumer also needs an ample supply of diapers for every day use . the consumer , as a part of a typical shopping trip , enters the baby aisle of a store and examines the diaper options . the consumer selects a brand of diapers , and notices other products located adjacent to and associated with these diapers . upon closer examination , the consumer reads some of the other product packaging and learns that a simple lotion liner 60 , when added to the diaper the consumer is already purchasing , may prevent diaper rash . the consumer thus purchases the package of diaper rash lotion liners 60 to have on hand for use only during those times when the baby is susceptible to diaper rash . the consumer may also purchase a package of extra absorbency liners 50 to have on hand for use only during occasional long car trips . the consumer may also purchase an infant toy and a package of specialty wipes . the consumer benefits from not needing to pay extra for an every day diaper that contains all of these features . the consumer also benefits because the various enhancement and associated products 20 , 160 are located in one place , rather than being spread across various shelves or an entire store . for a manufacturer , incorporating improvements into enhancement products rather than the basic absorbent article allows the manufacturer to make minimal changes to absorbent article machines , resulting in lower capital expenditures and optimizing manufacturing . in addition , researchers may focus on product improvements without considering the effect of the improvements on absorbent article machines . the manufacturer may contract manufacturing of secondary products and enter into joint marketing agreements with makers of related items . enhancement products may be rapidly introduced and evaluated , and enhancement products need not be as cost sensitive as improvements incorporated into every absorbent article . finally , customized enhancement products allow the manufacturer to more effectively meet global needs . from a business standpoint , an absorbent article system may expand a category because enhancement products may be used with competitors &# 39 ; absorbent articles . introduction of improvements in enhancement products may carry a lower risk than incorporating those improvements in an absorbent article . other objects and advantages of the present invention will become more apparent to those skilled in the art in view of the following description and the accompanying drawings . the invention has been described with reference to various specific and illustrative 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 . many alternatives , modifications and variations will be apparent to those skilled in the art in light of the foregoing description . accordingly , this invention is intended to embrace all such alternatives , modifications , and variations that fall within the spirit and scope of the appended claims .

a method for providing a system of absorbent articles including offering a chassis primarily performing a base function , wherein the chassis is an absorbent article ; and offering first and second enhancement products , wherein the chassis and the first and second enhancement products are adapted such that the first and second enhancement products may be coupled to the chassis . further , a method for educating a consumer with regard to various conditions requiring an absorbent article including providing first and second packages , each including a description of a condition and an enhancement product adapted to address the conditions ; allowing the consumer to learn about the conditions and what may be used to address the conditions ; and providing a third package including a chassis and description of a base condition , such that the chassis may be combined with the first and / or second enhancement products .

the following examples are given to illustrate the present invention but are not to be construed as limiting . dehydrated paprika ( 5 . 5 % moisture ) is ground in a hammer mill and the resulting ground paprika ( 95 % passing us 40 mesh ) is admixed with about 10 % by weight of soy bean oil and processed in a countercurrent extraction system involving three ( 3 ) pressing stages , each using an egon keller model kek - 100 screw press , with the extracts from the second and third stages being returned to the preceding mixing stage before being removed from the process at the end of the first press stage . a high shear , high speed pin mixer or equivalent is used to mix the soy oil or extracts from the second and third press stages into the ground spice or residual solid from the preceding stage . this recycling is continuous . the raw material paprika solids are continuously fed at a rate of about 240 lbs . per hour with a total contact time in each mixing stage of about 15 - 60 seconds . the residence time in each press is 5 - 60 seconds . the pressing stages are operated at about 10 , 000 psi internal pressure and about 200 degrees fahrenheit , which is maintained by cooling with water through the bore of the press shafts . the starting color value of the ground paprika solids is 200 asta . the principal components extracted and standardized in both the extract and the residual solid are the carotenoid pigments . the resulting final soy - paprika extract has a color value of about 1 , 375 asta and the reground paprika residual solid from the final ( 3rd ) press stage has a color value of about 85 asta . by varying the percentage of edible solvent employed from about 5 % to 20 %, the pressure from about 6 , 000 to 30 , 000 psi , the number of countercurrent mixing and pressing stages from 2 to 5 , with return of the extract from each press stage to the preceding mix stage before final removal from the process in the first press stage , varying the temperature from about 130 ° f . to 280 ° f ., and removing the seed from the paprika solids prior to grinding , the resulting extract ranges in color value from about 2 , 700 asta to about 800 asta and the residual solids range in color value from 180 asta to 35 asta . by regrinding the residual solids ( from the final stage ) just as is done with fresh , dehydrated paprika , a product in every way comparable to commercially available ground paprika solids is produced . after filtering or centrifuging off the fine particulate solids , the extract can be directly substituted for commercially available paprika oleoresin in every respect . by varying the pressing temperature of the process from about 130 ° f . to 325 ° f ., the hue of the reground residual solid is varied from slightly browned to a dark chocolate brown , demonstrating that the degree of brownness can be controlled by the pressing temperature employed . the degree of &# 34 ; brownness &# 34 ; is measured using a hunter labscan spectrocolorimeter with 0 degree illumination , 45 degree circumferential viewing , illuminant d65 , 10 degree observer , ceilab coordinate system . the hue of the paprika powder is measured by placing the powder in a 2 . 5 - inch diameter cuvette , shaking gently to ensure even coverage , and measuring through the bottom of the cuvette . the results of the varied operating temperatures of the process are shown in table i . the designation l * is indicative of the &# 34 ; lightness &# 34 ; of the sample with the higher numbers being lighter or less browned , and the lower numbers being darker or more browned . table i______________________________________processing temperature visual appearance l * values______________________________________130 ° f . red 40 . 18150 ° f . tan - red 37 . 25200 ° f . light brown red 33 . 22280 ° f . dark brown red 29 . 16325 ° f . chocolate red 22 . 85______________________________________ the data clearly demonstrate that the degree of browning can be controlled by varying the press temperature at which the process is conducted . this broadens the applications or uses of the residual solid to include a base for toasted chili powder and as a replacement for browned , caramelized paprika . the residual solid can be substituted for ground paprika or chili powder in many common applications and a separate processing step for browning to a desired degree is not required . the starting ground paprika solids have an aerobic plate count ( analysis run according to bacterial analytical manual by aoac , 8th edition , 1995 , and iso - grid methods manual , 3rd edition , 1989 ) of about 14 , 000 , 000 . the residual solids exiting the extraction system have a count of about 2 , 000 to 200 , 000 , with the lower count being achieved at the higher temperatures . this is a significant reduction and makes the residual solids per se suitable for any application where treatment with ethylene oxide or irradiation would normally be required . the foregoing example is repeated with all materials and conditions being the same , except that the soybean oil edible solvent is supplemented with an antioxidant blend at a concentration of 3 % by weight of the original ground paprika solids . the blend consists of about 29 % lecithin , 20 % powdered ascorbic acid , 5 % citric acid , 15 % tocopherol , and 1 % rosemary extract ( in accordance with chang and wu u . s . pat . no . 5 , 077 , 069 ). the stability of ( 1 ) the resulting extract and ( 2 ) the residual solids is compared in each case with an untreated control . in such evaluation , the paprika extracts are plated on flour salt to an extent of 2 . 4 % by weight with a mortar and pestle . two - gram samples are weighed into 13 × 100 mm test tubes . the test tubes are stored in a thermostatically - controlled oven at 65 ° c . samples are withdrawn periodically , extracted with acetone , and the color at 460 nm of a standard (%) dilution in acetone is determined spectrophotometrically . in the evaluation of the residual solids , two - gram samples of the reground residual solid are substituted for the flour salt dispersions . the procedure for the &# 34 ; standard dilution &# 34 ; is as follows : the initial color of the dispersion is determined by pouring two grams of the original dispersion into a 100 - ml flask . acetone is added up to the 100 - ml level . the flask is inverted several times . the flour salt is allowed to settle for five minutes . then three ml of the dilution is pipetted into a 25 - ml flask and diluted up to the 25 - ml level . the absorbance is read at 460 nm . the 460 nm color is determined by the formula : ## equ1 ## where the percent dispersion is determined by the formula : ## equ2 ## to translate to asta color , multiply the 460 nm color by 820 . the color is plotted against time and the time for 1 / 3 of the starting color to fade is reported as the 2 / 3 life . this is a highly - reproducible measurement , which is sufficiently accurate to evaluate the effectiveness of the antioxidants and will assist the practitioner to optimize formulations for specific uses . the final extract from the first press stage of the unprotected or unstabilized process has a color value of about 1375 asta and a 2 / 3 life of 6 . 5 hours as compared to a color value of about 1600 asta and a 2 / 3 life of 63 hours for the extract from the protected material . the color value of the unprotected or unstabilized residual solids is about 85 asta with a 2 / 3 life of 54 hours , compared to the protected solids which have a color value of about 95 asta and a 2 / 3 life of 155 hours . this clearly demonstrates that inclusion of antioxidants can improve not only the color yields from the extraction process but also at the same time improve the color stability of both the extract and the residual solids . other suitable antioxidants ( e . g ., lecithin , ethoxyquin , butylated hydroxy anisole ( bha ), butylated hydroxy toluene ( bht ), tertiary butyl hydroxy quinone ( tbhq ), sesame , tea catechins , and labiatae herb antioxidant activity , finely - divided ascorbic acid , tocopherol , citric acid ) can be substituted in whole or in part for the specific antioxidant mixture employed with similar desirable color - protective results , preferably a naturally - occurring antioxidant from an herb of labiatae family , e . g ., rosemary , sage , or thyme , or powdered ascorbic acid . dehydrated paprika solids ( 2 . 5 % moisture ) were ground in a hammer mill and the resulting ground paprika ( 95 % passing us 40 mesh ) was processed with about 15 % by weight of soy bean oil in a countercurrent extraction system as in example 1 involving two ( 2 ) pressing stages , with extracts from the second press stage being returned to the preceding ( first ) mix stage before being removed from the process at the first press stage . upon exiting the first press stage , distilled water was metered continuously into the crude extract at a rate of 75 % by weight of the gums and solids by means of an inline static mixer . the weight of the gums and fine particulate solids in the extract was determined by diluting one gram of the crude extract in nine grams of acetone . the mixture was spun down for three minutes at 2000 g &# 39 ; s in a laboratory centrifuge . the solids separated were air dried and the weight of the gums and solids was calculated as a percentage of the weight of the starting extract . the hydrated gums and solids removed from the extract were continuously returned to the final residual press solids via a high shear , continuous pin mixer installed immediately following a water - jacketed cooling screw which received the residual solids from the second press stage . prior to hydration and centrifugation , the extract contained approximately 10 % by weight of gums and fine particulate solids as determined by the above - described method . following hydration and centrifugation the gums and particulate solids amounted to no more than 1 % by weight of the extract and the extract was a crystal clear solution , free of any suspended insoluble materials . the color value of the starting ground paprika was about 150 asta . the pressing stages were operated at about 20 , 000 to 30 , 000 psi . the extraction process was started with the presses operating at about 80 ° f . as measured by the temperature of the cake exiting the presses . the temperature of the presses was controlled by the rate of flow of cooling water through the bore of the press shafts and the screen cages to keep the operating temperatures in the range of 80 ° to 180 ° f . over the time of the extraction run , the operating temperatures of the presses , as measured by the temperature of the cake exiting the presses , was gradually increased to about 255 ° f . by first slowing and then stopping the flow of cooling water to obtain operating temperatures of 180 °- 200 ° f ., and then by substituting steam for the water in the shaft and cages at gradually increasing pressures to achieve temperatures of 200 °- 255 ° f . samples of the extracted oil and press residual solids were pulled at various temperature intervals as the temperatures were increased . samples of the residual solids were pulled at two points , the first ( non - rehydrated ) immediately after exiting the cake - cooling screw following the final ( second ) pressing stage , and the second after the thus - cooled residual press solids were rehydrated to a moisture content of about 10 %. the samples were assayed for asta color , aerobic and anaerobic plate count , and color stability over time using methods employed in examples 1a and 1b . the advantages of operating the process at a temperature above 130 ° f ., as indicated by the temperature of the cake exiting the presses , can clearly be seen . the plate count of both the extract and the cake are progressively reduced as the temperatures are increased . ( tables 2 & amp ; 3 ) table 2______________________________________effect of increasing temperatureson the plate count of the extracttemperature degree f . aerobic plate count anaerobic plate count______________________________________ 80 1 , 900 , 000 790 , 000130 1 , 700 , 000 800 , 000150 1 , 700 , 000 660 , 000170 1 , 600 , 000 500 , 000175 1 , 500 , 000 425 , 000180 1 , 300 , 000 380 , 000190 360 , 000 150 , 000200 300 , 000 200 , 000215 240 , 000 150 , 000225 190 , 000 65 , 000235 170 , 000 32 , 000245 69 , 000 8 , 600255 3 , 800 830______________________________________ table 3______________________________________effect of increasing temperatures on the platecount of the press solidstemperature degree f . aerobic plate count anaerobic plate count______________________________________ 80 220 , 000 55 , 000130 160 , 000 35 , 000150 160 , 000 25 , 000170 100 , 000 20 , 000175 32 , 000 15 , 000180 80 , 000 7 , 400190 3 , 500 800200 9 , 800 3 , 400215 5 , 800 2 , 300225 4 , 100 500235 1 , 900 1 , 100245 5 , 400 100255 800 100______________________________________ the efficiency of extraction is dramatically improved as evidenced by the progressively decreasing asta values and the progressively decreasing residual extractable yields of the press residual solids . it is apparent that , to achieve residual extractable yields of less than about 20 % by weight of the cake , it is necessary to operate the presses at 130 ° f . or higher . ( table 4 ) moreover , for obvious reasons of efficiency , temperatures above 180 ° f ., and especially between about 180 ° f . and about 235 ° f ., are greatly preferred . table 4______________________________________press cake asta and residual yields atprogressively increasing temperaturestemperature degree f . press solids asta press solids residual yield______________________________________ 80 87 28 . 28 % 130 76 16 . 40 % 150 65 15 . 72 % 170 61 15 . 72 % 175 53 12 . 36 % 180 43 13 . 88 % 190 42 10 . 84 % 200 44 10 . 72 % 215 41 9 . 96 % 225 39 9 . 50 % 235 33 9 . 28 % 245 32 9 . 00 % 255 35 9 . 80 % ______________________________________ most importantly , the stability of the extract is not adversely affected and is in fact increased . the results , from example 2 , of an accelerated study on the stability of the extract , generated at varying press operating temperatures , can be seen in table 5 . the accelerated study was done according to the procedures described in example 1b with the colors reported as a percent of the starting color for each respective sample to adjust for the varying color yields at the respective temperatures . these results demonstrate that the extract produced at higher operating temperatures exhibits increased resistance to oxidative color deterioration . this is surprising , as explained in the following . table 5______________________________________press oleoresin ( extract ) stability , accelerated , 65 ° c . temperature degree f . hour 2 hour 4 hour 8 hour 12 hour 17______________________________________ 80 94 % 88 % 81 % 73 % 62 % 130 94 % 89 % 82 % 75 % 64 % 170 93 % 89 % 82 % 76 % 65 % 225 94 % 90 % 82 % 78 % 67 % 235 94 % 90 % 82 % 77 % 69 % 255 95 % 90 % 84 % 78 % 72 % ______________________________________ it is commonly believed that lipid - containing systems , when exposed to heat , will exhibit an increased rate of lipid oxidation that , once initiated , will proceed at an ever - increasing rate . ( rancidity and its measurement in edible oils and snack foods , a review , robards , kerr , and patsalides , analyst , february 1988 , vol 113 ). in fact , prior art ( u . s . pat . no . 4 , 681 , 769 ) claims a process for counter - current , high pressure extraction of capsicums at less than 100 ° f . and less than 500 psi for the express reason of protecting the extracted oil from oxidation . to confirm the positive effect of high temperature treatment in more controlled conditions , a forty gram sample of hexane - extracted oleoresin paprika , with no diluents added , was heated in a beaker on a heated stir plate at 100 ° c . for eight and one - half hours . a control sample which was unheated , a sample pulled from the heated beaker after four hours , and a sample of the material heated for the full eight and one - half hours were dispersed on flour salt to make dispersions of 1 . 2 % oleoresin by weight of flour salt . two gram - portions of the dispersions were weighed into test tubes and placed in a 65 ° c . oven . an initial asta color was run on each dispersion and then asta colors were run periodically and the results were plotted versus time to determine the relative stability of the heated and unheated samples . the results are shown in table 6 . it can be readily observed that the heat - treated samples , although they lose some initial color during the heating process , have improved stability over time , thus confirming the improved resistance to oxidation observed in table 5 . table 6______________________________________asta values of heated & amp ; unheated oleoresinpaprika ( extract ) over timehours unheated heated 4 @ 100 ° c . heated 8 @ 100 ° c . ______________________________________ 0 32 . 5 31 . 5 26 . 0 2 29 . 0 29 . 0 25 . 8 4 26 . 0 28 . 0 25 . 7 6 24 . 0 27 . 0 25 . 5 8 22 . 5 25 . 8 25 . 310 21 . 0 24 . 5 25 . 012 20 . 0 23 . 0 24 . 814 19 . 0 22 . 3 24 . 516 18 . 0 21 . 8 24 . 018 17 . 0 21 . 0 23 . 520 16 . 0 20 . 0 23 . 022 15 . 1 19 . 0 22 . 524 14 . 2 18 . 5 22 . 126 13 . 4 18 . 0 21 . 828 12 . 9 17 . 5 21 . 430 12 . 5 17 . 0 21 . 0______________________________________ the non - rehydrated press residual solids produced in example 2 exhibit decreased resistance to oxidative color loss as the press operating temperatures are increased as predicted by prior art ( bennett et al , u . s . pat . no . 4 , 681 , 769 ) and as seen in table 7 . table 7______________________________________stability of non rehydrated press solids at variouspress operating temperatures , expressed as percentof starting color retainedtemperature degree f . week 2 week 4 week 6______________________________________ 80 86 . 7 % 82 . 2 % 85 . 5 % 130 89 . 6 % 85 . 5 % 84 . 6 % 170 73 . 3 % 65 . 3 % 58 . 1 % 225 61 . 7 % 35 . 8 % 32 . 5 % 245 68 . 2 % 31 . 0 % 19 . 3 % ______________________________________ but , very importantly , it can be seen that the press residual solids which are rehydrated immediately after exiting the second press stage of the process ( example 2 ) exhibit significantly increased stability ( table 8 ) relative to the non - rehydrated solids , thus overcoming the claimed disadvantages from operating at temperatures above 100 ° f . as set forth in u . s . pat no . 4 , 681 , 769 . table 8______________________________________stability of rehydrated press solids at variouspress operating temperatures , expressed as percentof starting color retainedtemperature degree f . week 2 week 4 week 6______________________________________ 80 90 % 92 % 91 % 130 93 % 91 % 92 % 170 92 % 92 % 91 % 225 94 % 93 % 91 % 245 95 % 94 % 93 % ______________________________________ in fact , after discounting for the effect on pigment stability of increasing residual extractable yields in the press solids ( tables 4 & amp ; 11 ) obtained at the lower temperatures , the carotenoid pigments in the residual solids would show enhanced stability for a given residual extractable yield . these are surprising and unexpected results and clearly overcome the supposed obstacle of operating at elevated press temperatures and pressures . it is further surprising that the color stability of the residual press solids is significantly improved by controlling the water activity ( a w ) of the solids in ranges above those suggested for the stabilization of lipid - containing systems by extensive studies and particularly by nelson and labuza , water activity and food polymer science : implications of state on arrhenius and wlf models in predicting shelf life , k . a . nelson & amp ; t . p . labuza , journal of food engineering 22 , 271 - 289 ( 1994 ). water activity is defined as the ratio of the vapor pressure of water in a food to the vapor pressure of pure water at the same temperature . prior art suggests that maximum stability of lipid systems should be attained at water activities of about 0 . 3 with decreasing stability developing as the water activity is increased above this level . in this example we find precisely the inverse effect on stability of the carotenoid pigments for a given water activity . in order to confirm the effect of high temperatures in the pressing operation , and to confirm the effect of added moisture , a controlled test was performed on a laboratory scale where the effect of levels of extractable yield in the cake could be controlled to eliminate the effect of variable press cake residual yields on the stability of the carotenoids . a 3 , 000 gram sample of ground paprika solids ( 175 asta , 9 . 8 % extractable yield ) was dried in a lab tray dryer at 100 ° f . for 16 hours to a moisture content of about 2 %. one half of this sample was then heated in an oven at 220 ° f . for twenty minutes to approximate the temperature in a pressing operation according to the invention . the other unheated sample served as a control . one hundred gram samples of each of the two materials were rehydrated at approximately 1 % intervals up to about 12 % moisture . the water activity a w of each was determined using a rotronics hygroskop dt , model dt2 / 1 - 00iv , water activity instrument . samples were weighed into sealed test tubes , stored at ambient temperatures of about 72 ° f . in the dark , and the asta colors were determined over a period of eighteen weeks to determine the relative rates of color degradation . the color retained ( as a percentage of the starting color for each sample to compensate for the effect of color dilution with the rehydration water ) was plotted against time . table 9______________________________________percent color retained of unheated ground paprikaat various water activity rangeswater activity a . sub . w week 1 week 5 week 18______________________________________0 . 15 74 % 57 % 42 % 0 . 30 50 % 45 % 12 % 0 . 40 68 % 50 % 43 % 0 . 60 83 % 68 % 55 % ______________________________________ table 10______________________________________percent color retained of heated ground paprikaat various water activity rangeswater activity a . sub . w week 1 week 5 week 18______________________________________0 . 15 66 % 56 % 41 % 0 . 30 60 % 50 % 45 % 0 . 40 80 % 62 % 57 % 0 . 60 98 % 82 % 78 % ______________________________________ it can be seen in tables 9 & amp ; 10 that the stability of the carotenoid pigments follows almost precisely the inverse of the curve predicted by nelson & amp ; labuza ( fig2 ). it can also be seen from these tables that controlled temperature ( with concurrent browning ) significantly enhances the stability of the carotenoids above a water activity of 0 . 3 and particularly in the water activity range of 0 . 4 to 0 . 6 . water activity ranges higher than 0 . 6 were not tested as levels marginally higher than this range will support microbial growth which is not acceptable in a dry spice product . it can be concluded that the stability of the carotenoid pigments found in capsicums unpredictably does not follow the commonly - accepted and predicted pattern for lipid oxidation with respect to temperature and water activity as suggested in u . s . pat . no . 4 , 681 , 769 , or in the cited literature ( nelson and labuza , water activity and food polymer science : implications of state on arrhenius and wlf models in predicting shelf life , k . a . nelson & amp ; t . p . labuza , journal of food engineering 22 , 271 - 289 ( 1994 ); rancidity and its measurement in edible oils and snack foods , a review , robards , kerr , and patsalides , analyst , february 1988 , vol 113 ); describing the stability of lipid systems . in fact , high temperature treatment , combined with rehydration of the press solids to a water activity above 0 . 3 , preferably of 0 . 4 to 0 . 6 , significantly improves stability rather than decreases it . this is a very surprising and unpredicted result . it is well known that the lipid profile of capsicum and its extracts , without the addition of any diluents , comprises a mixture of saturated and unsaturated fatty acids , 60 - 70 % being unsaturated linoleic and linolenic , lipid and antioxidant content of red pepper , daood , biacs , et al ., central food research institute , budapest , hungary ( 1989 ) and the nature of fatty acids and capsanthin esters in paprika , nawar et al ., journal of food science , vol 36 ( 1971 ). in fact , daood et al suggest that &# 34 ; . . . the presence of triglycerides containing high amounts of unsaturated fatty acids may be an important factor contributing to the fading of paprika during processing and storage .&# 34 ; the present findings are just the opposite . without in any way being limited by theoretical considerations , it is hypothesized that the presently - discovered surprising and unpredicted inverse relationship shown ( in tables 9 & amp ; 10 ) between the stability of carotenoid pigments at given water activities is due to the fatty acids in the substrate being preferentially attacked by the oxidation reaction at the low ( from about 0 . 05 to 0 . 2 a w ) and higher water activity ranges ( above 0 . 3 , preferably about 0 . 4 to 0 . 6 a w ), thus protecting the carotenoids . at the intermediate water activity ranges ( 0 . 2 to 0 . 4 a w ), where the lipids are best protected , the carotenoids are more readily and preferentially attacked and exhibit low resistance to oxidative degradation . another controlled test was conducted to demonstrate the effect of different extractable yields in the residual solid press cake . the effect of higher amounts of unsaturated fatty acids is evident from the results illustrated in table 11 where fresh , refined , bleached , and deodorized soybean oil with no antioxidants was added at various percentages based on the weight of the paprika . the color over time was compared to the untreated control in an accelerated study at 65 ° c . a typical refined , bleached , and deodorized soy oil has a fatty acid composition of 22 . 3 % oleic ( 18 : 1 ), 51 % linoleic ( 18 : 2 ), and 6 . 8 % linolenic ( 18 : 3 ). ( riegel &# 39 ; s handbook of industrial chemistry , 9th edition , pg 278 ). it can be concluded that higher levels of unsaturated fatty acids , such as oleic , linolenic , and linoleic , which are found in most vegetable oils , will improve the color stability of the press residual solids . levels of extractable yield in the residual solids above about 15 - 20 % by weight of the residual solids is undesirable as the residual capsicum solids become difficult to handle for most uses and the efficiency of extraction is reduced , i . e ., less color can be removed from the spice as the residual yield is allowed to increase by decreasing either the pressure or temperature employed . table 11______________________________________percent color retained with varying amountsof soy oil added to ground paprikapercent addition hour 2 hour 4 hour 6 hour 8______________________________________ 0 % 65 % 59 % 52 % 50 % 5 % 90 % 83 % 74 % 72 % 10 % 92 % 84 % 75 % 74 % 15 % 94 % 87 % 80 % 78 % 20 % 96 % 91 % 83 % 81 % ______________________________________ it is readily apparent , comparing the results of the controlled test ( tables 9 & amp ; 10 ) on stability of heated vs unheated material , where oil is controlled at a constant level that , at a given added soy oil content in the press residual solids , the color stability of the residual press solids is significantly improved when the capsicum has been exposed to higher temperatures . this conclusion is not readily apparent in the results shown in table 8 where the amount of residual vegetable oil left in the press residual solids is higher in the low temperature ranges due to the decreased efficiency of the extraction process at lower temperatures ( table 4 ). the presence of higher amounts of residual oils there offers some protection which overshadows the increased protective effect at higher temperatures so evident in tables 9 & amp ; 10 . it can therefore be concluded that much , if not all , of the protection offered by operating the presses at temperatures lower than 100 ° f . ( as claimed in u . s . pat . no . 4 , 681 , 769 ) as compared to temperatures above 100 ° f . is simply due to the higher residual oil levels ( reduced extraction efficiency ) and that , for any given residual oil content , and with rehydrated residual solids , the operating temperatures above 130 ° f . give superior results , not only in an increased extraction efficiency which allows for a continuous , high speed process with increased throughput rates and significantly reduced microbial activity , but most surprisingly in an increased color stability of both the extract and the residual press solids , particularly when the press solids are rehydrated . as can be seen in table 4 , the press solids residual yield is much higher at temperatures below 100 ° f . and much higher ( 28 . 3 % residual yield ) than disclosed in u . s . pat . no . 4 , 681 , 769 ( 10 - 15 % residual yield ). in example 2 , table 4 , the model kek 100 screw press used for the test was operated at about 100 % of its rated capacity of 240 pounds per hour for typical oil seeds . in an effort to more closely model the residual yields of 10 - 15 % ( oil ) in the cake as disclosed in u . s . pat . no . 4 , 681 , 769 , the feed rate for this test was set at about 95 pounds per hour , thus allowing more residence time in the press to expel more extract and to reduce the residual yield of the press residual solids to 10 - 15 %. the following example according to bennett is a two - step production run . one lot , comprising about 300 lbs of 160 asta chili , ground to pass 20 mesh ( usss ), was transferred to a ribbon blender and blended with 13 . 7 % by starting weight of the ground chili of fortified soybean oil having 500 asta oleoresin for about 15 minutes and then allowed to stand for about 16 hours at room temperature ( 75 ° f .) before transfer to the feed hopper of an egon keller model kek - 100 screw press . the feed hopper provides for a controlled flow of the mixture of chili and fortified oil to the press at a rate of about 95 lbs per hour of fresh ground chili , the equivalent of about 800 lbs per hour in a french oil mill machinery company f - 44 press . both these feed rates represent about 40 % of the rated capacity of the respective screw presses on whole oil seeds . the production run was started with a cone setting of about 0 . 030 inches and with the internal worms configured so as to provide a pressure gradient of essentially little or no pressure up to about 500 pounds per square inch of pressure . at these low pressures and feed rates , effluent oil temperatures were maintained at less than 100 ° f . with cooling water as in bennett , and the residual yield ( oil ) in the press residual solids averaged about 12 . 5 %, just as prescribed by bennett , who states that : &# 34 ; temperatures above 100 ° f . should be avoided inasmuch as higher temperatures cause oxidation with a resultant destruction of delicate flavor and / or color principle .&# 34 ; with the press operating as described , the oil extracted , after centrifugation to remove the residual spice fines , assayed at about 1000 asta and the press cake residual solids fraction had a corresponding reduction in asta to about 115 . the press cake of the once - extracted ground fresh spice from the first pressing is further processed following the same procedure above described for the first blending / pressure extraction sequence using , however , fresh soybean oil as an additive in place of the fortified oleoresin soybean oil . the fortified soybean oil extracted assayed at approximately 500 asta . this 500 asta fortified soybean oil extract is recycled as an extractant on fresh ground chili . the extracted chili powder cake from this extraction step had a corresponding reduction in asta value to an average of about 65 asta ( ranged from 41 to 95 asta ). the results of this low temperature , low pressure test are compared to results of high temperature , high pressure conditions in example 2 and are shown in table 12 . table 12______________________________________comparison of low temperature / low pressure and hightemperature / high pressure high temp / high low temp / low pressure , pressure continuous 16 hour batch mixing from example 2______________________________________temperature , deg f . 95 235pressure , psi & lt ; 500 20 , 000 - 30 , 000final residual solids 65 33astafinal residual solids 12 . 5 % 9 . 3 % yieldfinal residual solids 41 . 5 % 22 % asta as a percent offresh chili astaasta loss in 1st 7 % 0 % mixing stageasta loss in 2nd 10 . 5 % 0 % mixing stagefinal oleoresin asta 1 , 000 1 , 000______________________________________ it can clearly be seen , as is also shown in example 2 ( effect of varying operating temperatures ), that the low temperature / low pressure batch process with extended contact times incurs significant color loss during the extended contact times necessary for low temperature / pressure extraction . in addition , the low temperature / pressure batch process does not remove the color as efficiently as with higher temperatures and pressures for any given size pressing operation . the foregoing example can scientifically be scaled up or extrapolated into a comparative two - stage production run using two model 44 - f french oil mill machinery company presses , as follows : one lot comprising about 3 , 840 lbs of 5 % moisture , 160 asta , 20 mesh , fresh ground chili solids ( capsicum annum ) is passed through a high speed , high shear , steam - jacketed paddle mixer on a continuous basis and fed directly into the press feed hopper at stage one , through the 1st stage press , into a 2nd stage paddle mixer , and then to the 2nd stage press . soybean oil is added continuously through a metering pump into the paddle mixer at stage 2 at the rate of 13 . 7 % by weight of the starting ground chili solids ( 525 lbs of oil for the 3840 lb run ). the raw material chili solids are continuously fed at a rate of about 2 , 500 lbs per hour to the system with a total contact time in each paddle mixer of about 15 seconds . the temperature of the chili / oil mix exiting the paddle mixer is maintained at about 180 ° f . at stage 2 and about 150 ° f . at stage 1 . the oil / extract expelled from the second pressing stage is returned on a continuous basis to the paddle mixer at stage one wherein the oil / extract and fresh ground paprika are mixed in preparation for the first pressing stage . the oil / extract and fresh ground paprika exit the first stage paddle mixer and enter the first stage press at about 150 ° f ., the temperature being controlled by the amount of steam on the paddle mixer jacket . the concentrated oil / extract expelled from the first pressing stage is hydrated with water to about 75 % by weight of the fines ( fine particulate solids ) and gums and is then centrifuged and the hydrated fines and gums are added to the residual press solids from the final ( second ) pressing stage in a high shear mixer , after the solids have passed through a water - jacketed cooling screw . the internal shaft and collar arrangements of the press are configured so as to provide internal pressures of about 20 , 000 to 30 , 000 psi and cooling water is maintained at a flow rate through the bore of the shaft and through the cage cooling jackets so as to maintain an exit oil temperature at the external cage surface of about 180 ° to 200 ° f . and an exiting residual solid cake temperature of about 235 ° f . the residual cake solid is cooled in a water - jacketed screw conveyor to about 85 ° f . and water , in addition to the hydration water used to remove the fines and gums from the extract , is injected into the high shear , continuous mixer to rehydrate the cake to a water activity of about 0 . 6 . the concentrated extract exiting press stage one has an asta value of about 1 , 000 and the residual press solid cake exiting stage two has an asta value of about 45 . the residual press solid cake has a reddish - brown appearance typical of lightly toasted chili powder . the aerobic plate count of the residual solid cake is about 70 , 000 . the same test is repeated ( according to the bennett example ). no heat is applied during the mixing stages and the press internals are reconfigured so as to provide for minimal friction and compression and the resultant minimal heat generation during the pressing operations . the working compression is supplied primarily by the cone at the cake discharge and is maintained at about 500 psi . oil is added at a rate of about 13 . 7 % by weight of the starting paprika solids ( 525 lbs for the 3840 lb batch ) and mixed in a ribbon blender for sixteen hours and then fed at ambient temperature ( about 75 ° f .) to the pressing system . the feed rate through the pressing stages is maintained at 800 pounds per hour . cooling water is supplied to the internal bore of the shafts and the cooling jackets to maintain exit oil temperatures of less than 100 ° f . on both the expelled oil and the residual press cake . the extract exiting the first pressing stage of the press is centrifuged without hydration of the gums and fine particulate solids . the concentrated extract exiting press stage one has an asta value of about 1 , 000 and the residual cake solid has an asta value of about 65 . the appearance of the cake is lacking the brownness characteristic of commercially - available ground paprika and chili powder and would require a separate browning step to make it acceptable for common uses . the material is difficult to regrind due to the high level of residual extractable yield left in the cake , it is not flowable , and it must be combined with other solid materials to make an acceptable product for sale . the aerobic plate count is about 220 , 000 . a comparison of the results of the two tests is shown in table 13 . table 13______________________________________ high temperature low temperature pressing pressing______________________________________mixing time , soy oil continuous , 16 hours ( seconds ) fresh oil temp , ° f . 75 75oil / chili stage 1 at press feed , ° f . 150 75oil / chili stage 2 at press feed , ° f . 180 75cake after stage 1 pressing , ° f . 225 95cake after stage 2 pressing , ° f . 235 95asta value , extract 1000 9952 / 3 life , extract , 65 ° c ., hours 25 16asta value , press cake 45 652 / 3 life , cake , 72 ° f ., weeks 32 10color recovery , extract 75 % 51 % aerobic plate count , extract 70 , 000 2 , 000 , 000aerobic plate count , cake 2 , 000 220 , 000overall color recovery ( extract 98 % 91 % and cake ) visual appearance , cake red - brown red - tanthroughput rate , lbs per hour 2 , 500 800______________________________________ it is readily apparent that there are substantial advantages to higher temperatures and pressures . the color recovery is enhanced , there is a 50 % increase in yield to the extract , the rate for a given press size is increased by over 300 %, the color stability of the extract is improved by 65 %, the color stability of the residual solids cake is improved by 300 %, and the aerobic plate count is reduced by a factor of greater than 30 in both the extract and the residual cake ; all without the oxidative color losses that are alleged to be an obstacle in u . s . pat . no . 4 , 681 , 769 . it is thereby seen that an improved countercurrent process for the extraction of capsicum solids using an edible solvent , whereby improved yields of both extract and residual solids are obtained , whereby both the extract and the residual solids have improved color stability and freedom from bacterial contamination due to the higher temperatures employed , whereby due to optional advantageous rehydration of residual solids and level of water activity employed an improved color stability in the residual solids is attained , whereby an extract in the form of a clear solution can be obtained by removal of gums and particulate solids in the form of their insoluble hydrates , whereby even greater color stability can be effected by the employment of edible antioxidants in the solvent utilized , and whereby controlled browning of the residual solids may be conveniently effected , all without the expected disadvantages of employing higher temperatures as clearly indicated by the prior art , and whereby all of the stated objects of the invention have been accomplished , has been provided . it is to be understood that the invention is not to be limited to the exact details of operation , or to the exact compositions , methods , procedures , or embodiments shown and described , as obvious modifications and equivalents will be apparent to one skilled in the art , and the invention is therefore to be limited only by the full scope which can be legally accorded to the appended claims .

principal components of paprika , red pepper , pungent chili , or other plants of the genus capsicum containing carotenoid pigments are simultaneously extracted and concentrated with an edible solvent in a series of mixing and high temperature and pressure mechanical pressing steps using edible solvent and a countercurrent extraction procedure . the extract containing the carotenoid pigments may be hydrated and then centrifuged to remove fine particulate solids and gums . a solution having several times the concentration of the carotenoid pigments and other flavor and aroma components of the starting raw material is obtained . the residual press solids may be cooled and hydrated following the last pressing operation . the residual press solids and extract have significantly reduced bacterial counts as a result of the temperatures , high pressure , and high shear utilized , as well as the low moisture levels employed , thus producing not only a food grade extract but also a food grade residual solid having low bacterial counts and predictable , standardized levels of the principal components of interest . the degree of browning or caramelization of the residual press solids is controlled , and the resistance to oxidative deterioration of the carotenoid pigments of both the extract and the residual solid is improved , by control of the temperature employed . additionally , edible antioxidants can be included in the solvent to enhance the stability of both the extract and the residual solid .

fig1 a shows a top perspective view 100 of an embodiment of an optical probe adapter . the optical probe adapter 100 has a optical fiber coupler 105 at the proximal end and a probe coupler 125 at the distal end . a fiber receiver 110 and cover 115 serve as a handle and also as a housing for an optical fiber , or optical fiber bundle . fig1 b shows a top view 101 of the optical probe adapter of fig1 a . a knob 120 provides a means of advancing or retracting the fiber housed within the optical fiber adapter . the probe coupler 125 has a conical taper 130 that accepts a probe ( e . g ., hypodermic needle ). the conical taper 130 may be a luer taper . a luer lock or other interlocking connector may be used in conjunction with the probe coupler 125 . however , since the optical probe adapter is only temporarily coupled to the probe , ease of removal is desired so that the probe position is not perturbed during removal . fig1 c shows a front view 102 of the optical probe adapter of fig1 a . the optical fiber coupler 105 has two optical fiber terminals 140 . in alternative embodiments , the optical fiber coupler 105 may have a greater or lesser number of optical fiber terminals . the optical fiber coupler 105 has two detents 135 that provide a means for locking the coupler into a mated connector . there are many types of optical fiber couplers that may be used . however , most conventional optical fiber adapters are designed for many make - and - break connections . for disposable or single use optical probe adapters , it is preferable that the optical fiber coupler 105 be kept mechanically simple . any complexity associated with obtaining a reliable connection should reside in the non - disposable component with which the optical coupler 105 may be mated . fig1 d shows a front perspective exploded view 103 of the optical probe adapter of fig1 a . an optical fiber bundle 140 is connected to the optical fiber coupler 105 . in other embodiments , a single fiber may be substituted for the optical fiber bundle 140 . the optical fiber bundle 140 resides in a cavity 145 in the receiver 110 . the cavity 145 has a series of radiused edges 150 that allow the optical fiber bundle to be compactly housed . in general , housing of the optical fiber bundle 140 requires that at least a portion of the optical fiber bundle 140 be stored in a curved configuration . for efficient packing at least one portion will typically have an arc of at least 90 degrees and may have a variable radius . the length of the optical bundle that is ultimately advanced through the probe coupler 125 is derived from the straightening of a curved portion . although spirals or coils may also be used as housing configurations for the optical fiber bundle 140 , the serpentine configuration shown in fig1 d has the advantage of avoiding twisting of the fiber during assembly and use . an arc length of 180 degrees is used in the serpentine configuration . the optical fiber 140 is advanced and retracted by a drive roller 160 acting against a pinch roller 170 . the driver roller 160 has a soft outer covering 164 that reduces localized stress in the area of contact with the optical fiber bundle 140 . similarly , the pinch roller 170 has a soft outer covering 172 . the conformation of the soft outer coverings 164 and 172 with the optical fiber bundle 140 increases the contact area and the overall friction that provides the force for advancing and retracting the optical fiber bundle 140 . in alternative embodiments other fiber advancing mechanisms may be used . an optional gasket 175 provides a seal between the face of the drive roller 160 and the cover 115 . alternatively , a seal may be established between the drive roller axle portion 165 a and the surface of the drive roller axle bore 180 . a keyway 162 in the driver roller bearing portion accepts a key 168 ( fig1 e ) that transmits torque applied to the knob 120 . the receiver 110 includes a drive roller axle bearing cavity 166 a and a pinch roller axle bearing cavity 176 a . the drive roller axle bearing cavity 166 a and a pinch roller axle bearing cavity 176 a are blind cavities ; however , through holes may be used in other embodiments . an optional storage cavity 155 provides a volume adjacent to drive roller 160 and pinch roller 170 . upon retraction , the optical fiber bundle 140 will not easily resume its initial configuration and the storage cavity provides a local storage site . although retraction may not be required to complete a particular medical procedure , it may be desirable to retract the optical fiber 140 for easier handling . fig1 e shows a back perspective exploded view of the optical probe adapter of fig1 a . the cover 115 has an optional storage cavity 155 similar to that associated with the receiver 110 . the cover 115 includes a drive roller axle bearing cavity 166 b and a pinch roller axle bearing cavity 176 b . an axle 174 supports pinch roller 170 . since it is desirable to minimize resistance to rotation , it is preferable that axle 174 not be fixed to pinch roller 170 . in contrast , drive roller axle portions 165 a and 165 b are integrated with drive roller 160 . a minimum resistance to rotation is desirable in the drive roller 160 so that it can hold the optical fiber 140 in a fixed position after alignment . a key 168 transmits the torque applied to knob 120 to the pinch roller 160 . the knob 120 , key 168 , and drive roller 160 may be fabricated as an integrated unit or as components that are separable in whole or in part . a removable knob 120 and key 168 are desirable when they would interfere with positioning of an attached probe after extension of the optical fiber bundle 140 . fig2 a shows a perspective view 200 of an embodiment of an optical probe adapter 205 with an attached hypodermic needle 210 . in alternative embodiments a cylindrical cross - section may be substituted for the rectangular cross - section . although the rectangular cross - section minimizes the size of the optical probe adapter , the radial symmetry of a cylindrical cross - section may provide greater ease of handling . although the hypodermic needle 210 is shown as shorter than the optical probe adapter 205 , the hypodermic needle 210 may be longer than the optical probe adapter 205 . for example , the optical probe adapter may have a length of about 10 centimeters and the hypodermic needle may have a length of 10 to 15 centimeters . fig2 b shows an alignment of an optical fiber 240 at the tip of the attached hypodermic needle 210 of fig2 a . fig3 shows a diagram 300 of an embodiment of a probe positioning system . an optical coherence tomography ( oct ) instrument 305 a provides illumination and receives a reflected light signal through an optic fiber 310 that has a connector 315 . the optical coherence tomography ( oct ) instrument 305 a may be a battery powered portable instrument . the connector 315 mates to the optical fiber adapter 320 via the fiber optic coupler 320 a . the housing 320 b contains a length of optical fiber that may be advanced to align with the distal tip 330 of a probe 325 . fig4 shows a flow chart diagram 400 for an embodiment of a method for inserting a probe using a system similar to that shown in fig3 . at step 405 an optical coherence tomography ( oct ) instrument is attached to an optical fiber probe adapter . this connection will typically be made using a cable . a probe is also attached to the optical fiber probe adapter . the probe may be connected by a simple press fit or it may be connected by a mechanical interlock such as a thread , bayonet , or twist lock . at step 410 the optical fiber is advanced from the optical fiber probe adapter and aligned within the probe . generally , the optical fiber will be advanced to the vicinity of the distal tip of the probe . however , if a portion of the probe is transparent , the optical fiber may reside entirely within the probe . at step 415 the probe is inserted to the desired location using the visual image provided by the oct instrument . probes for procedures such as catheterization and nerve blocks may be inserted with the optical fiber probe adapter . at step 420 the probe is disconnected from the optical fiber probe adapter . the probe may be disconnected without changing the alignment of the optical fiber within the probe , or the optical fiber may be realigned prior to being disconnected . at step 425 the optical fiber is withdrawn from the probe . at step 430 the optical fiber is retracted into the probe . retraction of the optical fiber into the probe is an optional step and may be performed prior to withdrawal of the optical fiber from the probe . at step 435 a therapeutic device such as a syringe or a catheter is coupled to the probe . while the invention has been described in detail with reference to preferred embodiments thereof , it will be apparent to one skilled in the art that various changes can be made , and equivalents employed , without departing from the scope of the invention .

an adapter couples a length of optical fiber to a hollow probe and to an optical coherence tomography instrument . the length of optical fiber may be greater than the length of the adapter itself . the optical fiber is fixed to an optical coupler at a proximal end of the adapter and may be maintained in a curved configuration by features located in an internal cavity of the adapter . an optical fiber advance mechanism be used to advance and / or retract the length of optical fiber to align it within the hollow probe .

fig1 illustrates a safety intravenous catheter assembly 10 in accordance with the present invention for use with a needle 12 . generally , safety intravenous catheter assembly 10 includes a catheter hub 18 , a catheter cannula 19 , a needle cover 22 , a stop bar 42 , and a needle case 44 . the various embodiments of the present invention , as described in greater detail below , result in the safety intravenous catheter assemblies which after inserting the catheter cannula into a patient and removing the needle from the catheter cannula and catheter hub , automatically provides a non - removable protective cover over a tip of the needle thereby reducing the risk of needlestick injuries to health workers . safety intravenous catheter assembly 10 is configured so that catheter hub 18 is inhibited from rotating relative to needle cover 22 . in the embodiment shown in fig1 - 8 , the fixedly connected catheter hub 18 and needle cover 22 does not rotate around needle 12 . in another aspect of the present invention , as explained in greater detail below in connection with fig9 - 13 , a fixedly connected catheter hub and needle cover may , however , be made to rotate around the needle . with reference again to fig1 , catheter cannula 19 is attached to catheter hub 18 and includes a first axial bore 20 extending through catheter cannula 19 and catheter hub 18 . needle cover 22 has a first upper end 24 insertable in axial bore 20 of catheter hub 18 . a second axial bore 26 extends through needle cover 22 and may be co - axial with axial bore 20 when assembled . the components of the assembly may be constructed from materials similar to those for pre - existing iv catheters and related parts . for example , sterile grade rigid plastic can be used to form catheter hub 18 , needle cover 22 , stop bar 42 and needle case 44 . stop bar 42 may alternatively be sterile grade stainless steel . needle 12 may comprise a sterile grade stainless steel . with reference to fig1 and 2 , catheter hub 18 includes a notch 28 extending outwardly from axial bore 20 of catheter hub 18 . a notch clip 30 is joined via a resilient arm 33 with needle cover 22 and positionable to engage notch 28 of catheter hub 18 . this enables catheter hub 18 to be fixedly connected so that catheter hub 18 does not rotate relative needle cover 22 when the two are fully engaged . an inner surface of notch clip 30 may be substantially parallel to second axial bore 26 . notch clip 30 in a rest position may be spaced from or in a non - forceful contact with needle 12 , so that notch clip 30 at most rests against needle 12 as in side - by - side non - forceful contact . for example , an annular space 31 may be provided adjacent notch clip 30 and second axial bore 26 . in addition , appropriately sizing the notch clip may result in the notch clip being spaced from the needle and spaced from the notch in the catheter hub . in this configuration , the assembly reduces and limits the frictional drag between notch clip 30 and needle 12 when needle 12 is inserted into and withdrawn from needle cover 22 . the notch clip and the needle cover may be monolithic and integrally formed as one - piece . alternatively , the notch clip could be an independent piece configured for a snap fit or bonded or glued relationship with the needle cover . as described above , the radially inward side or inner surface of the notch clip may be in or adjacent to the annular space 31 , e . g ., not continuously contacting , and at most co - planar with a second surface 27 ( fig3 ) defined by an outer circumference of the second axial bore when the notch clip is at rest . notch clip 30 and arm 33 are preferably made of a resilient type material having a characteristic which enables it to flex radially inward with minimal force . this force is provided by notch 28 and a bottom portion of the catheter hub 18 as the catheter hub disengages from the needle cover . this disengagement preferably only occurs when a needle tip 16 ( fig1 ) is located below or away from an upper distal portion of the notch clip , i . e ., when removing the protected needle from the catheter hub , as explained in greater detail below . with reference particularly to fig1 , embodiments of the present invention may include additional safety features such as a stop assembly joined with a second end 41 of needle cover 22 . the joined relationship may be obtained by forming integral or a conventional bonding or gluing process , or a snap - fit relation . the stop assembly serves to limit withdrawal of the needle from the needle cover by maintaining the tip of the needle inside second axial bore 26 of needle cover 22 . for example , the stop assembly may comprise stop bar 42 joined with the needle cover at the second end . in this embodiment the stop assembly further includes needle case 44 joined with the needle at a lower end 46 of the needle , such as by a conventional forming , bonding or gluing process . as should be apparent , the lower end of the needle is in fluid flow communication with the needle case via a chamber 43 a . the stop bar communicates with the needle case via an opening 45 in a second chamber 43 b . the stop bar 42 , needle case 44 , and a detent 47 are designed so that sliding movement of the stop bar has minimal frictional drag ( fig4 and 5 as described in greater detail below ). the stop bar and detent 47 may be of any design to stop the bar at the desired length of extension . the stop bar may also be designed to extend telescopically and then lock , which would decrease the needle case length . assembly and use of safety intravenous catheter assembly 10 is illustrated in fig3 - 8 . as will become apparent for the following description , the relationship between the notch and the notch clip , and the stop assembly , contributes to several of the features and advantages of the present invention . with reference to fig3 , initially first upper end 24 of needle cover is inserted in axial bore 20 of catheter hub 18 and the upper distal portion of notch clip is aligned to slip into notch 28 when needle cover is loaded into catheter hub 18 . this moves the upper distal portion of the notch clip completely out of the second axial bore which permits preferred unrestricted movement of needle 12 into the second axial bore , thus facilitating easy assembly of the device . next , with reference to fig4 , stop bar 42 of assembly 10 is inserted into needle case 44 and needle 12 is aligned with second axial bore 26 . when the needle is inserted in the second axial bore at least adjacent or past an upper distal portion of the notch clip , the notch clip can engage the side of the needle and notch 28 and lock the catheter hub in engagement with the needle cover . fig5 illustrates safety intravenous catheter assembly 10 in the configuration for insertion into a patient . the needle maintains the notch clip in the notch and automatically inhibits the catheter hub from disengaging from the needle cover prematurely . any of several approaches could be used for assembly such as where the needle case is intact and fully enclosed or by having a side opening which is later covered and sealed closed . with reference again to fig3 , if the needle case is fully enclosed in final form and , for example , opening 45 is slot shaped , the stop bar can be rotated ninety degrees and inserted into the needle case and rotated back ninety degrees . the stop bar then passes by resilient detent 47 , by having detent 47 retracted radially outward to permit the stop bar to be inserted . for example , this radial retraction can be accomplished via a hook externally or other device via a small opening in the outside wall of chamber 43 b or other conventional means . the process of catheter insertion of assembly 10 in a patient is illustrated in fig5 - 8 . initially , with reference to fig5 , the process involves placing needle tip 16 into a vessel lumen . after placing needle tip 16 into the vessel lumen , the user holds needle case 44 stationary ( which maintains needle 12 stationary ) and advances catheter cannula 19 into the vessel lumen until catheter hub 18 abuts the skin . then needle case 44 is withdrawn to completely withdraw needle 12 from catheter cannula 19 and partially withdraw needle 12 from catheter hub 18 . as shown in fig6 , as stop bar 42 is withdrawn from the needle case , detent 47 continues to be forced to the right until eventually , the l - shaped portion of the stop bar passes beyond the distal aspect of detent 47 and the detent can spring underneath the l - shaped portion . this action serves to stop the re - insertion of the stop bar into the second chamber 43 b . at this position needle tip 16 is adjacent to the upper distal portion of notch clip 30 . the stop bar is withdrawn a small amount more from the needle case , as shown in fig7 , so that the needle tip is located prior to the upper distal portion of the notch clip thereby allowing the catheter hub to be disengaged from the needle cover . this preferred small additional movement of the stop bar ensures that the catheter hub does not disengage from the needle cover until the stop bar &# 39 ; s l - shaped end is locked above detent 47 and the needle tip is thereby locked inside the needle cover . thereafter , as shown in fig8 , the catheter hub 18 can be fully disengaged from the needle cover 22 . any alternative mechanism to the detent can be used as long as it functions to lock into the final position , as described above , the l - shaped or other shaped end of the stop bar and such that there is preferably a minimum of frictional drag during catheter insertion . for example , fig1 and 19 illustrate alternative embodiments of the configurations for the needle cover and the stop mechanism . another aspect of the present invention is illustrated in fig9 - 13 , in which means are provided for rotatably attaching at least one of the needle case and the stop assembly in relation to the needle cover so that the needle cover and the catheter hub as a unit is rotatable around the axis of the needle particularly when inserting the cannula into the patient . for example , with reference to fig9 , therein illustrated are catheter hub 18 and a needle cover 122 . needle cover 122 includes a disk - shaped bottom portion 123 having an outwardly - extending flange 125 . the stop assembly includes a stop bar 142 having a disk - shaped member 160 having an upwardly - extending portion 162 with an inwardly - extending flange 164 which is attachable to outwardly - extending flange 125 of needle cover 122 , for example , in a snap - fit manner . in this configuration , the bottom portion of the needle cover and the disk - shaped member of the stop bar may be suitably sized to allow the bottom portion of the needle cover to rotate within the disk - shaped member of the stop bar . with reference to fig1 , therein illustrated are catheter hub 18 and a needle cover 222 . needle cover 222 includes a bottom portion 223 having an outwardly - extending flange 225 . the stop assembly includes a stop bar 242 having a ring - shaped member 260 having a pair of spaced - apart inwardly - extending flanges 264 for attaching to outwardly - extending flange 225 of bottom portion 223 , for example , in a snap - fit manner . the bottom portion of the needle cover and the ring - shaped member of the stop bar may be suitably sized to allow the bottom portion of the needle cover to rotate within the ring - shaped member of the stop bar . fig1 and 12 illustrate another embodiment of a catheter hub 18 ( fig1 ) and a needle cover 322 . needle cover 322 includes a bottom portion 323 having a groove 325 . the stop assembly includes a stop bar 342 having an upper end having a pair of outwardly - extending flanges 364 ( fig1 ) attachable to and movable within groove 325 . flanges 364 may be received in groove 325 in a snap - fit manner . the groove in the bottom the needle cover and the upper end of the stop bar may be suitably sized to allow the stop bar to easily rotate within the groove . fig1 illustrates a needle case 444 in which an opening 445 has an arcuate configuration to allow a stop bar 442 to rotate around the axis of the needle , e . g ., an amount less than 360 - degrees . from the present description , it will be appreciated by those skilled in the art that the opening may be an annular opening , for example , the center portion of the needle case may be attached to the bottom of the needle case , thereby permitting a 360 - degree rotation of the stop bar around the axis of the needle . from the present description , it will be appreciated by those skilled in the art that the various safety intravenous catheter assemblies described above may be configured for 360 - degree rotation of the catheter hub and needle cover as a unit around the axis of the needle , or configured for less than 360 - degree rotation . the needle cover and notch clip &# 39 ; s design provide selective sliding engagement with the side of the needle such that there is minimal , and preferably no , frictional drag so that catheter hub and needle cover as a unit may easily rotate around the needle axis , and also , so that the catheter hub and needle cover combined can easily move distally towards the needle tip during iv catheter insertion . in another embodiment as shown in fig1 , a safety intravenous catheter assembly 510 in accordance with the present invention may include the stop member comprising a ring - like stop 548 joined to the lower end of a needle cover 522 , and a needle 512 having a stop notch 550 located in the side of the needle . in operation , as the needle is withdrawn from the needle cover , ring - like stop 548 engages stop notch 550 thereby maintaining the tip of the needle inside needle cover 522 . then , the catheter hub 18 can be removed in a similar fashion as described previously . in this embodiment , the ring - like stop 548 is preferably constructed of a resilient material that is sized to automatically and continuously engage the circumference of needle 512 . when being assembled , the ring - like stop can be temporarily relaxed to enable insertion of the needle into needle cover 522 and passing stop notch 550 past ring - like stop 548 . other aspects of the invention may concern the notch clip . for example , as shown in fig1 - 11 , the notch clip is configured as a p - shaped member . in another embodiment , as shown in fig1 , a safety intravenous catheter assembly 610 in accordance with the present invention may include a notch clip comprising a ball bearing 630 which engages a concave notch disposed in catheter hub 618 to releasably lock a needle cover 622 to catheter hub 618 . fig1 illustrates still another embodiment a safety intravenous catheter assembly 710 in accordance with the present invention . when the needle diameter is sufficiently large , a needle cover 722 may not require a notch disposed opposite a notch clip 730 if the second axial bore is large enough to ensure the notch clip distal portion completely disengages notch 728 during withdrawal of the needle cover from the catheter hub . as understood herein , withdrawn , withdrawal or withdrawing means any movement of one member away from another member in the range from partial withdrawal ( at least some portion of the respective members are still in communication with each other ) to complete withdrawal ( no portion of the respective members are in communication with each other ). with reference again to fig5 - 8 , generally as the catheter cannula is advanced into a vessel and the needle is withdrawn from the second axial bore , the user can , if desired , hold or engage the exposed needle cover portion adjacent the stop bar . fig1 illustrates another embodiment of a safety intravenous catheter assembly 810 in accordance with the present invention . for example , when advancing a catheter cannula 819 into a vessel and withdrawing a needle 812 from a catheter hub 818 which is still fully engaged with a needle cover 822 , needle cover 822 may be provided a finger rest 856 . in this way , one can advance the catheter cannula and withdraw the needle without pushing directly with the catheter hub by instead pushing the catheter hub via the needle cover and most preferably the finger rest , thereby enabling cannula advancement and withdrawal of the needle with minimal , and preferably no , friction between the needle and the notch clip . finger rest 856 may comprise an annular ring or one or more protrusions extending from the needle cover . also , it is preferred that finger rest 856 extend no further than the outer circumference of the adjacent portion of the catheter hub 818 , though a longer extension may be desired by some users . alternatively , instead of using finger rest 856 , the user can advance the cannula and withdraw the needle by pushing directly with catheter hub 818 . various additional uses can be made with the safety intravenous catheter assemblies . for example , with reference again to fig1 , to assist in the insertion of the cannula into a blood vessel or body cavity , a flexible guide wire ( not shown ) can be inserted via an opening 52 in the chamber 43 a and advanced into the first end 46 of the needle and made to exit tip 16 ( i . e ., seldinger wire technique for vascular access ). in this regard a minor modification ( not shown ) of the chamber &# 39 ; s internal shape would facilitate easy access of a flexible guide wire into needle end 46 . alternatively , a syringe ( not shown ) can be attached to chamber 43 a via opening 52 , for communicating a fluid to or from the chamber 43 a . although not shown , opening 52 may be located in the center of the proximal end of the needle case , which is accomplished by making conventional modifications of the needle case . although preferred embodiments have been depicted and described in detail herein , it will be apparent to those skilled in the relevant art that various modifications , additions , substitutions and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the following claims .

a safety intravenous catheter assembly includes a needle , a catheter hub having an axial bore extending through the catheter hub and a notch extending outwardly in the axial bore , a needle cover , and a notch clip connected to the needle cover . the notch clip is selectively maintained adjacent the needle throughout a range of positions from being in forceful contact with the needle to being generally spaced from the needle and selectively maintained adjacent the catheter hub throughout a range of positions from being in forceful contact with the catheter hub to being generally spaced from the catheter hub to lock the catheter hub to the needle cover while being operable to move the needle relative to the notch clip in a near frictionless relationship .

embodiments of the present disclosure will now be described in detail with reference to the drawings . referring to fig1 and 2 , an electronic device 100 according to an exemplary embodiment is illustrated . the electronic device 100 includes a housing 10 , a drawer 20 received in the housing 10 , and a component 30 carried by the drawer 20 . in this embodiment , the component 30 is a hard disk drive ( hdd ), and the electronic device 100 is a notebook computer . in other embodiments , the component 30 can be a battery , a cd / dvd drive , or other components , and the electronic device 100 can be a desktop computer , a dvd player , or other electronic devices . the component 30 includes an interface portion 31 . the interface portion 31 is used for electrically connecting the component 30 to a circuit board ( not shown ) of the electronic device 100 . a plurality of limiting holes 33 is defined on opposite sides of the component 30 next to the interface portion 31 . the housing 10 includes a top wall 11 , a bottom wall 13 , and a side wall 15 connecting the top wall 11 to the bottom wall 13 . the top wall 11 , the bottom wall 13 , and the side wall 15 cooperate to define a receiving room 17 . an opening 150 is defined in the side wall 15 . the opening 150 is used for receiving for the drawer 20 to move in and out of the housing 10 . the drawer 20 includes a drawer assembly 21 , a guiding assembly 23 , and a locking assembly 27 . the drawer assembly 21 is received in the receiving room 17 and is used for carrying the component 30 . the drawer assembly 21 is configured to move in and out of the housing 10 via the opening 150 . the drawer assembly 21 includes a first limiting portion 151 , a second limiting portion 153 opposite to the first limiting portion 151 , a first slider 211 , a second slider 212 substantially parallel to the first slider 211 , and a face plate 213 perpendicularly connected to the first slider 211 and the second slider 212 . one end of the face plate 213 is connected to the first slider 211 , and the other end of the face plate 213 is connected to the second slider 212 . the two limiting portions 151 and 153 are set on the inside surface of the side wall 15 . each of the limiting portions 151 and 153 defines a first through hole 1510 . the opening 150 is between the two limiting portions 151 and 153 . the first slider 211 and the second slider 212 define two second through holes 2112 corresponding to the first through holes 1510 . the two sliders 211 and 212 , and the face plate 213 cooperate to define a receiving space 214 . the receiving space 214 is used for receiving the component 30 . a plurality of limiting poles 2110 is set on inner sides of the first slider 211 and the second slider 212 . the limiting poles 2110 corresponds to the limiting holes 33 of the component 30 . the drawer assembly 21 via the limiting poles 2110 is inserted into the corresponding limiting holes 33 . when the component 30 is carried out , the interface portion 31 is away from the face plate 213 , and electrically connects with the circuit board of the electronic device 100 . the face plate 213 is received in the opening 150 , and allows convenient manipulation by users for moving the drawer assembly 21 in and out of the receiving room 17 . in other embodiments , the drawer assembly 21 can be other structures as long as the drawer assembly 21 can carry the component 30 . for example , the assembly 21 can further include a bottom plate perpendicularly connected to the two sliders 211 and 212 , and the face plate 213 . the receiving space 214 , used for receiving the component 30 , is defined in the bottom plate , the two sliders 211 and 212 , and the face plate 213 . the face plate 213 is substantially rectangular and is configured to cover the opening 150 . a first receiving hole 2130 is defined in the middle of the face plate 213 . in this embodiment , the first receiving hole 2130 is substantially round . a limiting member 210 and two protrusions 2132 are set on the same side of the face plate 213 opposing the two sliders 211 and 212 . the limiting member 210 is substantially bridge - shaped and located above the first receiving hole 2130 . the limiting member 210 defines a second receiving hole 2100 . the second receiving hole 2100 is substantially elliptic and corresponds to the first receiving hole 2130 . one of the protrusions 2132 is set between the first slider 211 and the limiting member 210 , and the other one is set between the second slider 212 and the limiting member 210 . the guiding assembly 23 is used for supporting the drawer assembly 21 and guiding the drawer assembly 21 to slide in and out of the receiving room 17 . the guiding assembly 23 includes four guiding members 230 . each guiding member 230 includes a first fixing portion 231 , a second fixing portion 233 substantially parallel to the first fixing portion 231 , and a connecting portion 235 connecting the two fixing portions 231 and 233 and are configured to define a guiding groove 237 . the first fixing portion 231 is set on the bottom wall 13 and faces the top wall 11 . the guiding groove 237 is used for receiving one of the two sliders 211 and 212 . the guiding assembly 23 has four guiding members 230 , four guiding grooves 237 are defined accordingly . two of the four guiding grooves 237 receive the first slider 211 , and the other two grooves 237 receive the second slider 212 . thus , the drawer assembly 21 is slid along the guiding assembly 23 and in the four grooves 237 and against the connecting portion 235 . in this embodiment , the two fixing portions 231 and 233 , and the connecting portion 235 are substantially cylindrical . the cylindrical connecting portion 235 gives a low friction force to the sliding drawer assembly 21 . in other embodiments , the two fixing portions 231 and 233 can be other shapes . in the embodiment , screws can be engaged with the guiding assembly 23 and the bottom wall 13 , thus , the guiding assembly 23 is fixed on the bottom wall 13 . the guiding assembly 23 can also be fixed on the bottom wall 13 by means of any suitable adhesive . in other embodiments , the number of the guiding members 230 can be more than four , and the guiding assembly 23 can be another structure as long as the guiding assembly 23 can guide the drawer assembly 21 to slide in and out of the receiving room 17 . for example , the guiding assembly 23 can have two opposite grooves , one of the two grooves receives the fixing slider 211 , and the other one receives the second slider 212 . to keep the drawer assembly 21 from disengaging out of the receiving room 17 of the housing 10 , the locking assembly 27 is used for locking the drawer assembly 21 to the housing 10 . the locking assembly 27 includes a rotatable key 271 , an elastic member 270 , two moveable members 273 , and two rods 277 . the elastic member 270 is a spring . in other embodiments , the elastic member 270 can be a ring made of elastic material , such as rubber . the two moveable members 273 have the same structure . each of the two moveable members 273 defines two holes 2731 . referring to fig2 and 3 , the rotatable key 271 includes a keycap 2710 , a first fixing member 2712 , and two second fixing members 2714 extending from the same side of the keycap 2710 . the keycap 2710 is received in the first receiving hole 2130 of the face plate 213 , and can be rotated by an external force . in this embodiment , the out surface of the keycap 2710 is a rough texture for being rotated easily . the rough out surface of the keycap 2710 is formed by setting several embossed strips thereon . of course , the rough out surface of the keycap 2710 can be formed by defining several recesses thereon . one end of the first fixing member 2712 connected to the keycap 2710 is substantially round , and the other end of the first fixing member 2712 away from the keycap 2710 is substantially elliptic . the first fixing member 2712 extends through the second receiving hole 2100 of the limiting member 210 to be received in the second receiving hole 2100 . the elastic member 270 sleeves on the round end of the first fixing member 2712 and is positioned between the keycap 2710 and the limiting member 210 . the elliptic end of the first fixing member 2712 is free . the radius of the round end is smaller than the semi minor axis of the elliptic end . the two second fixing members 2714 are symmetrical about the first fixing member 2712 . ends of the two second fixing members 2714 are set on the keycap 2710 , the other ends are free . the two second fixing members 2714 extend through the corresponding holes 2731 . in this embodiment , the two second fixing members 2714 are bolts which are engaged with the keycap 2710 , thus , the two moveable members 273 are fixed to each corresponding second fixing member 2714 by bolts and cannot be moved away from the corresponding second fixing members 2714 . further referring to fig4 , the two rods 277 have the same structure . ends of the two rods 277 are received in the corresponding first through holes 1510 after passing through the second corresponding through holes 2112 . the other ends of the two rods 277 are substantially perpendicular to the shafts of the two rods 277 , respectively , and are received in the corresponding holes 2731 . thus , the two moveable members 273 connect the two rods 277 and 279 to the rotatable key 271 . when the keycap 2710 is pressed , the keycap 2710 drives the first fixing member 2712 to further extend through the second receiving hole 2100 of the limiting member 210 , thus the elastic member 270 is deformed . the free end of the first fixing member 2712 protrudes out of the second receiving hole 2100 . then when the keycap 2710 is rotated , the first fixing member 2712 is driven by the keycap 2710 to rotate until the elliptic end of the keycap 2710 is fastened with the limiting member 210 . as such , even if the pressure on the keycap 2710 is released , the first fixing member 2712 is still fastened with the limiting member 210 because of the elliptic end . the free end of the first fixing member 2712 will be received in the second receiving hole 2100 again until the keycap 2710 is rotated back . when the keycap 2710 is rotated back , the elastic member 270 is reset and drives the keycap 2710 to be reset . when the keycap 2710 is pressed and rotated , the keycap 2710 drives the two moveable members 273 to rotate about the centre of the second fixing members 2714 . the two moveable members 273 push or pull the rods 277 to further extend through or withdraw from the first through holes 1510 . when the two rods 277 pass through the first through holes 1510 , the locking assembly 27 locks the drawer assembly 21 in the receiving room 17 ( see fig5 ). when the two rods 277 withdraw from the first corresponding through holes 1510 , the locking assembly 27 unlocks the drawer assembly 21 from the housing 10 ( see fig6 ). in this embodiment , each of the two protrusions 2132 of the face plate 213 are above or below but near the two rods 277 , respectively , to balance a force exerted by the two moveable members 273 when the keycap 2710 is rotated . in other embodiments , one of the two moveable members 273 , and one of the two corresponding rods 277 can be removed . thus , the locking assembly 27 only uses one moveable member 273 and one corresponding rod 277 to lock and unlock . as described above , when the locking assembly 27 locks the drawer assembly 21 , carrying the component 30 , within the receiving room 17 of the housing 10 . the component 30 is enclosed for protection . when the drawer assembly 21 is unlocked with the locking assembly 27 , the component 30 can be carried , from the housing 10 . the component 30 can be move out of the drawer assembly 21 . thus , it is easy for users to remove or replace the component 30 . while various exemplary and preferred embodiments have been described , it is to be understood that the disclosure is not limited thereto . to the contrary , various modifications and similar arrangements ( as would be apparent to those skilled in the art ) are intended to also be covered . therefore , the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements .

a drawer received in an electronic device includes a drawer assembly and a locking assembly . the drawer assembly is detachable attached to the electronic device and can be used as a carrying case for components of the electronic device . the locking assembly includes a rotatable key set on the drawer assembly , a rod operable to fix or release the drawer assembly from the electronic device , and a moveable member movably connected between the rotatable key and the rod . the moveable member is driven by the rotatable key to drive the rod to fix or release the drawer assembly from the electronic device .

whether used in a hospital environment or in a home care environment , the present invention will generally have associated two main pieces of apparatus . firstly an active humidifier which controls the temperature of a heater plate heating a body of water to achieve a desired temperature and humidity of the gases being humidified . secondly a transport conduit from the humidifier to the patient is also required , which is preferably heated to reduce condensation , or “ rain out ”. referring to fig1 a humidifying apparatus as might be used in a hospital generally referenced 1 is shown . the apparatus comprises a body 2 containing heating means comprising a heating plate 20 having an electric heating element therein or in thermal contact therewith and control means for example electronic circuitry which may include a microprocessor for controlling the supply of energy to the heating element . the body 2 is removably engageable with a humidifying chamber 3 which contains water for humidifying gases . referring to fig2 which show the humidifier apparatus in more detail , the humidifying chamber 3 has edges which engage with collar 24 on the humidifier apparatus . the gases to be humidified may be a mixture of air , oxygen and anaesthetic for example which are supplied to the chamber through a gases inlet 4 . this might be connected to a ventilator , or in the case of cpap therapy a cpap blower . a gases outlet 5 is also provided and the gases outlet 5 is connected to the conduit 6 ( fig1 ) which conveys humidified gases to a remote destination such as an intubated patient at the end 7 of the conduit . alternatively , the end 7 of the conduit may have a gas mask attached thereto , which mask is used to cover a nose and / or mouth of a user so as to supply humidified gases to the user for breathing , as in the delivery of cpap therapy . the humidifier heater plate 20 has a temperature transducer 8 which is in electrical connection with the electronic control circuitry in body 2 of the apparatus so that the control means monitors the temperature of the heating plate . a heating element 10 is provided within the conduit 6 to help prevent condensation of the humidified gases within the conduit . such condensation is due to the temperature of the walls of the conduit being close to the ambient temperature , ( being the temperature of the surrounding atmosphere ) which is usually lower than the temperature of the humidified gases within the conduit . the heater element is effectively replaces the energy lost from the gases through conduction and convection during transit through the conduit . thus the conduit heater element ensures the gases delivered are at an optimal temperature and humidity . the present invention provides a means of controlling at least the heater plate and preferably also the conduit heater element without the need for any sensors , either in the humidifier chamber or positioned in the conduit . this is achieved by estimating the rate of flow of gases through the humidifier using parameters already available to the controller . for a given humidifier an appropriate level of power can then be determined to apply to the heater plate to achieve the desired temperature of gases delivered to the patient . additionally this may be used to provide a more appropriate level of energisation at this conduit heater element . this not only saves the cost of the extra sensors but also allows the apparatus connected to the end of the conduit to be simpler and lighter , in the preferred embodiment of the present invention the controller 100 , shown in fig3 uses a range of inputs to control both the power 108 supplied to the heater plate 110 as well as the power 114 supplied to the conduit heating element 116 ( if present ). in certain applications it may also be used to provide control instructions to auxiliary apparatus such as a blower fan . using an internal algorithm 106 the controller 100 estimates the power 108 to supply to the humidifier heater plate 110 to achieve a given humidity and or temperature of gases at the top of the humidifier chamber alternatively ( or estimates the temperature to achieve a given power ). it then uses a second algorithm 102 to estimate the required power 114 to supply to the conduit heater element 116 and the humidifier heater plate 110 to achieve optimal temperature and / or humidity of the gases delivered to the patient 118 . referring to fig4 when the humidifier starts up the controller executes a supervisory algorithm , which controls the heater plate and if present the conduit heater element . initially 128 the heater plate is controlled to a temperature of 40 ° c . and the conduit heater element may be energised with a duty cycle of for example 50 %. the heater plate temperature ( or alternatively the power supplied to the heater plate ) is then monitored 130 until it settles to a stabilised level . effectively a window 132 is superimposed over the heater plate temperature profile 134 of which an example is shown in fig5 . when the profile 134 ( over the entire period of the window 132 ) fits within the bounds of the window 132 , it is effectively considered to have stabilised . once this has occurred the controller enters a calculation stage . firstly , it calculates the flow rate of the gases 136 using any one of a number of methods which will be described later . secondly knowing the rate of flow of the gases the algorithm then calculates the required heater plate power 138 ( alternatively heater plate temperature ) to achieve a desired temperature / humidity of gases . a relationship has been empirically determined using a humidifier and a heated conduit such as that as described in u . s . pat . no . 5 , 640 , 951 , the contents of which are incorporated herein by reference . the actual relationship for any other arrangement would either have to be empirically determined by experimentation or theoretically calculated . for a desired temperature of gases exiting the humidifier of for example 37 ° c . the relationship between the power supplied to the heater plate ( p hp ), the rate of flow of gases ( f gas ) and the ambient temperature ( t amb ) is graphed in fig6 . from this an approximate general algebraic equation has been extrapolated which the controller can use to determine an approximate level of power to apply to the heater plate : p hp =(− 0 . 1239 × t amb + 5 . 383 )× f gas +(− 0 . 3112 × t amb + 10 . 738 ) thirdly the algorithm calculates the required power input to the conduit heater wire 140 to deliver a desired temperature of the gases to the patient . with gases flowing at a known rate of flow it is possible to calculate the resultant temperature of the gases once they have flowed through a conduit of known characteristics surrounded by the atmosphere at a known or assumed ambient temperature . thermal characteristics of the conduit will either be known or can be calculated by experimentation . this relationship is based off empirical data using a humidifier and a heated conduit such as that as described in u . s . pat . no . 5 , 640 , 951 . the actual relationship for any other arrangement would either have to be empirically determined by experimentation or theoretically calculated . with a conduit entry gas temperature of 37 ° c . and a temperature of gases delivered to the patient of 40 ° c ., the relationship between the flow rate of the gases ( f gas ), the power input to the conduit heater element ( p c ), the ambient temperature ( t amb ) is graphed in fig7 . this is extrapolated to a general algebraic expression : p c =(− 0 . 0005 * t amb + 0 . 0169 ) f gas 2 −[ 10 − 5 * t amb 3 − 0 . 0042 * t amb 2 + 0 . 2189 * t amb − 3 . 0075 ] f gas − 1 . 0169 * t amb + 38 . 956 practically this relationship can be simplified whereby p c is dependent only on t amb . this is an acceptable approximation for the conduit heater element , as it is not as crucial as the heater plate . once the heater plate and conduit heater element have been appropriately energised , the controller continues to monitor 142 the system for any changes in the variables . the main reason for this is to avoid thermal overshoot ie where the flow drops suddenly , the temperature of gases can become dangerously high . in order to monitor effectively , two methods are used . firstly the flow rate is monitored and secondly the change in flow rate ( with respect to time ) is also monitored . the first 144 is to allow the system to respond to any changes in the system . the second 146 is a fast response system in order to avoid thermal overshoot . effectively where either p hp or t hp is controlled constant , monitoring the other variable gives an indication of any change in flow , or any other variable which requires a recalculation . in order to monitor the flow a number of methods of estimating the flow are available . in the preferred embodiment of the present invention the flow is monitored for this purpose by monitoring the resistance of the heater wire 116 . the resistance will change according to the temperature of the heater wire , which will in turn be dependent on the flow of gases passing through the conduit 6 and the power supplied to the conduit heater element 116 . thus for a set input power , when the flow rate of the flow of gases changes , the temperature of the conduit heater element 116 will be affected and this will be reflected in the indication of the resistance of the conduit heater element 116 . the relationship between the airway and temperature 204 resistance ( r ) of the heater wire 116 is shown in fig8 and 9 . this indicates an almost linear relationship , which for this purpose can be considered linear . in this fashion large changes in the flow will be quickly detected by monitoring dr / dt 200 ; seen in fig9 and more gradually detected by monitoring r 202 seen in fig8 . a less preferred method is monitoring a variable x ( defined as p hp / t hp ), which is closely related to the flow rate , is constantly calculated and monitored . if it goes up there is a 30 minute delay before the controller initiates a recalculation , to avoid spurious readings and unnecessary calculations . if it goes down there is a 30 second delay before the controller recalculates , to avoid any possibility of the delivered gases being , even transiently , too hot . where large step changes occur the controller needs to react quickly . in such cases it will reset to initial conditions to wait until the system stabilises again , as any calculations in the interim would be pointless . to achieve this dx / dt is calculated and monitored . while a negative value is more dangerous , any deviation over a certain value will reset the controller . in a further alternative embodiment of the present invention the expected heater plate temperature is calculated using and if the actual heater plate temperature deviates by more than 5 ° c . then the program recalculates the required powers . ( 1 ) estimates the rate of flow of gases keeping all variables constant 136 . ( 2 ) estimate the required heater plate power / temperature to achieve a specified temperature / humidity of gases in the humidification chamber 138 . ( 3 ) calculate the power input to the heater wire to achieve a desired output temperature 140 . it will be appreciated that a greater level of power will be supplied to the conduit heater element if : it will also be appreciated that the heater plate temperature could be controlled to a set valve ( using closed loop control ) as opposed to power . in this case the power supplied would be monitored as a measure of system stability . furthermore where relationships are expressed algebraically they could equally be stored in look - up tables . generally when used in a hospital setting a humidifier such as that described in the present invention will be used in conjunction with a respirator to supply humidified gases to an intubated patient , or possibly using a respiratory mask . as such the humidifier will operate effective independently of the respirator and therefore must make all of its control decisions based on only the sensors contained therein . in the preferred embodiment of the present invention the flow rate of the gases passing through the humidification chamber can first be estimated by comparing the power input required 108 for the humidifier heater plate to the measured temperature 112 of the heater plate . in effect the higher the rate of flow of gases the larger the amount of power required by the heater plate in order to achieve a given heater plate temperature . thus for a given system the relationship between power to heater plate and flow rate for a given heater plate temperature can either be determined empirically or theoretically calculated . again using a humidifier and a heated conduit such as that as described in u . s . pat . no . 5 , 640 , 951 the following empirically determined relationship applies : f gas = - ( 0 . 831 - 0 . 0049 * t amb ) + abs | ( 0 . 831 - 0 . 0049 * t amb ) 2 - ( 4 * ( 0 . 00004 * t amb - 0 . 0057 ) * ( ( 14 . 348 - 0 . 25 * t amb ) - p hp ) ) | 2 * ( 0 . 0004 * t amb - 0 . 0057 ) where p hp is the power applied to the heater plate to achieve a given heater plate temperature in steady state of 50 ° c ., t amb is the ambient temperature and f gas is the gas flow rate . it will be appreciated this method is more appropriate in the hospital care environment where the ambient temperature can be assured with a high degree of confidence . in the homecare environment the present invention will often be employed in conjunction with a continuous positive airway pressure ( cpap ) device or such other breathing apparatus which will include a fan such as that described in u . s . pat . no . 6 , 050 , 260 , the contents of which are incorporated herein by reference . it will be appreciated that in such applications it may be possible to connect the controllers of the various devices together in an arrangement such that data may be readily exchanged . in such cases the rate of flow of the gases may be estimated directly from information available either from the fan or , where provided , a flow sensor . in this embodiment of the present invention the flow is estimated based on the loading of the fan . generally the fan will be controlled to run at a specified speed and therefore deliver a constant pressure output . the flow rate of the gases will depend on the restrictions in the flow path . in turn in order to maintain the specified speed a certain power input will be required for the fan . therefore an algebraic relationship between the actual gas flow rate and the power input to the fan can be developed for a fan of known characteristics . this relationship may either be determined empirically by experimentation or theoretically calculated using specified motor characteristics . a number of methods are known in the art for determining the loading on a motor from the supply it draws . the simplest such method would be to firstly meter the current drawn 148 from the fan 150 , as indicated in fig3 . the current 148 is the input to the conduit heater element controller 102 where either an algebraic relationship or a look up table is used to determine the flow rate of the gases . for example in u . s . pat . no . 5 , 740 , 795 , the contents of which are hereby incorporated herein by reference , a method is disclosed using both motor voltage and current to estimate the flow rate . while this represents one method , as mentioned above , it will be appreciated that other methods , such as based on just current , will be equally applicable . as mentioned in the second embodiment that in certain cases a flow sensor may already be provided in the gas flow path . this being the case , the gas flow rate 152 can be extracted directly from the flow sensor 154 and used as an input to the humidifier controller 100 , as indicated in fig3 . this is then used directly in the conduit heater element controller 102 to determine the power to apply to the heater plate 110 and conduit heater element 116 according to the algorithm shown in fig4 and described earlier . the present invention as described in the foregoing provides a novel method and apparatus for controlling the heater plate temperature in a humidifier for supplying humidified gases to a patient under respiratory therapy . this has the advantage of removing external sensors making the system simpler , cheaper and lighter . similarly it may also allow for effective control over energisation of the conduit heater element , ensuring the system as a whole operates correctly as well as being as efficient as possible .

a breathing assistance apparatus adapted to deliver humidified gases at a desired level of humidity to a patient including a humidifier and a heated conduit is disclosed . the humidifier includes a controller which determines the flow rate of the gases and then determines the required power input to the humidifier to deliver the gases to the patient at the required patient humidity . this means the need for external sensors is dispensed with and thus the apparatus is simple and less bulky . the resistance of the conduit heater element is monitored to give a coarse indication of flow rate .

referring now to the drawings , and more particularly to fig1 through 5 , the preferred embodiment of the present invention relates generally to a stabilized kite adapted for operation under a wide range of ambient air speeds . the kite , referred to generally by the reference designator 10 , has a wing or body 12 , fig1 with selected portions thereof held under tension or stretched conditions as further described below so as to be disposed in a substantially planar manner . the wing 12 is defined by an upper surface 14 and lower surface 16 . while the wing 12 may be any of numerous shapes -- triangular ; deltoid ; rectangular ; pentagonal ; symmetrical about longitudinal axis such as arrowhead , eagle , gull , and the like ; the body shape shown in the preferred embodiment is basically triangular . the triangular wing or body 12 is further defined by a centrally located central line or longitudinal axis 18 that bisects at the front of the wing the leading angle or apex 20 . the leading angle or apex 20 is in turn defined by the leading edges 22 and 24 of the wing . in a rectangular wing , the apex angle is 180 ° or 90 °; however , in the preferred embodiment the angle is approximately 70 °. depending from the wing portion of the kite is a keel or keel portion 26 structured to assume during flight of the kite a position lying within a plane that includes the central line or longitudinal axis 18 , said plane being substantially normal to the plane of the wing . on symmetrical , but nonplanar wing shapes , such as bird - like shapes having two joined , concave wing surfaces , the wing plane for purposes of the definition herein is further defined by two correspondingly positioned points in each of the wing surfaces and by a point on the central line such as the apex . the keel is commonly structured as a triangular body with a keel apex 28 defined as the point of the keel extending farthest away from the wing plane . in the triangular wing , as shown by the preferred embodiment , the keel portion is substantially adjacent the leading angle of the kite . rearward along the central line is found a stabilization or apertured elevating cell , generally indicated by reference designator 30 and shown in detail in fig4 . the construction of the stabilization cell 30 is best understood when discussed as hereinbelow in the fully open position as would be assumed during flight of the kite with forces operating to place the wing in a substantially planar and horizontal condition and the keel in a substantially planar and vertical condition . besides the keel and stabilization cell being structurally associated with the common wing portion , the two elements are interconnected by a keel cell strut or stabilization strut means 32 which is operationally described below . the structure of the elevating cell is further defined by an upper cell wall 34 shown herein as being coplanar with the wing , extending on either side of a spine 36 , a right cell wall 38 cell dividing wall 40 , and a left cell wall 44 . the cell walls 38 and 44 have stiffening or reinforcement means 42 and 46 , respectively , attached thereto . similarly , lower cell wall 50 is structured to accomodate stiffening means or transverse cell strut 48 . the cell walls 38 , 40 and 44 are disposed in the preferred embodiment in planes parallel to that of the keel whereas cell walls 34 and 50 are disposed in planes parallel to or identical to the wing plane . in the preferred embodiment well - known means are employed for supporting and extending the triangular wing . the leading edges of the wing are supported by wing support pockets 52 and 54 housing therein leading edge stiffening means 56 and 58 , respectively . these stiffeners may be housed adjacent to or spaced rearwardly form leading angle 20 so as to provide differing flexibility of the overall kite with the forward / rearward displacement of the stiffening means . also , in the preferred embodiment in which the design provides for a spine 36 , shown herein as a dowel 64 structurally associated with the triangular wing 12 and housed in a pocket 62 , additional longitudinal wing support is gained . similar longitudinal support is indirectly gained from keel / cell strut 32 housed in a pocket 60 . the dowels 32 and 64 are restrained by the pocket arrangement described above thereby resulting in the extension or spreading of the wing surface . transverse wing support is provided by a strut 66 shown in the cross sectional view fig2 and the attachment detail in fig5 . the strut 66 is supported external to wing 12 by end clip means or fasteners 68 for cooperative relation with eyelets 70 adjacent leading edge strut 58 . the kite 10 is reinforced by plastic tabs 72 , preferably formed from mylar sheeting on both sides of wing 12 and surrounding eyelets 70 . the kite 10 is tethered through one of several eyelets 74 adjacent keel apex 28 . other embodiments are shown in fig6 and 7 in which kites 110 and 210 with respective wing shapes 112 and 212 are illustrated . referring now to the drawings , and more particularly to fig8 yet another embodiment of the present invention relates generally to a stabilized kite adapted for operation under a wide range of ambient air speeds . in fig8 those portions indicated as 300 series designators have corresponding elements in the preferred embodiment , fig1 . the kite , referred to generally by the reference designator 310 . fig8 has an elliptical wing or body 312 with selected portions thereof held under tension or stretched conditions as further described below so as to be disposed in a substantially planar manner . the wing 312 is defined by an upper surface 314 and lower surface 316 . as previously described , the wing 312 may be any of numerous shapes , the body shape shown in the additional embodiment is basically elliptical . the elliptical wing or body 312 is further defined by a centrally located central line or major axis 318 that bisects at the front of the wing the nose or apex portion 320 . the nose or apex portion 320 is in turn defined by the leading edges 322 and 324 of the wing . depending from the wing portion of the kite is a keel or keel portion 326 structured to assume during flight of the kite a position lying within a plane that includes the central line or major axis 318 , said plane being substantially normal to the plane of the wing . on symmetrical , but nonplanar wing shapes such as bird - like shapes having two joined , concave wing surfaces , the wing plane for purposes of the definition herein is further defined by two correspondingly positioned points in each of the wing surfaces and by a point on the central line such as the apex . the keel is commonly structured as a triangular body with a keel apex 328 defined as the point of the keel extending farthest away from the wing plane . in the elliptical wing , as shown in this embodiment , the keel portion is substantially adjacent the nose of the kite . rearward along the central line is found a stabilization or apertured elevating cell 330 and is identical to that structure as shown in detail in fig4 generally indicated by designator 30 , and described hereinabove . as to materials , it has been found that modern synthetic fabrics of the industrial nylon variety , including ripstop , or spinnaker nylon , and plastic film , or sheet , such as polyethylene and mylar are preferably for the kite cover or wing material of this invention . a number of synthetic fabrics , woven from artificial fibers including rayon , nylon , terylene or dacron yarn are available in many grades of weight and porosity . in their lighter , more closely woven grades the fabrics made therefrom are strong and supple , easily workable and realtively inexpensive . ripstop , or spinnaker nylon , a high - performance fabric reinforced with a monofilament grid , originally developed for the sails of racing yachts , is one of the best cover fabrics available , if properly used it is virtually indestructible , and is manufactured in a wide range of weights , porosity ratings , and colors . polyethylene or similar thermoplastics of high flexibility and strength are available in sheet or film form . the thermoplastics are quick and easy to work and can be joined either by pressure - sensitive tape or suitable cement ; though being thermoplastic it can also be heat - sealed . the strut or framing of this invention also may be selected from a wide choice of materials including ash or spruce dowels , plastic extrusions and tubing , metal extrusions and tubing , and bamboo . in operation , the kite provides maneuverability in gentle winds as low as 3 miles per hour and in strong winds as high as 30 miles per hour . in lauching the kite , it will assume an ascending attitude and continue to ascend until the lift forces on the wing approaches the downward forces , i . e ., weight of the kite line , downward pull of the operator , etc . when the equilibration point is approached the kite begins to &# 34 ; plane &# 34 ; or assume a substantially horizontal position . the air currents then under the wing enter the forward aperture of the elevating cell and fills the cell ( s ) with air . it is believed , although not fully understood , that the air forced through the cell ( s ) causes the lower cell wall and the upper cell wall to act as wing services and the left , right and center cell walls to act additional keel area . the keel / cell strut serves the kite in the flying mode by holding open the elevating cell through the transmission of downward forces exerted upon the kite line .

a kite is described in which a wing of flexible material is disposed symmetrically about a central line ; a wing spreader is structurally associated with the wing for providing equal and opposite extension forces operable at the central line ; and an improved stabilizer is provided . the stabilizer has a keel depending from and structurally associated with the lower surface of the wing being attached thereto along one end of the central line , an apertured elevating cell through which air is drawn while kite is in flight with two side walls and upper and lower walls , the cell depending from and structurally associated with the lower surface of the wing along the other end of the central line , and a stabilizer strut for holding open the apertured elevating cell during flight being disposed between the keel and the lower wall of the apertured elevating cell .

the novel cleansing puff 10 of the invention is illustrated in fig1 and is manufactured by assembling the components shown in fig2 . puff 10 includes an inner tubular open mesh net 12 , one or more pieces of solid soap 14 of rectangular shape , and an outer tubular open mesh net 16 , with nets 12 and 16 being of recyclable , expandable elastic organic polymer material . the diameter of tubular net 12 , in its unexpanded state , is smaller then the width of soap piece 14 , preferably within the range of one quarter to three quarters of the width . the preferred size of the soap pieces 14 is such that the total combined weight of the pieces will be between one quarter ounce and six ounces , depending upon whether the puff 10 is to be a limited use puff , or a body puff . the diameter of tubular net 16 , in its unexpanded state , is larger than the width of soap pieces 14 and preferably is two to six times the width of pieces 14 . the length of tubular net 12 is such that it can contain a plurality of soap pieces 14 ( two pieces as shown in fig5 ) placed end to end lengthwise in the net , plus up to about six inches beyond the soap pieces at one end 20 and up to about twenty four inches beyond the soap pieces at the other end 22 . the length of tubular net 16 will vary from approximately three feet to fifteen feet , depending on the size of the puff desired . puff 10 is assembled by placing soap pieces 14 end - to - end within net 12 , spaced apart at section 24 , and located with respect to ends 20 and 22 as described above and shown in fig5 . because the diameter of net 12 is smaller than the width of soap pieces 14 , net 12 holds pieces 14 tightly in place so that the pieces can not move any significant amount radially or longitudinally in the net . next , as shown in fig6 the subassembly of fig5 is placed within the larger diameter outer net 16 . net 16 is then collapsed or bunched longitudinally in accordion fashion , forming a multitude of bends or folds 26 surrounding the approximate length of net 12 occupied by soap pieces l4 . the short free end 20 of net 12 protrudes beyond one end 30 of bunched net 16 and the longer free end 22 of net 12 protrudes beyond the other end 32 of bunched net 16 . in order to prevent migration of the ends 30 and 32 from the areas adjacent the ends of soap pieces 14 , the free ends 20 and 22 of net 12 may be passed through openings in the mesh of the ends 30 and 32 of net 16 to effectively anchor the net around soap pieces 14 . to complete the fabrication of puff 10 , the subassembly of fig6 is then folded longitudinally back upon itself along the hollow net section 24 , bringing end 20 of net 12 together with that portion 34 of end 22 immediately adjacent soap pieces 14 . end 20 and portion 34 are then secured together by a tied knot or by heat sealing so that the soap pieces 14 are bound tightly end - to - end at both ends and can &# 39 ; t move freely in any direction . this causes the bunched net 16 and bends 26 to assume an approximately circular puff configuration with the soap pieces 14 retained in approximately the center of the puff . if necessary , another length of narrow plastic netting can be wrapped around the outer perimeter of net 16 , either horizontally or vertically , and secured to more tightly bind net 16 to the solid soap . in an actual puff , the soap pieces are hidden by the multitude of bends 26 emanating around the circular configuration . the remaining extended length of end 22 is then looped back upon itself and the free end is tied or heat sealed to portion 34 , thus forming a convenient bracelet / handle 40 which may be used to hold the puff during use or to hang the puff between uses . this provides an advantage in that the puff with integral soap can be easily handled during use , by placing the handle around the wrist , and will eliminate the possibility of dropping the slippery bar of wet soap . additionally , by providing for a means of hanging the soap between uses will allow for quick drying of the entire surface of the pieces of soap . this will prevent the formation of soap slime which occurs from the prolonged contact of soap with a wet surface , and will substantially increase the useful life of the solid soap product . throughout the useful life of the puff 10 , soap pieces 14 are retained within the approximate center of the puff , thus assuring uniform lathering accompanying the mildly stimulating effect of the netting to the skin . in constructing nets 12 and 16 , various types , textures , and colors of plastics may be used , including an anti - bacterial plastic . the connections between the mesh of plastic nets 12 and 16 may be by ties , hot glue , or heat welding . soap pieces 14 may be of various shapes . similarly , various types of soaps may be used in varying amounts to accommodate varying uses , e . g . single - use , disposable devices for hotels , etc ., or medium and long use for personal , commercial , or industrial purposes . the forgoing relates to preferred exemplary embodiments of the invention , it being understood that other variants and embodiments thereof are possible within the spirit and scope of the invention , the latter being defined by the appended claims .

a body cleansing puff , constructed of organic polymer netting , which contains a plurality of pieces of solid soap product . the puff is composed of multiple layers of organic polymer netting which serve several purposes including containment of the pieces of solid soap product and the formation of a convenient handle for hanging the device , the provision of surfaces for the production of soap lather , and the production of a product which imparts a mildly stimulating effect to the skin .

novel intramedullary bone stents : intravascular stents are commonly used in arteries to hold the artery open , e . g ., to treat stenosis caused by a buildup of plaque on the walls of the artery . thus , these intravascular stents are designed to maintain patency of the blood vessel . intravascular stents are inserted into the artery in a crimped state and expanded to a larger diameter . see , for example , fig1 , which shows expanding stents used in blood vessels . to date , stents have not been used in orthopedic applications to reduce a fracture site . in accordance with the present invention , and looking now at fig1 , there is shown an intramedullary bone stent 5 . intramedullary bone stent 5 is placed into the intramedullary canal 10 of a bone 15 , bridging the fracture 20 . as the intramedullary bone stent 5 expands , applying hoop stress to the bone 15 , the intramedullary bone stent 5 shortens , reducing the fracture 20 and rigidly holding the bone 15 in the correct position . in one preferred form of the invention , the intramedullary bone stent 5 is formed out of a shape memory alloy ( sma ). an intramedullary bone stent 5 can be superior to current fixation methods because the intramedullary bone stent 5 can have a modulus of elasticity closer to that of bone , does not create regions of stress shielding , and does not impair blood flow at the fracture site . additionally , intramedullary bone stents 5 may be beneficial in treating pediatric patients with open growth plates , where nails , rods , and screws may interfere with bone development at the growth plate . shape memory material ( e . g ., nitinol ) stent : from its earliest use in orthodontic arch wires to its more - recent dominant role in cardiovascular implants such as intravascular stents , endografts , and filters , shape memory materials ( e . g ., nitinol , titanium - niobium , and shape memory polymers ) all possess unique properties that have made it the material of choice for a variety of medical applications . the vast majority of medical applications take advantage of nitinol &# 39 ; s ( niti &# 39 ; s ) unusual superelastic properties . more particularly , while conventional engineering materials typically have an elastic limit much less than 1 % strain , nitinol can experience fully recoverable strains up to 8 %. see fig1 , which shows the stress - strain properties of nitinol , with comparison being made to various materials . this superelastic capability allows a properly designed nitinol component to radically transform its shape during service , fueling the trend toward minimally invasive procedures . for example , a nitinol intravascular stent may be designed to be delivered through a 2 - mm sheath and expand to support a 10 - mm vessel . similarly , an endoscopic instrument may be delivered through a 15 - mm opening , expand to 60 mm to retrieve a specimen , and then collapse to exit through a similarly sized port . in short , if a medical component must be delivered in a compressed state and then become an expanded shape , nitinol is likely to offer design advantages unavailable with other materials . today there are a wide range of intravascular prostheses on the market for use in the treatment of aneurysms , stenosis , and other vascular irregularities . balloon expandable ( i . e ., non - nitinol ) and self - expanding intravascular stents ( i . e ., nitinol ) are well known for restoring patency in a stenosed vessel , e . g ., after an angioplasty procedure , and the myriad usages of coils and stents are known techniques for treating aneurysms . the biocompatibility of nitinol has been well documented . in nitinol , nickel and titanium are distributed in a regular crystal lattice order , exhibiting high atomic bonding forces with mixed covalent and metallic character , thus it is difficult for nickel to leave the bulk material . the surface of niti is well passivated because titanium is more readily oxidized than nickel . niti devices exhibit a ti - based oxide layer which is responsible for the corrosion resistance of this material and acts as an effective barrier to nickel ion release . from a biological point of view , the integrity of the outermost surface layer and its ability to repassivate are crucial importance for the biocompatibility of niti . self - expanding intravascular stents generally are retained in a contracted delivery configuration using a sheath , then the nitinol intravascular stent self - expands when the sheath is retracted . such niti stents commonly have a major drawback in intravascular applications , for example , the intravascular stents may experience large length shrinkage during radial expansion ( referred to as “ foreshortening ”) and may shift within the blood vessel prior to engaging the blood vessel wall , resulting in improper placement . the reason that intravascular stents become shorter during radial expansion is because the angles of the struts within the intravascular stents increase ( from parallel to the centerline of the stent to an angle of 15 °- 60 ° to the centerline of the stent ) when the intravascular stents expand radially , thereby shortening the length of the intravascular stents . in other words , the intravascular stent is made of a series of “ zs ”, and when the intravascular stent is collapsed , the “ z &# 39 ; s ” are flat and look more like dashes . during radial expansion of the intravascular stent , the dashes open to z &# 39 ; s , shortening the intravascular stent . see fig1 , which shows the radial expansion of a nitinol intravascular stent . foreshortening is explained in terms of a deformation in longitudinal direction after expansion of the stent . it is calculated as follows : as seen in the cp stent ™ foreshortening chart shown in fig1 , foreshortening is a consequence of the radial expansion of the intravascular stent . the success of vascular stents in the restoration of blood flow is limited by restenosis . recent data generated from computational fluid dynamics ( cfd ) models suggest that the vascular geometry created by an implanted stent causes local alterations in wall shear stress ( wss ) that are associated with neointimal hyperplasia ( nh ). foreshortening is a potential limitation of intravascular stent design that may affect intravascular stent performance and the rate of restenosis . the angle created between axially aligned stent struts and the principal direction of blood flow varies with the degree to which the intravascular stent foreshortens after implantation . progressive degrees of intravascular stent foreshortening are also associated with strut misalignment relative to the direction of blood flow as indicated by analysis of near - wall velocity vectors , suggesting that foreshortening may predispose the stented vessel to a higher risk of neointimal hyperplasia . additionally , during foreshortening , there can be unfavorable shearing between the stent struts and the vascular wall , potentially causing hemorrhaging . there are dozens of metal and bioresorbable intravascular stent designs on the market today ( see http :// www . nitinol . com / media / reference - library / 009 . pdf ), and intravascular stent designers have been working to overcome the aforementioned foreshortening problem of intravascular stents for many years . see , for example , u . s . pat . no . 6 , 761 , 731 “ balloon - stent interaction to help reduce foreshortening ”. intramedullary bone stent : the present application relates generally to the provision and use of novel intramedullary bone stents to repair a bone fracture and facilitate bone fusion by the intramedullary stent &# 39 ; s radial expansion and axial compression during foreshortening . in one preferred form of the invention , the novel intramedullary bone stents are formed out of shape memory material ( e . g ., nitinol ). thus , in one preferred form of the invention , there is provided an osteosynthetic nitinol intramedullary bone stent implant for disposition within the intramedullary canal of a bone , whereby to span a fracture line , and effect fracture / fusion repair . the novel fracture repair devices , systems , and methods of the present invention also include those for repairing intentional fracture sites , such as but not limited to osteotomies created for reconstructive purposes . bony fusions of surgically resected joints throughout the body are also within the scope of the present invention . such nitinol intramedullary bone stent fracture fixation devices , systems and methods of the present invention help maintain compressive loads across the fracture site for longer periods of time compared to prior devices . the novel bone stent is an intramedullary device . more particularly , the medullary cavity ( medulla , innermost part ) is the central cavity of a bone shaft where red bone marrow and / or yellow bone marrow ( adipose tissue ) is stored ; hence , the medullary cavity is also known as the marrow cavity . located in the main shaft ( cortical bone ) of a long bone ( diaphysis ), the medullary cavity has walls composed of spongy bone ( cancellous bone ) and is lined with a thin , vascular membrane ( endosteum ). however , the medullary cavity is the area inside any bone ( long , flat , etc .) that holds the bone marrow . the clavicle is the only long bone that does not contain a medullary cavity . this area is involved in the formation of red blood cells and white blood cells . see fig1 , which shows the anatomy of the medullary cavity of the femur . the intramedullary bone stent , preferably made of shape memory materials such as nitinol , can be used to support , stabilize and reduce bone fractures ( see fig1 ). the benefits of an intramedullary bone stent appliance include : the intramedullary bone stent uniformly conforms to the intramedullary geometry and uniformly expands and locks , both axially and radially , along the length of the bone , which minimizes or eliminates interfragmentary motion . there is a widely held opinion that interfragmentary sliding ( shear ) motion is detrimental to the repair of bone fractures . in order for a fracture to heal , it needs stability and blood flow . blood brings the components for healing to the fracture site . these include oxygen , healing cells , and the body &# 39 ; s own substances necessary for healing ( e . g ., growth factors ). the blood supply to the injured bone usually comes back on its own during the healing period . the use of an intramedullary bone stent , without screw holes , compressive plates , or invasive nails , allows for a near normal blood supply to the fracture site by reducing or minimizing additional vascular damage . the sustained compressive therapy offered by the intramedullary bone stent can also be osteoinductive , due to its piezoelectric effects on osteoblasts themselves . the intramedullary bone stent is designed to apply compressive forces at the fracture site , by foreshortening and / or training the niti to pull the bone segments in compression . the intramedullary bone stent , however , is “ spring - like ”, and will oscillate and vibrate to some extent , causing mechanical loading to catalyze osteoblast , bone remodeling and fracture healing . in pediatrics , where it is often difficult to use an intramedullary device because of the concern of disrupting the growth plate , a fracture through the growth plate requires perfect reduction , and pinning may be necessary . rotational malalignment in the fingers is a frequent complication and can be easily detected after reduction by flexing all the fingers together . fingers should be immobilized by syndactylization , or “ neighbor strapping ”, with the adjacent finger for a maximum of three weeks . a short forearm cast with an aluminum splint is another alternative . physical therapy might be necessary . in the younger child , more durable immobilization should be used to prevent the child from removing it . open reduction for phalangeal fractures is required for displaced intra - articular fractures and oblique , shortened midshaft fractures . niti intramedullary bone stents can traverse the growth plate with a collapsed intramedullary bone stent diameter comparable to the size of a large needle , minimizing damage to the growth plates . now , using an intramedullary bone stent , the intramedullary fixation becomes feasible in children for the first time . when a conventional bone fracture compression plate made of high modulus 316l stainless steel ( 200 gpa ) relative to cortical bone ( 15 gpa ) is used , this results in stress - shielding the bone under the plate and is believed to cause osteoporosis that weakens the bone under the plate . relieving the bone from carrying a load over an extended period of time is believed to contribute to the development of this type of osteoporosis , also known as osteopenia . when the plate and screws are removed from the healed bone , the bone may re - fracture due to the weakening which resulted from the development of osteoporosis or osteopenia . unlike 316 - l stainless steel and titanium ( ti 6al - 4v ), nitinol has a very similar elastic modulus compared to bone , in the range of 5 gpa to about 70 gpa . the niti intramedullary bone stent material will more naturally load the fracture site because it has a stiffness close to human tissue so that stress shielding does not occur which is a problem with stiff plates and im nails . see fig1 , which is a chart showing the measure of the stiffness or modulus of elasticity of various materials . in addition to niti having a similar modulus of elasticity to bone , the intramedullary bone stent &# 39 ; s stiffness can be designed to have comparable stiffness to bone by changing the dimensions of the intramedullary bone stent , i . e ., strut thickness , strut width , strut angle and strut frequency . fig1 shows struts shaped like a “ z ” that can be used to make up the structure of an intramedullary bone stent of the present invention . thus , in accordance with the present invention , and looking now at fig1 , an intramedullary bone stent 5 is restrained in a radially - contracted , longitudinally expanded condition ( e . g ., within a sheath , not shown ), advanced down the intramedullary canal 10 of a bone 15 so as to span a fracture line 20 , and then the restraint of the intramedullary bone stent 5 is released , so that the intramedullary bone stent radially expands to grip the surrounding bone and longitudinally contracts so as to place the bone fragments in compression , whereby to facilitate healing of the fracture . preferably , intramedullary bone stent 5 is formed out of a shape memory material so that the intramedullary bone stent 5 has a modulus of elasticity similar to that of bone , whereby to minimize stress shielding and thereby enhance bone healing . unlike a conventional intramedullary nail , the force of the expanding ni — ti intramedullary bone stent can be engineered to apply enough radial force to stabilize the fracture yet be somewhat flexible in areas away from the fracture site . see fig1 and 20 , which show the strain and force characteristics for a simple beam of the type used in an intramedullary bone stent . in addition , the expanding radial hoop force can be engineered to overcome the collapse , buckling and / or pinching loads at and near the fracture site . see fig2 , which shows the calculations for the hoop and bending stiffness of an intramedullary bone stent . stent foreshortening to create dynamic interference fit with compressive loads against the fracture site : when an intravascular stent is deployed in an artery or vein , it radially expands and simultaneously shortens , which can cause the intravascular stent to undesirably tear the wall of the artery or vein as the intravascular stent foreshortens . thus , in vascular applications , foreshortening is problematic and undesirable — and much effort has gone into minimizing the negative effects of foreshortening . in the case of the present invention , where an intramedullary bone stent is provided , the struts of the intramedullary bone stent can intentionally be made with barbs or tangs so as to aggressively grip the surrounding bone tissue in order to pull the bone fragments on either side of the fracture together , effectively compressing the bone fracture when stent foreshortening takes place . see , for example , fig2 , which shows a nitinol intramedullary bone stent 5 having integral barbs 25 for gripping the inner wall of the host bone . thus , the present invention advantageously harnesses the foreshortening effect to provide desired compression . the tension applied by the shortening intramedullary bone stent to the bone may better maintain close apposition of the bone fragments , and better establish compression across the fusion zone , during the healing process . in this respect it will be appreciated that bones in contact with each other , and under compressive load , heal together faster than bones held apart . significantly , with the present invention , the novel shape memory alloy intramedullary bone stent is longitudinally stretched ( and radially contracted ) during the insertion procedure , e . g ., by loading the intramedullary bone stent within a constraining sheath . once the intramedullary bone stent is properly positioned within the intramedullary canal ( which is done manually , while being viewed via fluoroscopy ), the shape memory alloy intramedullary bone stent is released from its constraint so as to radially expand and longitudinally contract , whereby to engage the bone fragments on opposing sides of the fracture line and draw them together in compression . this action maintains the target fusion bones in close apposition . the niti intramedullary bone stent offers sustained compression for longer time periods than static , non - adaptive intramedullary devices . unlike plates and screws , the niti intramedullary bone stent will maintain compressive load across the fracture site well after the fracture is healed . the intramedullary bone stent will not compromise blood flow because holes in the bone are not created from screws and or staples , nor will they apply deleteriously localized stresses concentrations in small areas like bone staples and screws do . furthermore , because the intramedullary bone stent is contained wholly within the bone , the niti intramedullary bone stent will not cause tissue scaring like bone screws and staples do . the niti intramedullary bone stent of the present invention can create ample compressive forces on the bone tissue that can stimulate rapid bone regeneration in order to fill in deficient bone fractures or to fix an implant firmly within adjacent bone . to succeed , the niti intramedullary bone stent must be habitable , especially for bone - forming cells ( e . g ., osteoblasts ) such that they can colonize on the strut surfaces and synthesize new bone tissue . additionally , osseointegration is preferred in the spaces between the struts . for successful implants , sufficiently regenerated bone fills the gap between an implant and juxtaposed bone , thus the implant is attached firmly with the surrounding bone . frequently implant materials are not compatible with bone cell responsible for bone formation , but rather they promote the formation of undesirable soft connective tissue . fibrous soft tissue , as opposed to hard bony tissue , has been shown to improperly fix orthopedic implants into surrounding bone which leads to loosening under physiological loading conditions and eventual implant failure . the niti intramedullary bone stent offers surgeons the ability to eliminate traditional device performance issues that can negatively impact the ability to achieve a solid fusion . osteoblast response to mechanical strain : the mechanical environment of a fracture site has been known to play an important role in fracture healing and tissue differentiation for many years . appropriately applied mechanical conditions have been known to accelerate fracture healing and there are many mechanical properties that influence the healing process including strain rate , frequency , magnitude , number of cycles , and number of days of stimulation among others . the majority of investigations into the effects of the local mechanical environment on bone repair actively control the motion at the defect . these devices allow for a prescribed motion at set time points . normally , these devices are powered by an external actuator or through a sliding mechanism that allows a set motion to occur during normal ambulation , which is called dynamization . studies using this model have found that larger fracture gap sizes lead to poorer fracture healing and that gap size plays a significant role in the progression of repair . these studies also showed that small controlled movements in smaller gaps can increase bone formation , callus size and tensile strength . the disadvantages of this model are that the motion is limited to compressive strains and , over time , the motion will decrease as healing progresses and tissues progressively fill the defect , altering the experimental conditions . this same conclusion was drawn in studies applying a variety of different controlled micromotions at many different frequencies , as well as with applied axial dynamization . studies suggest that changing the mechanical environment in a healing fracture provides strong evidence that micromotion plays a vital role in fracture repair ; however , too large of interfragmentary motion disrupts fracture repair . some researchers believe that bone formation occurs in areas of low to moderate tensile strain , cartilage formation occurs under hydrostatic pressure , and fibrous tissue growth occurs in areas of moderate to high tensile strain . and some researchers have hypothesized that small strains and small hydrostatic pressures (& lt ;± 0 . 15 mpa ) lead to direct bone formation , compressive hydrostatic pressures above 0 . 15 mpa lead to chondrogenesis and therefore endochondral ossification , and all other stimuli lead to connective tissue or fibrocartilage formation . niti intramedullary bone stents can be designed to create both compressive and tensile force at the fracture site , being stiff to stabilize but just flexible enough to cause ample hydrostatic pressure (& lt ;± 0 . 15 mpa ) to create direct bone formation at the fracture site . types of stents : there are a number of different types of devices for stenting of body passages . these may be classified into two general categories : expandable meshes , which include self - expanding types and non - self - expanding types , and non - expandable meshes , which are typically made of plastic or polymeric material . the self - expanding meshes can be made of a material , such as nitinol , which changes configuration upon heating to body temperature , and exhibits superelastic behavior . other self - expanding meshes are made of resilient mesh material which can be flexed down into a small diameter tube and held in place in such a configuration until it is released , at which time it expands to a larger diameter configuration . the non - self - expanding meshes are expanded by use of an inflatable balloon which is placed inside the mesh in a small diameter configuration , and then inflated , thereby expanding the mesh to a larger diameter configuration . the balloon is then deflated for removal , leaving the mesh in its expanded configuration . both types of mesh constructs may be applied to the present invention . the expandable mesh intramedullary bone stents can be made from a variety of materials , e . g ., stainless steel . the expandable mesh intramedullary bone stents can be made in a variety of configurations such as a coiled spring , a variety of zig - zag patterns ( including various stents known as “ z ” stents ), braided filament , and other collapsible configurations that can have external barbs and / or hooks to help grip the bone tissue . the struts of the intramedullary bone stents can have ribs or teeth to help dig into the bone during axial compression or shortening of stent to help compress the fracture together . see fig2 , which shows examples of different stent designs . one type of expandable stent comprises a cylindrical member having a slit cut along its length , so that the edges along the length can overlap to allow for compression to a reduced size . a further configuration which may be described as a perforated tube which comprises a generally rigid tube with openings cut therein to allow for radial expansion under force of an expansion balloon or by expansion due to heating . the expandable mesh stents can be braided , woven , knitted , formed , molded , machined or made by other methods known in the art . various mesh designs are disclosed , for example , in u . s . pat . nos . 4 , 512 , 338 , 4 , 503 , 569 , 4 , 922 , 905 , 4 , 733 , 665 , 4 , 950 , 227 , 5 , 089 , 006 and 5 , 061 , 275 . other materials , configurations and methods of manufacture in addition to those described above are known . as used herein , the term “ expandable mesh ” is meant to include , without limitation , self - expanding and non - self - expanding configurations made of any generally rigid or springy material which , when expanded , have an open network or arrangement which would otherwise allow for tissue in - growth , and would not otherwise prevent fluid flow through its walls . several of these prior art mesh stents have been utilized with a polymeric sheath or cover ; however , since these sheaths must be stretched to increase in size , they exert a force that resists expansion , which tends to limit the final expanded size of the mesh . additionally , this resistance may make expansion more problematic . alternatively , the sheath may be folded or bundled over the mesh when it is compressed , so that no force is exerted upon expansion . shape memory alloy ( sma ) stents conform to different shapes of intramedullary canals : the proximal and middle phalanges from 83 pi pjs were analyzed set in clear plastic , sectioned in the transverse plane , and measured ( ash and unsworth 1997 ). the medullary canals were marked on the sagittal and frontal planes and shadowgraphs of the intact bones analyzed . it was found that the phalangeal shaft bone was thicker laterally than dorsally and palmarly , and thicker dorsally than palmarly for the proximal and middle phalanges throughout the length the hand and wrist . the shape and size of the transverse cross - section of the medullary canal changed throughout the length of the shaft . the centerline of the medullary canal coincided with the midline of the bone in the frontal plane and was approximately a straight line along the length of the canal . in the sagittal plane it was slightly palmar to the midline , and the angle between the centerline and the baseline of the bone changed along the length of the canal . see fig2 , which shows the medullary canal of a bone in side view , and fig2 , which shows transverse cross - section of phalangeal bones . the problem with using a machined round pin and / or nail to stabilize the fracture is that the round and straight pin or nail will not conform evenly to the bend and change of bore shape in the medullary canal . significantly , the flexible sma intramedullary bone stent of the present invention will conform to the varying geometries of the intramedullary canal . the flexible sma intramedullary bone stent will radially expand until a certain pressure stops the expansion , which allows the intramedullary bone stent to conform to the specific geometry of the intramedullary canal in terms of straightness and roundness . also , if the phalangeal shaft bone is thicker in one area vs . the other area , the sma intramedullary bone stent can be designed to expand more in the thicker section vs . the thinner bone section to allow for uniform strain on the bone tissue . zw stent — radial expansion and axial compression : today many intravascular stents are introduced while held inside a polymer sheath . when the sheath is retracted , the intravascular stents expand . if the intravascular stent is nitinol , it expands superelastically . if the intravascular stent is stainless steel it is expanded with a balloon . either way , when the sheath is pulled away , the intravascular stent radially expands against the artery . as the sheath is incrementally removed , the expanding intravascular stent applies pressure to the artery . this pressure helps to hold the intravascular stent in place while the sheath is further pulled away , which leaves the more radially expanded exposed stent behind . see the images a , b , c in fig2 . in accordance with one preferred form of the present invention , an intramedullary bone stent can be engineered to incrementally expand radially when the sheath is removed and then pull in compression . for example , and looking now at fig2 , there is shown an intramedullary bone stent 30 which has the conventional “ z ” struts 35 that expand radially and , adjacent to the “ z ” struts 35 , there can be “ w ” struts 40 which are normal to the “ z ” s . the z struts 35 radially expand and the w struts 40 pull in compression . so , in addition to the traditional stent foreshortening effect which can be used to compress a fracture , the design of the intramedullary bone stent can be further enhanced so as to increase both radial expansion and longitudinal foreshortening . if desired , the intramedullary bone stent designs can have angular zigzags to help with torsional stability . so , the intramedullary bone stent could have z struts , w struts , and / or off center line zigzags to improve torsional stability . bone stents can be used in the phalanges , metacarpals , carpals , metatarsals , tarsals , humerus , radius , ulna , femur , tibia and fibula , among other bones . see fig2 , which shows various bones where bone stents may be efficacious for fracture fixation . it should be understood that many additional changes in the details , materials , steps and arrangements of parts , which have been herein described and illustrated in order to explain the nature of the present invention , may be made by those skilled in the art while still remaining within the principles and scope of the invention .

a method for providing stabilization and compression of a bone fracture , the method comprising : providing an intramedullary prosthesis sized for insertion into the intramedullary canal of a bone and having a distal end , a proximal end and a porous structure therebetween , wherein in a first state , the prosthesis is longitudinally expanded and radially contracted , and in a second state , the prosthesis is longitudinally contracted and radially expanded , conforms to the shape of the adjacent bone and exerts forces on the adjacent bone ; and positioning the intramedullary prosthesis within the intramedullary canal of a bone so that the intramedullary prosthesis spans the bone fracture , whereby to provide stabilization and compression of the bone fracture .

referring now to the drawings , and particularly to fig1 the invented landscape border member or unit 10 includes a generally planar base 12 , which base is stepped to define a higher surface 14 connected by a step 15 to a lower surface 16 . a first wall 18 is fixed to and upstanding from base 12 , the wall being inclined at an angle greater than a right angle from the planar surface 14 , as shown in fig3 . an upper planar top wall 20 , which is generally parallel to the surfaces 14 and 16 is fixed to the first wall or face wall 18 at its upper edge , one end of top wall 20 having a rounded extension 21 provided with a pivot which depends from the underside of top wall 20 , and comprises a downwardly extending pivot pin 22 . the other end of surface 20 carries a pivotal connector 26 . the baseplate 12 is stepped as shown with the upper surface 14 of the higher step elevated from the surface 16 of the lower step by approximately the thickness of the upper step . the baseplate is angled as shown in fig1 and 2 so that it is tapered outwardly at both ends . the preferred angle a is from 15 ° to 45 ° with the optimum angle being 17 °. the angle of step 15 can be from 0 ° ( i . e ., normal to the front edge of the baseplate ) to 30 ° in either direction , but again , the optimum angle is 17 ° and parallel to the right edge of the lower surface 16 , as shown . a vertical hole 17 is provided in surface 16 for accommodating a stake or spike , not shown . the face wall 18 preferably is inclined at an angle b from the vertical , i . e ., from 0 . 5 to 20 °, preferably from 1 ° to 10 °, which is particularly advantageous for shipping , as the inclination of face wall 18 allows the individual units to be nested with other units . it should be noted that if the angle b is zero , then the wall 28 is a section of a cylinder rather than a section of a frustum of a cone . the end of upper surface 20 includes is extended to form contiguous horizontal projection 21 which is rounded , having an arcuate edge , and which carries pivot pin 22 on its lower side , the arc of projection 21 having a common center with the pivot pin . pin 22 may be cylindrical , tapered , or partially cylindrical as at 22a with a double taper 22b , 22c , as shown in fig3 . the end of member 10 opposite projection 21 includes a frusto - conical wall section 28 extending from the lower surface 16 of the baseplate to an upper generally circular pivot connector plate 30 which is provided with a central vertical hole 32 therethrough and preferably a tapered entrance 36 to the hole 32 to allow a snap - in connection of the pivot pin 22 . the wall section 28 is set back the thickness of face wall 18 . the rear of the unit 10 may include a stiffener 38 extending downwardly from the top - plate 20 for the purpose of additional rigidity of the unit . this stiffener preferably is inclined oppositely from the first or face wall 18 . angle c , as shown in fig4 is from 1 ° to 20 °, preferably from 4 ° to 8 °. each end 40 of top plate 20 has a taper d of from 5 ° to 30 °, but preferably about 15 °. the angles d limit the amount of deflection or angular rotation between adjacent units of an assembly , as shown in fig8 . tapered connector hole entrance 36 may have a single taper angle e , as shown in fig2 or it may have a double taper including taper angle f , which allows the width of wall 28 to be narrowed . the alternative embodiment shown in fig9 through 11 has a frusto - conical section 28 &# 39 ;, the curved surface of which extends to the end of the rear stiffener . the pivot connector plate 30 &# 39 ; is circular with a central hole 32 &# 39 ; to receive the pivot pin 22 . the lower surface of baseplate 12 may be extended so the edge of the baseplate is tangential to the base of the frusto - conical section 28 &# 39 ;, as shown in fig9 through 11 . the alternative embodiment shown in fig1 has a frusto - conical section 28 &# 34 ;, the curved surface of which extends to the end of the rear stiffener . the upper generally circular pivot connector plate 30 &# 34 ; is provided with a central vertical hole 32 &# 34 ; therethrough and tapered entrance 36 &# 34 ; to the hole 32 &# 34 ; to allow a snap - in connection of pivot pin 22 , in the same manner as shown in fig1 . the preferred material of construction is a plastic , which is resistant to ultraviolet rays , such as polypropylene , polyethylene , or vinyl . preferably the material is reground polypropylene , which may contain up to 40 % filler as a stiffener , such filler being talc , mica or calcium carbonate . alternative materials include wood , wood by - products , metal , sheet metal , hard rubber , tile , or masonry such as vermiculite . for temporary use , the material of construction can be highly compressed peat moss , which will eventually decompose and become part of the adjoining soil . other suitable alternative plastic materials are : fiberglass reinforced plastic , polyvinyl chloride , chlorinated polyvinyl chloride , polyvinylidene fluoride , vinyl esters , epoxy resins , ultra high molecular weight polyethylene , fluorinated ethylene propylene , acrylonitrile - butadiene - styrene , fiberglass reinforced vinyl ester , fiberglass reinforced epoxy , polyphenylene sulfide , and fiberglass reinforced polyvinylchloride . the exterior surface of the border unit can be patterned to look like tree bark , brick , wood , or glazed or unglazed ceramic tile , if desired . the surface of the unit can be textured by any convenient means , such as by bead blasting or shot blasting , to form an aesthetic facing . plastic construction materials can include color tinting in the basic formulation , such as brown , green , or other desired color . in operation , the desired number of border units 10 is determined merely by making a linear measurement of the location in which the border assembly is to be placed . each unit being identical in length , the linear measurement is divided by the length of one unit from pivot to pivot . the first unit is placed in the desired location , and may be staked into place in the ground by placing a stake 44 through hole 17 , as shown in fig7 . each succeeding unit is positioned with the pivot pin in the pin receiver , the unit 10 is then oriented properly , and staked , as necessary . the pivot pin 22 can be positioned in the receptacle 32 either from above , or by snapping it into place from the end of the unit . from the foregoing , it is readily apparent that i have invented an improved edger / border / retainer member for use in plant husbandry , which is particularly useful for defining a terrace edge for lawns , gardens , sidewalks , or driveways , which is lightweight and easy to handle , requires no digging to emplace , which enables a mower to cut the adjacent grass completely , which obviates the need for a trimmer , preventing the damage a trimmer can cause to standard border means such as a retainer wall , and which retains mulch or the like around plants or trees . it is to be understood that the foregoing description and specific embodiments are merely illustrative of the best mode of the invention and the principles thereof , and that various modifications and additions may be made to the apparatus by those skilled in the art , without departing from the spirit and scope of this invention , which is therefore understood to be limited only by the scope of the appended claims .

an improved precast plastic landscape border assembly for use as yard edging , around trees , and in terracing , the assembly comprising a plurality of identical border units . each border unit has an upper pivotal connector at one end , a connector receiver at the other end , a generally upstanding wall portion , and a stepped horizontal base plate or mower strip , the base plate preferably carrying an angled extension portion .

referring to the fig1 the depicted remedial device 10 is shown in a flat open position with its interior surface 12 facing upward . the device has a flexible substrate 14 of generally rectangular configuration with side portions 16 and 18 being readily visible . top portion 20 of the flexible substrate in the depicted physical orientation rests intermediate the side portions 16 and 18 , all of which can possibly better be perceived in fig2 . lower end 22 of the flexible substrate 14 is intended to be secured to a person &# 39 ; s left forearm with upper end 24 thereafter residing in the palm region of the person &# 39 ; s left hand . when the flexible substrate 14 has been applied to an ailing left wrist in this manner its top or upper portion 20 can be seen to reside along the wearer &# 39 ; s forearm longitudinal axis 26 as further depicted in fig2 . the palm or upper end 24 of the flexible substrate 14 further includes an elastic cuff portion 28 extending along its length together with a projection 30 extending forwardly therefrom . the projection 30 terminates with a releasable strip or tab 32 for the purpose of securing the palm end 24 of the flexible substrate 14 to the wearer . when secured in this manner , the projection 30 extends backwardly between the wearer &# 39 ; s left thumb and forefinger as again shown in fig2 . correspondingly , palm end 24 of the secured device can also be seen to terminate adjacent the metacarpal joints ( not shown ) of the wearer &# 39 ; s hand . the flexible substrate 14 in the illustrated embodiment comprises a porous cloth material 34 to which is integrally joined still other essential features of the present device . a cushioning pad 36 is included in the palm region 38 of the flexible substrate 14 while releasable fastening means 40 , 42 and 44 are joined thereto at side portion 18 . said releasable fastening strips engage a longitudinally extending releasable strip 46 disposed adjacent opposite side portion 16 of the flexible substrate 14 but which becomes aligned along its top or upper portion 20 when the device is applied to the wearer &# 39 ; s wrist as shown in fig2 . underlying strip 46 is a first splint member 48 which extends longitudinally along the wearer &# 39 ; s point beyond the wrist . a second splint member 50 is integrally joined to the flexible substrate 14 adjacent to the first splint member but inward therefrom and which extends longitudinally in the same direction as the first splint member . when the device 10 is applied to the wearer &# 39 ; s wrist said cooperating splint member 50 becomes aligned on the left side portion of said wrist as can be seen in fig2 . accordingly , first splint member 48 primarily limits vertical movement of the wrist involved while splint member 50 cooperates in limiting lateral or horizontal wrist movement . both splint members of a relatively rigid material such as metal or fiberglass can be sewn into enclosed pockets of the flexible substrate in a customary manner . in fig2 there is depicted a plan view of the fig1 remedial device 10 which exposes its exterior surface 52 . as shown , said device has been applied to an ailing left wrist of wearer 54 with the flexible substrate 14 fitting entirely around the wearer &# 39 ; s forearm 56 . same numerals identify common features in said device 10 as previously employed in the fig1 description . the applied device can be further seen to envelop the entire wrist region of a wearer extending beyond said wrist region in both longitudinal directions . accordingly , the flexible substrate 14 is applied so that side portions 16 and 18 overlap with the releasable strip portions thereof 40 , 42 and 44 being joined to a single releasable strip 46 . further engaging releasable strip 32 extending from projection 30 located at the palm end 24 of flexible substrate 14 to releasable strip 46 firmly secures device 10 in place . the cushioning pad 36 of flexible substrate 14 now rests against the left palm of the wearer while elastic cuff 28 effectively grips the wearer &# 39 ; s hand around its entire periphery to avert contaminant entry . it also can be seen that first splint member 48 becomes positioned along the forearm longitudinal axis 26 when device 10 has been secured in place while cooperating second splint member 50 becomes aligned substantially coincident therewith on the left side of the wearer &# 39 ; s wrist . a still further advantage achieved from constructing the flexible substrate of the illustrated device embodiment with cloth or plastic material is washability . since this remedial device is customarily worn in a work environment over long periods , the relative ease with which such integral device can be readily washed represents a distinct improvement . it can further be appreciated that modifying the illustrated device to accommodate the same ailment in a right wrist of a wearer simply requires that the component parts of said embodiment be reversed so as to relocate the second splint member on the outside or right side of said wrist . it will be apparent from the foregoing description that a remedial device has been provided which is particularly adapted for improved treatment of carpal tunnel syndrome . it is not intended to limit the present invention on the specific device embodiments herein illustrated , however , since persons skilled in the art will recognize that further modifications can be made therein without departing from the true spirit and scope of the present invention . for example , various materials can be employed in the construction of said device both for the flexible substrate portion as well as for splint members integrally joined thereto . additionally , it is contemplated that still other known releasable fastening means can be employed in said device than herein illustrated with comparable results . a still further contemplated modification to the illustrated device utilizes integral cushioning means located under one or both splint members to provide added comfort for the wearer . consequently , it is intended to limit the present invention only by the scope of the following appended claims :

a therapeutic wrist support is provided allowing a person with carpal tunnel syndrome to manipulate the wrist without further aggravating this ailment . the device employs a flexible substrate which includes integral splint elements physically positioned to allow limited wrist movement in both vertical and horizontal directions with respect to the longitudinal axis of the wearer &# 39 ; s forearm . positioning of the splint elements is also made dependent upon whether the left or right wrist of the wearer is involved .

to identify the antigen ( s ) recognized by the antibody 11bd - 2e11 - 2 , cell membranes expressing this antigen were subjected to gel electrophoresis and transferred using western blotting to membranes to determine the proteins detected by this antibody ( as disclosed in ser . no . 10 / 810 , 744 ). previous work demonstrated binding by facs of 11bd - 2e11 - 2 to the breast cancer line mda - mb - 231 ( mb - 231 ). previous work also demonstrated 11bd - 2e11 - 2 efficacy against the ovarian cancer cell line ovcar - 3 . accordingly , membrane preparations from these 2 cell lines were used for antigen identification . additional western blotting and immunoprecipitation studies have also demonstrated a similar binding pattern of 11bd - 2e11 - 2 to a2058 membrane preparations . total cell membranes were prepared from confluent cultures of mb - 231 breast cancer or ovcar - 3 ovarian cells . media was removed from cell stacks and the cells were washed with phosphate buffered saline . cells were dissociated with dissociation buffer ( gibco - brl , grand island , n . y .) for 20 min at 37 ° c . on a platform shaker . cells were collected and centrifuged at 900 g for 10 min at 4 ° c . after centrifugation , cell pellets were resuspended in pbs and centrifuged again at 900 g for 10 min at 4 ° c . to wash . pellets were stored at − 80 ° c . cell pellets were resuspended in homogenization buffer containing 1 tablet per 50 ml of complete protease inhibitor cocktail ( roche , laval qc ) at a ratio of 3 ml buffer per gram of cells . the cell suspension was subjected to homogenization using a polytron homogenizer on ice in order to lyse the cells . the cell homogenate was centrifuged at 15 , 000 g for 10 min at 4 ° c . to remove the nuclear particulate . supernatant was harvested , divided into tubes and then centrifuged at 75 , 600 g for 90 min at 4 ° c . supernatant was carefully removed from the tubes and each membrane pellet was resuspended in approximately 5 ml homogenization buffer . the resuspended pellets from all tubes were combined together in one tube and centrifuged at 75 , 600 g for 90 min at 4 ° c . supernatant from the tubes was carefully removed , and the pellets were weighed . solubilization buffer containing 1 percent triton x - 100 was added to the pellets at a ratio of 3 ml buffer per gram of membrane pellet . membranes were solubilized by shaking on a platform shaker at 300 rpm for 1 hr on ice . the membrane solution was centrifuged at 75 , 600 g to pellet insoluble material . the supernatant containing the solubilized membrane proteins was carefully removed from tubes , assayed for protein content , and stored at − 80 ° c . membrane proteins were separated by sds - polyacrylamide gel electrophoresis . 20 μg of membrane protein was mixed with sds - page sample buffer containing 100 mm dtt and was loaded onto a lane of an 8 percent sds - page gel . a sample of prestained molecular weight markers ( invitrogen , burlington , on ) was run in a reference lane . electrophoresis was carried out at 100 v for 10 minutes , followed by 150 v until sufficient resolution of the prestained molecular weight markers was observed . proteins were transferred from the gel to pvdf membranes ( millipore , billerica , mass .) by electroblotting for 16 hr at 40 v . transfer was assessed by noting complete transfer of the prestained markers from the gel to the membrane . following transfer , membranes were blocked with 5 percent skim milk powder in tris - buffered saline containing 0 . 5 percent tween - 20 ( tbst ) for 2 hr . membranes were washed once with tbst and then incubated with 5 μg / ml 11bd - 2e11 - 2 diluted in 3 percent skim milk powder in tbst for 2 hr . after washing 3 times with tbst , membranes were incubated with goat anti - mouse igg ( fc ) conjugated to horseradish peroxidase ( hrp ) from jackson immunologicals ( west grove pa .). this incubation was followed by washing 3 times with tbst , followed by incubation with the hrp substrate 3 , 3 ′, 5 , 5 ′- tetramethyl benzidine ( tmb ) ( substrate kit from vector laboratories , burlington on ). in fig1 , 11bd - 2e11 - 2 clearly binds to 3 molecular weight regions of the separated mb - 231 ( lane 1 ) and ovcar - 3 ( lane 2 ) membrane proteins . by comparison to the molecular weight ( mw ) standards , the antibody binds to proteins of mw approximately 150 , 240 and 280 kda . all further studies were done using the mb - 231 membranes since stronger reactivity was seen with this cell line . in order to determine if the antigen ( s ) recognized by the antibody 11bd - 2e11 - 2 were glycoproteins , mb - 231 membranes were incubated with different combinations of pngase f , endo - o - glycosidase , sialidase , galactosidase and glucosaminidase . membranes were separated by sds - page followed by western blotting as described with 11bd - 2e11 - 2 . fig2 demonstrates the result of 11bd - 2e11 - 2 binding to mb - 231 membranes that were incubated in deglycosylation buffer only ( lane 1 ), in a combination of pngase f , endo - o - glycosidase , sialidase , galactosidase and glucosaminodase ( lane 2 ), in a combination of pngase , endo - o - glycosidase and sialidase ( lane 3 ), in sialidase only ( lane 4 ), in endo - o - glycosidase only ( lane 5 ), and in pngase only ( lane 6 ). treatment of mb - 231 membranes with glycosidases does not eliminate binding of 11bd - 2e11 - 2 , however a molecular weight shift of the proteins is observed in all lanes , indicating that the antigen recognized by 11bd - 2e11 - 2 was a glycoprotein . the identification of the antigen for 11bd - 2e11 - 2 was carried out by isolating the cognate ligand through immunoprecipitation of solublized membrane gylcoproteins with the antibody . 100 μl of protein g dynabeads ( dynal biotech , lake success n . y .) were washed 3 times with 1 ml of 0 . 1 m sodium phosphate buffer ph 6 . 0 . 100 μg of 11bd - 2e11 - 2 in a total volume of 100 μl 0 . 1 m sodium phosphate buffer ph 6 . 0 was added to the washed beads . the mixture was incubated for 1 hr with rotational mixing . unbound antibody was removed and the 11bd - 2e11 - 2 coated beads were washed 3 times with 0 . 5 ml 0 . 1 m sodium phosphate ph 7 . 4 containing 0 . 1 percent tween - 20 . the 11bd - 2e11 - 2 coated beads were washed 2 times with 1 ml 0 . 2 m triethanolamine ph 8 . 2 . 11bd - 2e11 - 2 was chemically crosslinked to the beads by adding 1 ml of 0 . 02 m dimethylpimelimidate in 0 . 2 m triethanolamine ph 8 . 2 and incubating with rotational mixing for 30 min . the reaction was stopped by incubating the beads with 1 ml of 0 . 05 m tris ph 7 . 5 , for 15 min with rotational mixing . the 11bd - 2e11 - 2 crosslinked beads were washed 3 times with 1 ml of 1 mm kh 2 po 4 , 10 mm na 2 hpo 4 , 137 mm nacl , 2 . 7 mm kcl ( pbs ) containing 0 . 1 percent tween - 20 . the 11bd - 2e11 - 2 crosslinked beads were pre - eluted by incubation with 0 . 1 m citrate ph 3 . 0 for 3 min followed by 3 washes in 0 . 1 m pbs containing 0 . 1 percent tween - 20 . a second set of antibody crosslinked beads were prepared in the same manner described using a mouse igg 1 antibody ( clone 107 . 3 from bd biosciences , oakville on ) to trinitrophenol , an irrelevant molecule , which was used as a negative igg 1 isotype control . the 11bd - 2e11 - 2 crosslinked beads were blocked by incubating in 1 percent bsa in 0 . 1 m sodium phosphate ph 7 . 4 with rotational mixing for 30 minutes at 4 ° c . the beads were washed 3 times with 0 . 1 m sodium phosphate ph 7 . 4 . 500 μg of total membrane preparation from mb - 231 cells was incubated with the 11bd - 2e11 - 2 crosslinked beads with rotational mixing for 2 . 5 hr at 4 ° c . the immunocomplex bound beads were washed three times with 1 ml of 1 mm kh 2 po 4 , 10 mm na 2 hpo 4 , 287 mm nacl , 2 . 7 mm kcl containing 1 percent triton x - 100 . 11bd - 2e11 - 2 bound protein was eluted from the 11bd - 2e11 - 2 crosslinked beads by incubation with 30 μl of 0 . 1 m citrate ph 3 . 0 for 3 min with gentle mixing . the eluted protein was brought to neutral ph by the addition of 9 μl of 1m tris ph 9 . the neutralized eluted protein was stored at − 80 ° c . the 11bd - 2e11 - 2 crosslinked beads were washed with 3 ml pbs containing 0 . 1 percent tween - 20 . the igg 1 isotype control ( clone 107 . 3 ) crosslinked beads were incubated with mb - 231 membrane proteins and processed in the same manner as the 11bd - 2e11 - 2 beads . two batches of 11bd - 2e11 - 2 immunoprecipitated protein from mb - 231 membrane proteins were produced as described and combined together . the same was done for the igg1 ( clone 107 . 3 ) isotype control beads . sixty - two percent of this immunoprecipitate mixture ( corresponding to the amount of protein immunoprecipitated from 620 μg of mb - 231 membrane proteins ) was loaded onto a single lane of a 4 - 20 percent gradient sds - page gel . the same amount of material produced from the 107 . 3 crosslinked beads was loaded in an adjacent lane , as was 20 μg of mb - 231 membrane proteins . a sample of unstained molecular weight markers ( invitrogen , burlington on ) or pre - stained molecular weight markers were run in reference lanes . the sample was separated by electrophoresis at 100 v for 10 min , followed by 150 v for 60 minutes . proteins were stained by incubating the gel in sypro ruby ™ ( biorad , mississauga , on ). in a parallel western blot , 18 percent of the immunoprecipitate mixture , which corresponded to the amount of protein immunoprecipitated from 180 μg of mb - 231 membrane proteins , and the same amount of material produced from the igg1 isotype control ( clone 107 . 3 ) crosslinked beads , were separated by electrophoresis . proteins were transferred from the gel to pvdf membranes ( millipore , billerica , mass .) by electroblotting for 16 hr at 40 v . after transfer , the membrane was blocked with 5 percent skim milk powder in tbst for 2 hr . the membrane was probed with 5 μg / ml 11bd - 2e11 - 2 diluted in 3 percent skim milk powder in tbst for 2 hr . after washing 3 times with tbst , the membrane was incubated with goat anti - mouse igg ( fc ) conjugated hrp for 1 hr . this incubation was followed by washing 3 times with tbst , followed by incubation with the hrp substrate tmb . fig3 depicts the gel and western blot obtained from the proteins immunoprecipitated by 11bd - 2e11 - 2 . on the gel ( panel a ) lane 1 represents the molecular weight standard and lane 2 represents the mb - 231 membrane proteins . there were two distinct bands of mw 240 and 280 kda in the lane containing the 11bd - 2e11 - 2 immunoprecipitated material ( lane 3 ) that were not present in the lane containing the 107 . 3 immunoprecipitated material ( lane 4 ). on the corresponding western blot ( panel b ), 11bd - 2e11 - 2 reacts strongly with the 11bd - 2e11 - 2 immunoprecipitated proteins of mw 240 and 280 kda ( lane 3 ). on the western blot 11bd - 2e11 - 2 also reacts strongly to an additional band in the 11bd - 2e11 - 2 immunoprecipitated protein at 150 kda ; this band was not detectable on the stained gel . the reactivity profile of 11bd - 2e11 - 2 to 11bd - 2e11 - 2 immunoprecipitated protein was similar to that seen in the mb - 231 total membranes ( lane 2 ). there was no reactivity of 11bd - 2e11 - 2 to proteins immunoprecipitated by igg1 isotype control ( clone 107 . 3 ; lane 4 ), indicating that the binding of 11bd - 2e11 - 2 to the immunoprecipitated protein was specific , and not due to the presence of contaminating proteins . the regions of the gel corresponding to the 240 and 280 kda protein immunoprecipitated by 11bd - 2e11 - 2 ( fig3 , panel a , lane 3 ) were cut out using sterile scalpels . these gel slices were then used for identification of proteins by mass spectrometry using maldi / ms and lc / ms / ms . the samples were subjected to proteolytic digestion on a progest workstation using trypsin , and a portion of the resulting digest supernatant was used for maldi / ms analysis . spotting was performed robotically ( proms ) with ziptips ; peptides were eluted form the c18 material with matrix ( α - cyano 4 - hydroxy cinnamic acid ) prepared in 60 percent acetonitrile , 0 . 2 percent tfa . maldi / ms data was acquired on an voyager de - str instrument ( applied biosystems , foster city calif . and the observed m / z values were submitted to profound ( proteometrics software package ) for peptide mass fingerprint searching . profound queried a locally stored copy of the ncbinr database . an additional portion of the digest supernatant was analyzed by nano lc / ms / ms on a micromass q - tof2 using a 75 μm c18 column at a flow - rate of 200 nl / min . ms / ms data were searched using a local copy of mascot . the proteins identified by maldi / ms and lc / ms / ms are presented in table 1 . confirmation of the putative antigen was carried out by determining whether known anti - mcsp antibodies would react with the protein immunoprecipitated by 11bd - 2e11 - 2 and vice versa . immunoprecipitates were prepared in the same manner as described previously except with the addition of the mouse anti - mcsp monoclonal antibody 9 . 2 . 27 ( igg2a ) ( chemicon , temecula calif .) and the mouse igg2a antibody ( clone g155 - 178 from bd biosciences ; oakville on ) to trinitrophenol , an irrelevant molecule , which was used as a negative igg2a isotype control . 11bd - 2e11 - 2 immunoprecipitate , igg1 isotype control ( clone 107 . 3 ) immunoprecipitate , anti - mcsp ( clone 9 . 2 . 27 ) immunoprecipitate , igg2a isotype control ( clone g155 - 228 ) immunoprecipitate and mb - 231 membranes were separated by sds - page on six replicate 10 percent gels . electrophoresis and western blotting were carried out as described above . the membranes were incubated with 5 μg / ml of 11bd - 2e11 - 2 , igg1 isotype control ( clone 107 . 3 ), anti - mcsp ( clone 9 . 2 . 27 ), igg2a isotype control ( clone g155 - 228 ), rabbit polyclonal anti - rat ng2 antibody ( mcsp is the human homologue of rat ng2 ; chemicon , temecula calif .) and normal rabbit igg ( sigma , saint louis mo .) diluted in 3 percent skim milk powder in tbst for 2 . 5 hr . fig4 demonstrates the results of the western blotting as described . fig4 ( panel a ) shows the binding of 11bd - 2e11 - 2 to 11bd - 2e11 - 2 immunoprecipitate ( lane 1 ), igg1 isotype control ( clone 107 . 3 ) immunoprecipitate ( lane 2 ), anti - mcsp ( clone 9 . 2 . 27 ) immunoprecipitate ( lane 3 ), igg2a isotype control ( clone g155 - 228 ) immunoprecipitate ( lane 4 ), mb - 231 membranes ( lane 5 ) and sample buffer only ( negative control ) ( lane 6 ). 11bd - 2e11 - 2 recognized the same three bands of approximately 150 , 240 and 280 kda in both the mb - 231 membranes and in the 11bd - 2e11 - 2 immunoprecipitate . only the upper 280 kda band was recognized in the anti - mcsp ( clone 9 . 2 . 27 ) immunoprecipitate lane . there is no reaction in either of the isotype control immunoprecipitate lanes , indicating that the reactivity of 11bd - 2e11 - 2 to the immunoprecipitates was due to proteins being specifically bound and immunoprecipitated by both 11bd - 2e11 - 2 and 9 . 2 . 27 . in a parallel blot ( panel b ) probed with igg1 isotype control ( clone 107 . 3 ), no reactivity was observed in any of the lanes , indicating that the reactivity observed in the blot probed with 11bd - 2e11 - 2 was specific . panel c shows the binding of rabbit polyclonal anti - rat ng2 antibody to a parallel blot . anti - ng2 binds to two bands of approximately 150 and 240 kda in the 11bd - 2e11 - 2 immunoprecipitate ( lane 1 ) while it does not bind to proteins of this molecular weight range in any of the other lanes . in a parallel blot ( panel d ), normal rabbit igg shows faint non - specific reactivity to proteins in both the igg2a immunoprecipitate ( lane 4 ) and mb - 231 membranes ( lane 5 ). therefore the same reactivity in these lanes on panel c ( probed with rabbit anti - ng2 ) should be regarded as non - specific . in a parallel blot ( panel e ) anti - mcsp ( clone 9 . 2 . 27 ) shows only very faint binding to one band in the anti - mcsp ( clone 9 . 2 . 27 ) immunoprecipitate lane ( lane 3 , indicated by arrow ); this band is not seen in the mb - 231 membranes ( lane 5 ) which indicates that 9 . 2 . 27 may have a low affinity for this antigen and only show reactivity when it is present in a concentrated form such as it is in the immunoprecipitated sample . in the final parallel blot ( panel f ) probed with igg2a isotype control ( clone g155 - 228 ), no reactivity was observed in any of the lanes , indicating that the reactivity observed in the blot probed with anti - mcsp ( clone 9 . 2 . 27 ) was specific . these results demonstrate that 11bd - 2e11 - 2 immunoprecipitated protein was recognized by the rat homologue of mcsp , and that anti - mcsp immunoprecipitated protein was recognized by 11bd - 2e11 - 2 . the mass spectroscopic identification combined with the confirmation using known commercial antibodies demonstrates that the antigen for 11bd - 2e11 - 2 is mcsp . this is also consistent with the deglycosylation experiments in example 2 , as the core protein of mcsp is a glycoprotein . antibody epitope mapping experiments were carried out in order to determine the region ( s ) of the mcsp molecule that were recognized by 11bd - 2e11 - 2 . an overlapping peptide array based on the amino acid sequence of mcsp was synthesized and covalently bound to a cellulose membrane in a stepwise manner , resulting in a defined arrangement . each peptide was 18 amino acids long with an overlap of 9 amino acids . the peptide array was incubated with blocking buffer for several hours . 11bd - 2e11 - 2 was conjugated to horseradish peroxidase ( hrp ) using a modified periodate method following the method of wilson and nakane . following blocking , the peptide array was incubated with 1 μg / ml 11bd - 2e11 - 2 - hrp in blocking buffer . in a separate experiment , the peptide array was incubated with a sheep anti - mouse igg - hrp as a negative control . the peptide array was washed with tbst and incubated with a chemiluminescent substrate . the light emitted during the chemiluminescent reaction was quantified for each spot on the peptide array using a charge coupled device ( ccd )- camera , resulting in a signal intensity value ( boehringer light units ; blu ) for each peptide . for this experiment all signals below 7500 blu were considered as background . the binding data for the peptide array is listed in fig5 represents a graphical image of the binding data . 11bd - 2e11 - 2 bound most strongly to peptides # 26 and # 71 . weaker binding , which was greater than background , was recognizable on peptides # 3 , # 66 , # 170 , # 251 , # 252 and # 256 . these results indicated that 11bd - 2e11 - 2 may bind to a discontinuous epitope with two major binding sites ( peptides # 26 and # 71 ) as well as to a number of other sites . as outlined in ser . no . 10 / 743 , 451 , the hybridoma cell line 11bd - 2e11 - 2 was deposited , in accordance with the budapest treaty , with the american type culture collection , 10801 university blvd ., manassas , va . 20110 - 2209 on nov . 11 , 2003 , under accession number pta - 5643 . in accordance with cfr 1 . 808 , the depositors assure that all restrictions imposed on the availability to the public of the deposited materials will be irrevocably removed upon the granting of a patent . 11bd - 2e11 - 2 monoclonal antibody was produced by culturing the hybridoma ( pta - 5643 ) in cl - 1000 flasks ( bd biosciences , oakville , on ) with collections and reseeding occurring twice / week . the antibody was purified according to standard antibody purification procedures with protein g sepharose 4 fast flow ( amersham biosciences , baie d &# 39 ; urfé , qc ). as previously described in ser . no . 10 / 348 , 231 , 11bd - 2e11 - 2 was compared to a number of both positive ( anti - fas ( eos9 . 1 , igm , kappa , 20 micrograms / ml , ebioscience , san diego , calif . ), anti - her2 / neu ( igg1 , kappa , 10 microgram / ml , inter medico , markham , on ), anti - egfr ( c225 , igg1 , kappa , 5 microgram / ml , cedarlane , homby , on ), cycloheximide ( 100 micromolar , sigma , oakville , on ), nan 3 ( 0 . 1 %, sigma , oakville , on )) and negative ( 107 . 3 ( anti - tnp , igg1 , kappa , 20 microgram / ml , bd biosciences , oakville , on ), g155 - 178 ( anti - tnp , igg2a , kappa , 20 microgram / ml , bd biosciences , oakville , on ), mpc - 11 ( antigenic specificity unknown , igg2b , kappa , 20 microgram / ml ), j606 ( anti - fructosan , igg3 , kappa , 20 microgram / ml ), igg buffer ( 2 %)) controls in a cytotoxicity assay ( table 2 ). breast cancer ( mda - mb - 231 ( mb - 231 ), mda - mb - 468 ( mb - 468 ), mcf - 7 ), colon cancer ( ht - 29 , sw1116 , sw620 ), lung cancer ( nci h460 ), ovarian cancer ( ovcar - 3 ( ovcar )), prostate cancer ( pc - 3 ), and non - cancer ( ccd 27sk , hs888 lu ) cell lines were tested ( all from the atcc , manassas , va .). the live / dead cytotoxicity assay was obtained from molecular probes ( eugene , oreg .). the assays were performed according to the manufacturer &# 39 ; s instructions with the changes outlined below . cells were plated before the assay at the predetermined appropriate density . after 2 days , purified antibody or controls were diluted into media , and then 100 microliters were transferred to the cell plates and incubated in a 5 percent co 2 incubator for 5 days . the plate was then emptied by inverting and blotted dry . room temperature dpbs containing mgcl 2 and cacl 2 was dispensed into each well from a multi - channel squeeze bottle , tapped three times , emptied by inversion and then blotted dry . 50 microliters of the fluorescent calcein dye diluted in dpbs containing mgcl 2 and cacl 2 was added to each well and incubated at 37 ° c . in a 5 percent co 2 incubator for 30 minutes . the plates were read in a perkin - elmer hts7000 fluorescence plate reader and the data was analyzed in microsoft excel and the results were tabulated in table 3 . the data represented an average of four experiments tested in triplicate and presented qualitatively in the following fashion : 4 / 4 experiments greater than threshold cytotoxicity (+++), 3 / 4 experiments greater than threshold cytotoxicity (++), 2 / 4 experiments greater than threshold cytotoxicity (+). unmarked cells in table 1 represent inconsistent or effects less than the threshold cytotoxicity . 11bd - 2e11 - 2 was specifically cytotoxic in breast and ovarian cancer cells , and did not affect normal cells . the chemical cytotoxic agents induced their expected cytotoxicity while a number of other antibodies which were included for comparison also performed as expected given the limitations of biological cell assays . in toto , it was shown that the 11bd - 2e11 - 2 antibody has cytotoxic activity against two cancer cell types . the antibody was selective in its activity since not all cancer cell types were susceptible . furthermore , the antibody demonstrated functional specificity since it did not produce cytotoxicity against non - cancer cell types , which is an important factor in a therapeutic situation . as previously described in ser . no . 10 / 348 , 231 and ser . no . 10 / 810 , 744 , binding of 11bd - 2e11 - 2 to the above - mentioned panel of cancer and normal cell lines plus the following additional ovarian cancer cell lines ( a2780 - cp , a2780 - s , c - 14 , ov2008 , hey , occ - 1 , ovca - 429 and es - 2 + seap ) was assessed by flow cytometry ( facs ). cells were prepared for facs by initially washing the cell monolayer with dpbs ( without ca ++ and mg ++ ). cell dissociation buffer ( invitrogen , burlington , on ) was then used to dislodge the cells from their cell culture plates at 37 ° c . after centrifugation and collection the cells were resuspended in dulbecco &# 39 ; s phosphate buffered saline containing mgcl 2 , cacl 2 and 2 or 25 percent fetal bovine serum ( fbs ) at 4 ° c . ( wash media ) and counted , aliquoted to appropriate cell density , spun down to pellet the cells and resuspended in staining media ( dpbs containing mgcl 2 and cacl 2 ± 2 percent fbs ) containing 11bd - 2e11 - 2 or control antibodies ( isotype control or anti - egfr ) at 20 μg / ml on ice for 30 min . prior to the addition of alexa fluor 488 - conjugated secondary antibody the cells were washed once with wash media . the alexa fluor 488 - conjugated antibody in staining media was then added for 20 to 30 min . the cells were then washed for the final time and resuspended in staining media containing 1 μg / ml propidium iodide or 1 . 5 percent paraformaldehyde . flow cytometric acquisition of the cells was assessed by running samples on a facscan using the cellquest software ( bd biosciences , oakville , on ). the forward ( fsc ) and side scatter ( ssc ) of the cells were set by adjusting the voltage and amplitude gains on the fsc and ssc detectors . the detectors for the three fluorescence channels ( fl1 , fl2 , and fl3 ) were adjusted by running cells stained with purified isotype control antibody followed by alexa fluor 488 - conjugated secondary antibody such that cells had a uniform peak with a median fluorescent intensity of approximately 1 - 5 units . live cells were acquired by gating for fsc and propidium iodide exclusion ( when used ). for each sample , approximately 10 , 000 live cells were acquired for analysis and the resulted are presented in tables 4 and 5 . tables 4 and 5 tabulated the mean fluorescence intensity fold increase above isotype control and is presented qualitatively as : less than 5 (−); 5 to 50 (+); 50 to 100 (++); above 100 (+++) and in parenthesis , the percentage of cells stained . representative histograms of 11bd - 2e11 - 2 antibodies were compiled for fig6 . 11bd - 2e11 - 2 displayed specific tumor binding to the breast tumor cell line mda - mb - 231 ( table 4 ) and several ovarian tumor cell lines including es - 2 + seap ( table 5 ). there was also binding of 11bd - 2e11 - 2 to non - cancer cells , however that binding did not produce cytotoxicity . this was further evidence that binding was not necessarily predictive of the outcome of antibody ligation of its cognate antigen , and was a non - obvious finding . this suggested that the context of antibody ligation in different cells was determinative of cytoxicity rather than just antibody binding . ihc studies were conducted to characterize 11bd - 2e11 - 2 antigen distribution in humans . ihc optimization studies were performed previously in order to determine the conditions for further experiments . 11bd - 2e11 - 2 monoclonal antibody was produced and purified as stated above . as disclosed in ser . no . 10 / 810 , 744 , binding of antibodies to 20 normal human tissues was performed using a frozen human normal organ tissue array ( clinomics , watervliet , n . y .). slides were postfixed for 10 min in cold (− 20 ° c .) acetone and then allowed to come to room temperature . slides were rinsed in 4 ° c . cold phosphate buffered saline ( pbs ) 3 times for 2 min each followed by blocking endogenous peroxidase activity with washing in 3 percent hydrogen peroxide for 10 min . slides were then rinsed in pbs 3 times for 5 min followed by incubation in universal blocking solution ( dako , toronto , ontario ) for 5 min at room temperature . 11bd - 2e11 - 2 , anti - human muscle actin ( clone hhf35 , dako , toronto , ontario ) or isotype control antibody ( directed towards aspergillus niger glucose oxidase , an enzyme which is neither present nor inducible in mammalian tissues ; dako , toronto , ontario ) were diluted in antibody dilution buffer ( dako , toronto , ontario ) to its working concentration ( 5 μg / ml for each antibody except for anti - actin which was 2 μg / ml ) and incubated overnight for 1 hr at room temperature . the slides were washed with pbs 3 times for 2 minutes each . immunoreactivity of the primary antibodies was detected / visualized with hrp conjugated secondary antibodies as supplied ( dako envision system , toronto , ontario ) for 30 min at room temperature . following this step the slides were washed with pbs 3 times for 2 min each and a color reaction developed by adding dab ( 3 , 3 ′- diaminobenzidine tetrahydrachloride , dako , toronto , ontario ) chromogen substrate solution for immunoperoxidase staining for 10 min at room temperature . washing the slides in tap water terminated the chromogenic reaction . following counterstaining with meyer &# 39 ; s hematoxylin ( sigma diagnostics , oakville , on ), the slides were dehyrdated with graded ethanols ( 95 - 100 %) and cleared with xylene . using mounting media ( dako faramount , toronto , ontario ) the slides were coverslipped . slides were microscopically examined using an axiovert 200 ( zeiss canada , toronto , on ) and digital images acquired and stored using northern eclipse imaging software ( mississauga , on ). results were read , scored and interpreted by a pathologist . table 6 presents a summary of the results of 11bd - 2e11 - 2 staining of an array of normal human tissues . from the table , there were 2 main categories of tissue staining . a group of tissues was completely negative . these tissues included normal thyroid , bronchus and cardiac muscle of the left ventricle ( fig7 ). the second group of tissues included tissues in which staining was positive in the tissue section , but was limited to smooth muscle fibers of blood vessels and / or the epithelium ( fig8 ). these results suggested that the antigen for 11bd - 2e11 - 2 was not widely expressed on normal tissues , and that the antibody would bind only to a limited number of tissues in humans . the normal human tissue staining of 11bd - 2e11 - 2 resembles that previously reported for an anti - mcsp antibody ; b5 . b5 was previously shown to bind to skin keratinocytes , lung alveolar epithelium and capillary endothelium . an ihc study was undertaken to determine the cancer association of the 11bd - 2e11 - 2 antigen with human breast cancers ( disclosed in ser . no . 10 / 810 , 744 ). a comparison was made for actin ( positive control ), and an antibody directed towards aspergillus niger glucose oxidase , an enzyme which is neither present nor inducible in mammalian tissues ( negative control ). a breast cancer tissue array derived from 15 breast cancer patients and 5 samples derived from non - neoplastic breast tissue in breast cancer patients were used ( clinomics , watervliet , n . y .). the following information was provided for each patient : age , sex , and diagnosis . the procedure for ihc from example 6 was followed . table 7 provides a binding summary of 11bd - 2e11 - 2 antibody staining of a breast cancer tissue array . each array contained tumor samples from 15 individual patients . overall , 62 percent of the 8 ( 7 of the tissue samples were either completely detached or not representative ) patients tested were positive for the 11bd - 2e11 - 2 antigen . also for 11bd - 2e11 - 2 , 0 out of 3 ( again 2 of the tissue samples were completely detached ) normal breast tissue samples from breast cancer patients were positive ( fig9 ). for the 11bd - 2e11 - 2 antigen there did not appear to be a trend to greater positive expression with higher tumor stage . however , this result was limited due to the small sample size . the 11bd - 2e11 - 2 staining was specific for cancerous cells ( fig9 ). the staining pattern , from 11bd - 2e11 - 2 , showed that in patient samples , the antibody was highly specific for malignant cells thereby making it an attractive druggable target . the breast tumor tissue staining of 11bd - 2e11 - 2 resembles that previously reported for the anti - mcsp antibody b5 . b5 was previously shown to bind to 60 percent of breast carcinoma tumor tissue . an ihc study was undertaken to determine the cancer association of the 11bd - 2e11 - 2 antigen with human melanoma cancers . a comparison was made for an anti - cd63 antibody ( nik - c3 ; medicorp , montreal qc ); positive control ), and an antibody directed towards aspergillus niger glucose oxidase , an enzyme which is neither present nor inducible in mammalian tissues ( negative control ). a melanoma cancer tissue array derived from 35 melanoma cancer patients and 10 samples derived from normal skin tissue in melanoma cancer patients was used ( tristar technology group , llc , bethesda , md .). the procedure for ihc from example 6 was followed except for the following modifications . the color reaction developed by adding aec ( dako , toronto , ontario ) chromogen substrate solution for immunoperoxidase staining for 10 minutes at room temperature . washing the slides in tap water terminated the chromogenic reaction . following counterstaining with meyer &# 39 ; s hematoxylin ( sigma diagnostics , oakville , on ), the slides were cleared with distilled water . table 8 provides a binding summary of 11bd - 2e11 - 2 antibody staining of a melanoma cancer tissue array . each array contained tumor samples from 35 individual patients and normal skin from 10 patients . overall , 67 percent of the 33 ( 2 of the tissue samples were completely pigmented ) patients tested were positive for the 11bd - 2e11 - 2 antigen ( fig1 ). in addition , 0 out of 6 ( 4 of the tissue samples were non representative or not available ) normal skin tissue samples from melanoma cancer patients were positive ( fig1 ). the 11bd - 2e11 - 2 staining was specific for cancerous cells ( fig1 ). the staining pattern , from 11bd - 2e11 - 2 , showed that in patient samples , the antibody was highly specific for malignant cells thereby making it an attractive druggable target and demonstrating the utility of 11bd - 2e11 - 2 as a potential drug . as disclosed in ser . no . 10 / 810 , 744 and with reference to fig1 , 6 to 8 week old female scid mice were implanted with 2 million mda - mb - 468 human breast cancer cells in 100 microlitres saline injected subcutaneously in the scruff of the neck . tumor growth was measured with calipers every week . when the majority of the cohort reached a tumor volume of 100 mm 3 , 5 - 6 mice were randomized into each of 2 treatment groups . 11bd - 2e11 - 2 or buffer control was administered intraperitoneally with 10 mg / kg / dose at a volume of 300 microliters after dilution from the stock concentration with a diluent that contained 2 . 7 mm kcl , 1 mm kh 2 po 4 , 137 mm nacl and 20 mm na 2 hpo 4 . the antibodies were then administered 3 times per week for a total of 10 doses in the same fashion until day 66 post - implantation . tumor growth was measured about every seventh day with calipers for the duration of the study or until individual animals reached ccac end - points . body weights of the animals were recorded for the duration of the study . at the end of the study all animals were euthanised according to ccac guidelines . at the time of randomization the mean tumor volumes and the standard deviations in each group were similar . statistically there was no difference in body weight between the groups . this indicated that true randomization had occurred . as shown in fig1 , the antibody 11bd - 2e11 - 2 suppressed tumor growth by 25 percent in comparison to buffer control at the end of the 3 - week treatment period ( p = 0 . 52 ). although this was not a significant difference , a trend towards reduced tumor volume in comparison to the buffer control was observed throughout the study . therefore , 11bd - 2e11 - 2 has shown efficacy in an established breast cancer model . as disclosed in ser . no . 10 / 810 , 744 and with reference to fig1 and 14 , 6 to 8 week old female athymic nude mice were intraperitoneally implanted with 10 million es - 2 + seap human ovarian cancer cells stably transfected to express human placental secreted alkaline phosphatase ( seap ). the 10 million ovarian cancer cells were resuspended in 500 microlitres serum - free α - mem . tumor growth was confirmed with the sacrifice of 3 mice on day 7 . following the confirmation of tumor growth on day 7 , 8 mice were randomized into each of 2 treatment groups . 11bd - 2e11 - 2 or buffer control was administered intraperitoneally with 10 mg / kg / dose at a volume of 250 microliters after dilution from the stock concentration with a diluent that contained 2 . 7 mm kcl , 1 mm kh 2 po 4 , 137 mm nacl and 20 mm na 2 hpo 4 . the antibodies were then administered once per day for 5 doses and then once every other day for another 5 doses for a total of 10 doses . tumor burden was extrapolated by measuring circulating seap levels and assessed visually upon necropsy for the duration of the study or until individual animals reached ccac end - points . body weights of the animals were recorded for the duration of the study . at the end of the study all animals were euthanised according to ccac guidelines . at the time of randomization circulating plasma seap levels ( indicative of tumor burden ) were analyzed . there was not a significant difference in the average seap level between the 11bd - 2e11 - 2 and buffer control treatment group . however , within groups there was variable tumor take - rate . as shown in fig1 , the antibody 11bd - 2e11 - 2 displayed a trend for improved survival in a cohort of the treatment group . as illustrated in fig1 , one animal receiving 11bd - 2e11 - 2 treatment had a decreased amount of circulating seap to nearly negligible levels . the low level of circulating seap continued on until approximately 60 days post - implantation . with reference to the data shown in fig1 , 4 to 8 week old , female scid mice were implanted with 0 . 75 million a2058 human melanoma cancer cells in 100 microliters saline injected subcutaneously in the scruff of the neck . the mice were randomly divided into 2 treatment groups of 5 . on the day after implantation 20 mg / kg of 11bd - 2e11 - 2 test antibody or buffer control was administered intraperitoneally at a volume of 300 microliters after dilution from the stock concentration with a diluent that contained 2 . 7 mm kcl , 1 mm kh 2 po 4 , 137 mm nacl and 20 mm na 2 hpo 4 . the antibody or buffer control was then administered once per week for a period of 7 weeks in the same fashion . tumor growth was measured about every 7th day with calipers for up to 10 weeks or until individual animals reached the canadian council for animal care ( ccac ) end - points . body weights of the animals were recorded for the duration of the study . at the end of the study all animals were euthanised according to ccac guidelines . as shown in fig1 , 11bd - 2e11 - 2 treatment resulted in decreased tumor growth compared to treatment with the buffer control . on day 55 ( 5 days after the end of treatment ), the mean tumor volume in the 11bd - 2e11 - 2 treated group was 58 percent of the buffer control ( p = 0 . 046 , unpaired t - test ). therefore , 11bd - 2e11 - 2 displayed efficacy in the treatment of breast , ovarian and melanoma in vivo models of human cancer and reduced tumor burdens in comparison to controls in those same cancers . with reference to fig1 , 6 to 8 week old female scid mice were implanted with 0 . 5 million a2058 human melanoma cancer cells in 100 microlitres saline injected subcutaneously in the scruff of the neck . tumor growth was measured with calipers every week . when the majority of the cohort reached a tumor volume of 100 mm 3 , 5 mice were randomized into each of 2 treatment groups . 11bd - 2e11 - 2 or buffer control was administered intraperitoneally with 20 mg / kg / dose at a volume of 300 microliters after dilution from the stock concentration with a diluent that contained 2 . 7 mm kcl , 1 mm kh 2 po 4 , 137 mm nacl and 20 mm na 2 hpo 4 . the antibodies were then administered 3 times per week for a total of 10 doses in the same fashion until day 44 post - implantation . tumor growth was measured about every seventh day with calipers for the duration of the study or until individual animals reached ccac end - points . body weights of the animals were recorded for the duration of the study . at the end of the study all animals were euthanised according to ccac guidelines . at the time of randomization the mean tumor volumes and the standard deviations in each group were similar . statistically there was no difference in body weight between the groups . this indicated that true randomization had occurred . as shown in fig1 , the antibody 11bd - 2e11 - 2 suppressed tumor growth by 49 percent in comparison to buffer control after the treatment period ( p = 0 . 1272 ; unpaired t - test ). although this was not a significant difference , a trend towards reduced tumor volume in comparison to the buffer control was observed throughout the study . therefore , 11bd - 2e11 - 2 has shown efficacy in both an established breast , ovarian and melanoma cancer model . in all , these results in which 11bd - 2e11 - 2 produced benefits ( improved survival and / or decreased tumor burden in comparison to control treatment ) in mulitple models of human cancer suggest pharmacologic and pharmaceutical benefits of this antibody for cancer therapy in mammals , including man . the preponderance of evidence shows that 11bd - 2e11 - 2 mediates anti - cancer effects through ligation of an epitope present on mscp . for the purpose of this invention , said epitope is defined as a “ mscp antigenic moiety ” characterized by its ability to bind with a monoclonal antibody encoded by the hybridoma cell line 11bd - 2e11 - 2 , antigenic binding fragments thereof or antibody conjugates thereof . it has been shown , in example 3 , 11bd - 2e11 - 2 antibody can be used to immunoprecipitate the cognate antigen from expressing cells such as mda - mb - 231 cells . further it could be shown that the 11bd - 2e11 - 2 antibody could be used in detection of cells and / or tissues which express a mscp antigenic moiety which specifically binds thereto , utilizing techniques illustrated by , but not limited to facs , cell elisa or ihc . thus , it could be shown that the immunoprecipitated 11bd - 2e11 - 2 antigen can inhibit the binding of 11bd - 2e11 - 2 to such cells or tissues using facs , cell elisa or ihc assays . further , as with the 11bd - 2e11 - 2 antibody , other anti - mscp antibodies could be used to immunoprecipitate and isolate other forms of the mscp antigen , and the antigen can also be used to inhibit the binding of those antibodies to the cells or tissues that express the antigen using the same types of assays . all patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains . all patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference . it is to be understood that while a certain form of the invention is illustrated , it is not to be limited to the specific form or arrangement of parts herein described and shown . it will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification . one skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned , as well as those inherent therein . any oligonucleotides , peptides , polypeptides , biologically related compounds , methods , procedures and techniques described herein are presently representative of the preferred embodiments , are intended to be exemplary and are not intended as limitations on the scope . changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the appended claims . although the invention has been described in connection with specific preferred 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 which are obvious to those skilled in the art are intended to be within the scope of the following claims .

this invention relates to the diagnosis and treatment of cancerous diseases , particularly to the mediation of cytotoxicity of tumor cells ; and most particularly to the use of cancerous disease modifying antibodies , optionally in combination with one or more chemotherapeutic agents , as a means for initiating the cytotoxic response . the invention further relates to binding assays which utilize the cdmabs of the instant invention .

cis - dichiorodiamineplatinum ( ii ) ( cisplatin or cddp ) is an example of an anticancer drug that can induce cancer drug resistance . [ scanlon , 1991 .] kataoka and co - workers incorporated cisplatin into block copolymer micelles to circumvent the drug resistance . the micelle - encapsulated cisplatin had an improved cytotoxicity . [ noshiyama , 2003 ; nishiyama , 1999 ; nishiyama , 2001 .] we synthesized a water - soluble carboxylic acid - containing poly ( ester ) grafted with peg side chains . in water , cddp complexes with the carboxylic acid of the poly ( ester ) and forms nanogel domains of about 100 - 200 nm that can be used for controlled delivery of ccdp or other drugs to cancer tissue . the reaction scheme for producing 2 , 2 - bis ( acryloxymethyl ) propionic acid is illustrated in fig1 . 2 , 2 - bis ( hydroxymethyl ) propionic acid ( 10 . 1 g , 0 . 075 mol ) was stirred at 0 - 5 ° c . in dried dichloromethane . triethylamine ( 15 . 2 g , 0 . 15 mol ) was added with stirring . acryloyl chloride ( 13 . 64 g , 0 . 15 mol ) was added dropwise to the solution in 1 . 5 h . the resulting mixture was stirred for 0 . 5 h and then filtered . the filtrate was concentrated by removal of the solvent under vacuum and the residue was dissolved in 50 ml na 2 co 3 aqueous solution ( 10 % w / v ). hydrochloric acid ( 6n ) was then dropped in with vigorous stirring , until the ph reached 2 . 0 . finally , dichloromethane ( 3 × 50 ml ) was added to the solution . the dichloromethane solution was then concentrated by removal of the solvent under vacuum . the crude product was recrystallized with ethyl acetate / hexane mixed solvent and yielded the 2 , 2 - bis ( acryloxymethyl ) propionic acid as white crystals . 1 h nmr ( cdcl 3 , 400 mhz ) δ = 11 . 47 ( s , 1h ); 5 . 7 - 6 . 8 ( m , 6h ), 4 . 4 ( s , 4h ), 1 . 38 ( s , 3h ). the reaction scheme for synthesizing the peg macromonomer is illustrated in fig2 . poly ( ethylene glycol ) methy ether ( mn ca . 2000 ) ( 10 . 0 g , 0 . 005 mol ) and 2 , 2 - bis ( acryloxymethyl ) propionic acid ( 3 . 03 g , 0 . 0125 mmol ), n , n - dicyclohexylcarbodiimide ( dcc ) ( 2 . 588 g , 0 . 0125 mol ), 4 - dimethylaminopyridine ( 0 . 152 g , 0 . 00125 mol ) and a polymerization inhibitor were dissolved in 50 ml of dry dichioromethane and stirred at room temperature for 72 h . the mixture was then filtered and washed with a small volume of dichioromethane . the filtrate was precipitated in ether , and purified by reprecipitation to give the product as white powder . the reaction scheme for synthesizing poly ( ester )- graft - peg is illustrated in fig2 . 2 , 2 - bis ( acryloxymethyl ) propionic acid ( 0 . 242 g . 0 . 001 mol ), peg macromonomer ( 2 . 224 g , 0 . 001 mol ) and piperazine ( 0 . 172 g . 0 . 002 mol ) were dissolved in 20 ml of n , n - dimethylformamide and stirred at room temperature for 7 days . the molecular weight and polydispersity of the polymer were measured by gpc and calibrated with peg standards . the reaction scheme for synthesizing the nanogels is illustrated in fig3 . poly ( β - aminoester )- graft - peg and cddp were dissolved in distilled water ([ cooh ]/[ cddp ]= 7 . 4 ) and stirred for a certain period of time at room temperature or heated at 70 ° c . for 10 minutes and then kept stirring at room temperature for 12 h . the size of the formed nanogels was evaluated by nanosizer ( malvern instruments ). the graft copolymers with peg side chains ( m n = 2000 ) was prepared by direct condensation . the peg chain density was controlled by the molar ratio of 2 , 2 - bis ( acryloxymethyl ) propionic acid to the peg macromonomer . the pendent carboxyl acid groups are used for the complexation with cddp . composition of the copolymer was measured with 1 hnmr by the ratio of the och 2 ch 2 signal intensity in peg ( 3 . 60 ppm ) and that of ch 3 − in 2 , 2 - bis ( acryloxymethyl ) propionic acid ( 1 . 38 ppm ). polyester - graft - peg with varied contents can be synthesized in a similar method . the peg grafted polymer and cddp reacted in distilled water . the carboxylic groups of the graft - copolymer complexed with cddp , and thus the polymer was crosslinked to form the gel core , while the peg chains formed the hydrophilic corona ( fig3 ). the average size was 220 - 240 nm ( fig4 ). heating can decrease the size of the nanogel . when heated at 70 ° c . for ten minutes , the average size of the nanogels was reduced to 150 - 160 nm . the nanogels are negatively charged . the negatives and the peg outer layer impart “ stealth properties ” to the nanogels suitable for in vivo drug delivery to cancerous tissues via the epr effect . particularly , the polymers alone showed no or little cytotoxicity . the cisplatin - containing nanogels had low in vitro cytotoxicity to skov - 3 ovarian cancer cells compared to free cisplatin . similar phenomena were reported in the cisplatin - containing micelles and other water soluble cisplatin conjugates ( cabral et al . 2005 ; nishiyama et al . 2003a ; nishiyama et al . 2003b ; nishiyama et al . 1999 ). however , the nanogels had similar in vivo anticancer activity to cisplatin tested in nude mice inoculated with skov - 3 tumors . grafting targeting groups to the nanogels is expected to further increase the anticancer activity . in conclusion , the reaction of cddp and peg - grafted copolymer in distilled water led to the spontaneous formation of cddp - incorporated micelles . the size of the micelles can be reduced by heating . these nanogels are useful for drug delivery . the foregoing description and drawings comprise illustrative embodiments of the present inventions . the foregoing embodiments and the methods described herein may vary based on the ability , experience , and preference of those skilled in the art . merely listing the steps of the method in a certain order does not constitute any limitation on the order of the steps of the method . the foregoing description and drawings merely explain and illustrate the invention , and the invention is not limited thereto , except insofar as the claims are so limited . those skilled in the art who have the disclosure before them will be able to make modifications and variations therein without departing from the scope of the invention . bogman , k . ; peyer , a . k . ; torok , m . ; kusters , e . ; drewe , j . hmg - coa reductase inhibitors and p - glycoprotein modulation , br . j . pharmacol . 132 ( 2001 ), 1183 - 92 . gottesman , m . m . mechanisms of cancer drug resistance , annu . rev . med . 53 ( 2002 ), 615 - 627 . nishiyama , n ., yokoyama , m ., aoyagi , t ., okano , t ., sakurai , y ., kataoka , k ., langmuir , 15 ( 1999 ), 377 - 383 . nishiyama , n ., kato , y ., sugiyama , y ., kataoka , k ., pharm . res ., 7 ( 2001 ), 1035 - 1041 . nishiyama , n ., okazaki , s ., cabral , h ., miyamoto , m ., kato , y ., sugiyama , y ., nishio , k ., matsumura , y ., kataoka , k ., cancer res ., 63 ( 2003 ), 8977 - 8983 . pastan , i . and gottesman , m . m . multidrug resistance , annu . rev . med . 42 ( 1991 ), 277 - 286 . pinzani , v . ; bressolle , f . ; hang , l . j . ; galtier , m . ; blayac , j . p . ; balmes , p . cisplatin - induced renal toxicity and toxicity - modulating strategies — a review , cancer chemother . pharmacol . 35 ( 1994 ), 1 - 9 . rosenberg , b . ; vancamp , l . ; trosko , j . e . ; mansour , v . h . platinum compounds : a new class of potent antitumor agents , nature 222 ( 1969 ), 385 . scanlon , k . j . ; kashani - sabet , m . ; tone , t . ; funato , t . pharmacol . therap . 52 ( 1991 ), 385 - 406 . takahara , p . m . ; rosenzweig , a . c . ; frederick , c . a . ; lippard , s . j . crystal - structure of double - stranded dna containing the major adduct of the anticancer drug cisplatin , nature 377 ( 1995 ), 649 - 652 . von hoff , d . d . ; schilsky , r . ; reichert , c . m . ; reddick , r . l . ; rozencweig , m . ; young , r . c . ; muggia , f . m . toxic effects of cis - dichlorodiammineplatinum ( ii ) in man , cancer treat . reports 63 ( 1979 ), 1527 - 1531 .

a nano - sized hydrogel is made of a water - soluble chain containing carboxylic acid moieties and polyethylene side chains . such a nanogel is applicable as a cancer - drug delivery agent or an imagining agent , where either a cancer drug , such as cisplatin , or an imaging agent , such as gd3 +. the complexation of the cancer drug or the imaging agent with the carboxyl moieties leads to the hydrogel formation .

fig1 of the drawing shows a guide sleeve 1 and a pressure line 2 extending through the guide sleeve 1 , wherein the pressure line 2 is provided with an opening 3 for releasing a pressure fluid . an elastic hose - type sheath 4 is placed in the manner of a stocking and flush at the ends thereof on the circular cylindrical pressure line 2 . the sheath 4 is glued in a pressure - tight manner at its ends to the circumference of the pressure line 2 at 5 and 6 . instead of providing a glued connection , it would also be possible to press the elastic sheath 4 at the ends thereof by means of rings against the pressure line . a hollow - cylindrical supporting implant 7 is placed around the elastic sheath 4 . as can be seen in fig2 , the cylindrical wall 8 of the implant 7 is a mesh - like material with openings 9 , wherein wires of the mesh extend at an acute angle relative to each other . the wall 8 can be tangentially expanded in the manner of expanded metal in the direction of double arrow 21 , so that the supporting implant 7 is radially expanded . at its end opposite the sheath 4 or the supporting implant 7 , the pressure line 2 is in connection with a schematically illustrated device 10 for supplying an incompressible pressure fluid 11 , wherein this device 10 includes a pressure cylinder 12 and a piston 13 . the piston 13 may be movable manually , preferably by means of a screw - type pressure gauge , or by means of a motor drive . reference numeral 14 denotes a schematically illustrated control and monitoring device which includes a pressure indicator 16 and a display 17 for the supplied quantity of pressure fluid . the manner of operation of the device is shown in fig1 and 2 and shall now be explained in connection with fig3 and 4 . for stabilizing a broken vertebra , initially a duct 18 is drilled through the pedicle 20 , wherein a catheter and a drilling tool extending through the catheter can be used for this purpose . as shown in fig3 and 4 , the guide sleeve 1 is now placed in the duct 18 and the pressure fluid 2 with the supporting implant 7 can be forwardly pushed into the interior of the compressed vertebra which has compression folds at 19 . the incompressible pressure fluid 11 is pressed by means of the device 10 into the pressure line 2 , the pressure fluid 11 emerges from the opening 3 and the elastic sheath 4 is expanded into a balloon . the expanding sheath or balloon 4 expands the supporting implant 7 , as illustrated in fig4 , wherein the wall 8 of the supporting implant 7 is plastically deformed in the direction of arrow 21 shown in fig2 and the acute angles between the mesh wires at 17 are widened . the quantity of supplied pressure fluid during the expansion can be read at the display 17 of the control and monitoring device 14 and , thus , the extent of the achieved expansion can be determined . the expansion or supply of pressure fluid is stopped when a predetermined value of the supplied pressure fluid quantity has been reached . the control and monitoring device 14 further ensures that the application of pressure is stopped immediately if the balloon 4 ruptures during the expansion , for example , due to a material defect , and pressure fluid is released from the vertebra ; this is the case when the supplied pressure fluid quantity increases significantly over time , while the pressure stays constant or increases only slightly . after the required expansion has been achieved , the pressure fluid is withdrawn through the opening 3 which is located near the lowest point of the balloon 4 . the pressure line 2 with the empty pressure balloon or the empty sheath 4 can now be pulled back through the guide sleeve 1 . the plastically deformed supporting implant 7 maintains its shape and supports the vertebra in such a way that it maintains the shape shown in fig4 and the damage shown at 19 can heal . a filler material is introduced into the interior of the supporting implant . fig2 is a cross - sectional view of another embodiment of a supporting implant 7 a according to the invention . the supporting implant 7 a has in its wall 8 a folds 22 , wherein the folds on opposite sides have different lengths , so that the expanded implant has a rectangular shape in cross - section . in the embodiment described above , a salt solution containing an x - ray contrast agent is used as the pressure fluid . of course , two of the above - described supporting implants can be and are usually inserted into a broken vertebra , wherein ducts are drilled in both pedicles for inserting a catheter . while specific embodiments of the invention have been shown and described in detail to illustrate the inventive principles , it will be understood that the invention may be embodied otherwise without departing from such principles .

a device for straightening and stabilizing the vertebral column , particularly for stabilizing broken vertebrae , includes a supporting implant which is plastically expandable by internal pressure . the supporting implant can be placed into the interior of a vertebral body which has been fractured under compression or between adjacent vertebral bodies . a pressure balloon to which pressure fluid can be admitted may be arranged in the interior of the supporting implant for producing the internal pressure .

fig1 a illustrates the multi - dimensional features of a stereo pulse oximeter 100 according to the present invention . shown in fig1 a is an exemplary stereo pulse oximeter configuration in which a first sensor 110 is attached to a neonate &# 39 ; s left hand , a second sensor 120 is attached to one of the neonate &# 39 ; s feet , and a third sensor 130 is attached to the neonate &# 39 ; s right hand . in general , these sensors are used to obtain oxygen status and photoplethysmograph measurements at peripheral sites , including a person &# 39 ; s ears and face , such as the nose and regions of the mouth in addition to hands , feet and limbs , but not including internal sites such as internal organs and the brain . each sensor 110 , 120 , 130 provides a stream of data through a corresponding sensor interface 114 , 124 , 134 to the digital signal processor ( dsp ) 150 . for example , the first sensor 110 is connected to an input 112 of the first sensor interface 114 , and the output 118 of the first sensor interface 114 is attached to a first data channel input 152 of the dsp 150 . similarly , the second sensor 120 provides data to a second data channel input 154 and the third sensor 130 provides data to a third data channel input 158 . fig1 b illustrates an alternative embodiment of the separate sensors 110 , 120 , 130 ( fig1 a ). a stereo sensor 140 has multiple branches 112 , 122 , 132 each terminating in a sensor portion 114 , 124 , 134 . each sensor portion 114 , 124 , 134 has two light emitters and a light detector , as described below , and is attachable to a separate patient site . thus , the stereo sensor 140 advantageously provides a single sensor device having multiple light emitters and multiple light detectors for attachment to multiple patient tissue sites . a combination of the stereo sensor 140 and a single patient cable 142 advantageously allows a single connection 144 at the stereo pulse oximeter 100 and a single connection 146 at the stereo sensor 140 . the dsp 150 can independently process each data channel input 152 , 154 , 158 and provide outputs 162 typical of pulse oximetry outputs , such as arterial oxygen saturation , sp a o 2 , the associated plethysmograph waveform and the derived pulse rate . in contrast with a conventional pulse oximeter , however , these outputs 162 include simultaneous measurements at each of several patient tissue sites . that is , for the configuration of fig1 a , the stereo pulse oximeter 100 simultaneously displays sp a o 2 and an associated plethysmograph waveform for three tissue sites in addition to the patient &# 39 ; s pulse rate obtained from any one of sites . further , the dsp 150 can provide unique outputs unavailable from conventional pulse oximeters . these outputs 164 include venous oxygen saturation , sp v o 2 , a comparison of arterial and venous oxygen saturation , δ sat = sp av o 2 = sp a o 2 − sp v o 2 , and pleth , which denotes plethysmograph shape parameters , for each site . in addition , the dsp 150 can provide cross - site outputs that are only available using stereo pulse oximetry . these unique cross - site outputs 168 include δsat xy = sp ax o 2 − sp ay o 2 , which denotes the arterial oxygen saturation at site x minus the arterial oxygen saturation at site y . also included in these outputs 168 is δpleth xy , which denotes a comparison of plethysmograph shape parameters measured at site x and site y , as described in detail below . the stereo pulse oximeter also includes a display 180 capable of showing the practitioner the oxygen status and plethysmograph parameters described above . the display 180 has a multiple channel graphical and numerical display capability as described in more detail below . fig2 depicts one stereo pulse oximeter data channel having a sensor 110 and a sensor interface 114 providing a single data channel input 152 to the dsp 150 . the sensor 110 is used to measure the intensity of red and infrared light after transmission through a portion of the body where blood flows close to the surface , such as a fingertip 202 . the sensor 110 has two light emitters , each of which may be , for example , a light - emitting diode ( led ). a red emitter 212 , which transmits light centered at a red wavelength and an infrared ( ir ) emitter 214 , which transmits light centered at an infrared wavelength are placed adjacent to , and illuminate , a tissue site . a detector 218 , which may be a photodiode , is used to detect the intensity of the emitted light after it passes through , and is partially absorbed by , the tissue site . the emitters 212 , 214 and detector 218 are secured to the tissue site , with the emitters 212 , 214 typically spaced on opposite sides of the tissue site from the detector 218 . to distinguish between tissue absorption at the two wavelengths , the red emitter 212 and infrared emitter 214 are modulated so that only one is emitting light at a given time . in one embodiment , the red emitter 212 is activated for a first quarter cycle and is off for the remaining three - quarters cycle ; the infrared emitter 214 is activated for a third quarter cycle and is off for the remaining three - quarters cycle . that is , the emitters 212 , 214 are cycled on and off alternately , in sequence , with each only active for a quarter cycle and with a quarter cycle separating the active times . the detector 218 produces an electrical signal corresponding to the red and infrared light energy attenuated from transmission through the patient tissue site 202 . because only a single detector 218 is used , it receives both the red and infrared signals to form a time - division - multiplexed ( tdm ) signal . this tdm signal is coupled to the input 112 of the sensor interface 114 . one of ordinary skill in the art will appreciate alternative activation sequences for the red emitter 212 and infrared emitter 214 within the scope of this invention , each of which provides a time multiplexed signal from the detector 218 allowing separation of red and infrared signals and determination and removal of ambient light levels in downstream signal processing . to compute sp a o 2 , pulse oximetry relies on the differential light absorption of oxygenated hemoglobin , hbo 2 , and deoxygenated hemoglobin , hb , to compute their respective concentrations in the arterial blood . this differential absorption is measured at the red and infrared wavelengths of the sensor 110 . the relationship between arterial oxygen saturation and hemoglobin concentration can be expressed as : that is , arterial oxygen saturation is the percentage concentration of oxygenated hemoglobin compared to the total concentration of oxygenated hemoglobin and deoxygenated hemoglobin in the arterial blood . sp a o 2 is actually a measure of the partial oxygen saturation of the hemoglobin because other hemoglobin derivatives , such as cohb and methb , are not taken into consideration . fig3 shows a graph 300 of the optical absorption properties of hbo 2 and hb . the graph 300 has an x - axis 310 corresponding to wavelength and a y - axis 320 corresponding to hemoglobin absorption . an hb curve 330 shows the light absorption properties of deoxygenated hemoglobin . an hbo 2 curve 340 shows the light absorption properties of oxygenated hemoglobin . pulse oximetry measurements are advantageously made at a red wavelength 350 corresponding to 660 nm and an infrared wavelength 360 corresponding to 905 nm . this graph 300 shows that , at these wavelengths 350 , 360 , deoxygenated hemoglobin absorbs more red light than oxygenated hemoglobin , and , conversely , oxygenated hemoglobin absorbs more infrared light than deoxygenated hemoglobin . in addition to the differential absorption of hemoglobin derivatives , pulse oximetry relies on the pulsatile nature of arterial blood to differentiate hemoglobin absorption from absorption of other constituents in the surrounding tissues . light absorption between systole and diastole varies due to the blood volume change from the inflow and outflow of arterial blood at a peripheral tissue site . this tissue site might also comprise skin , muscle , bone , venous blood , fat , pigment , etc ., each of which absorbs light . it is assumed that the background absorption due to these surrounding tissues is invariant and can be ignored . thus , blood oxygen saturation measurements are based upon a ratio of the time - varying or ac portion of the detected red and infrared signals with respect to the time - invariant or dc portion . this ac / dc ratio normalizes the signals and accounts for variations in light pathlengths through the measured tissue . further , a ratio of the normalized absorption at the red wavelength over the normalized absorption at the infrared wavelength is computed : where red ac , and ir ac are the root - mean - square ( rms ) of the corresponding time - varying signals . this “ red - over - infrared , ratio - of - ratios ” cancels the pulsatile signal . the desired sp a o 2 measurement is then computed from this ratio . fig4 shows a graph 400 depicting the relationship between rd / ir and sp a o 2 . this relationship can be approximated from beer - lambert &# 39 ; s law , as outlined below . however , it is most accurately determined by statistical regression of experimental measurements obtained from human volunteers and calibrated measurements of oxygen saturation . the result can be depicted as a curve 410 , with measured values of rd / ir shown on a y - axis 420 and corresponding saturation values shown on an x - axis 430 . in a pulse oximeter device , this empirical relationship can be stored in a read - only memory ( rom ) look - up table so that sp a o 2 can be directly read - out from input rd / ir measurements . according to the beer - lambert law of absorption , the intensity of light transmitted through an absorbing medium is given by : where i 0 is the intensity of the incident light , ε i , λ . is the absorption coefficient of the i th constituent at a particular wavelength λ , c i is the concentration coefficient of the i th constituent and x i is the optical path length of the i th constituent . as stated above , assuming the absorption contribution by all constituents but the arterial blood is constant , taking the natural logarithm of both sides of equation ( 3 ) and removing time invariant terms yields : ln ( l )=−[ ε hbo2 , λ c hbo2 + ε hb , λ c hb ] x ( t ) ( 4 ) rd ( t )=−[ ε hbo2 , rd c hbo2 + ε hb , rd c hb ] x rd ( t ) ( 5 ) ir ( t )=−[ ε hbo2 , ir c hbo2 + ε hb , ir c hb ] x ir ( t ) ( 6 ) taking the ratio rd ( t )/ ir ( t ) and assuming x rd ( t )≈ x ir ( t ) yields : rd / ir =[ ε hbo2 , rd c hbo2 + ε hb , rd c hb ]/[ ε hbo2 , ir c hbo2 + ε hb , ir c hb ] ( 7 ) then equation ( 1 ) can be solved in terms of rd / ir yielding a curve similar to the graph 400 of fig4 . fig2 also depicts the sensor interface 114 for one data channel . an interface input 112 from the sensor 110 is coupled to an analog signal conditioner 220 . the analog signal conditioner 220 has an output 223 coupled to an analog - to - digital converter ( adc ) 230 . the adc output 118 is coupled to the dsp 150 . the analog signal conditioner also has a gain control input 225 from the dsp 150 . the functions of the analog signal conditioner 220 are explained in detail below . the adc 230 functions to digitize the input signal 112 prior to further processing by the dsp 150 , as described below . the sensor interface 114 also has an emitter current control input 241 coupled to a digital - to - analog converter ( dac ) 240 . the dsp provides control information to the dac 240 via the control input 241 for a pair of emitter current drivers 250 . one driver output 252 couples to the red emitter 212 of the sensor 110 , and another driver output 254 couples to the ir emitter 214 of the sensor 110 . fig5 illustrates one embodiment of the analog signal conditioner 220 . the analog signal conditioner 220 receives a composite intensity signal 112 from the sensor detector 218 ( fig2 ) and then filters and conditions this signal prior to digitization . the embodiment shown has a preamplifier 510 , a high pass filter 520 , a programmable gain amplifier 530 and a low pass filter 540 . the low pass filter output 223 is coupled to the adc 230 ( fig2 ). the preamplifier 510 converts the current signal 112 from the detector 218 ( fig2 ) to a corresponding amplified voltage signal . the gain in the preamplifier 510 is selected in order to prevent ambient light in the signal 112 from saturating the preamplifier 510 under normal operating conditions . the preamplifier output 512 is coupled to the high pass filter 520 , which removes the dc component of the detector signal 112 . the corner frequency of the high pass filter 520 is set well below the multiplexing frequency of the red and infrared emitters 212 , 214 ( fig2 ). the high pass filter output 522 couples to the programmable gain amplifier 530 , which also accepts a programming input 225 from the dsp 150 ( fig2 ). this gain is set at initialization or at sensor placement to compensate for variations from patient to patient . the programmable gain amplifier output 532 couples to a low - pass filter 540 to provide anti - aliasing prior to digitization . as described above , pulse oximetry measurements rely on the existence of a pulsatile signal . the natural heart beat provides a pulsatile signal that allows measurement of arterial oxygen saturation . in the systemic circulation , all arterial pulsations are damped before flow enters the capillaries , and none are transmitted into the veins . thus , there is no arterial pulse component in the venous blood and absorption caused by venous blood is assumed canceled by the ratio - of - ratio operation described above . venous blood , being at a relatively low pressure , will “ slosh back and forth ” during routine patient motions , such as shivering , waving and tapping . this venous blood sloshing creates a time - varying signal that is considered “ noise ” and can easily overwhelm conventional ratio - based pulse oximeters . advanced pulse oximetry techniques allow measurement of sp v o 2 under these circumstances . for example , such advanced techniques are disclosed in u . s . pat . no . 5 , 632 , 272 , which is assigned to the assignee of the current application . this measurement is only available during motion or other physiological events causing a time - varying venous signal . the venous blood may also have a pulsatile component at the respiration rate , which can be naturally induced or ventilator induced . in adults , the natural respiration rate is 10 - 15 beats per minute ( bpm ). in neonates , this natural respiration rate is 30 - 60 bpm . the ventilator induced pulse rate depends on the ventilator frequency . if this respiration induced venous pulse is of sufficient magnitude , advanced pulse oximetry techniques , described below , allow measurement of sp v o 2 . a controlled physiological event , however , can be created that allows for a continuous measurement of venous oxygen saturation , independent of motion or respiration . u . s . pat . no . 5 , 638 , 816 , which is assigned to the assignee of the current application discloses a technique for inducing an intentional active perturbation of the blood volume of a patient , and is referred to as an “ active pulse .” because peripheral venous oxygen saturation , sp v o 2 , is a desirable parameter for stereo pulse oximetry applications , it is advantageous to provide for a continuous and controlled pulsatile venous signal . fig2 depicts an active pulse mechanism used in conjunction with a pulse oximetry sensor . an active pulser 260 physically squeezes or otherwise perturbs a portion of patient tissue 270 in order to periodically induce a “ pulse ” in the blood at the tissue site 202 . a pulser drive 280 generates a periodic electrical signal to a transducer 262 attached to the patient . the transducer 262 creates a mechanical force against the patient tissue 270 . for example , the pulser 260 could be a solenoid type device with a plunger that presses against the fleshy tissue to which it is attached . the dsp 150 provides pulse drive control information to a digital to analog converter ( dac ) 290 via the control input 291 . the dac output 292 is coupled to the pulser drive 280 . this allows the processor to advantageously control the magnitude of the induced pulse , which moderates scattering as described below . the pulser 260 could be a pressure device as described above . other pressure mechanisms , for example a pressure cuff , could be similarly utilized . other methods , such as temperature fluctuations or other physiological changes , which physiologically alter a fleshy medium of the body on a periodic basis to modulate blood volume at a nearby tissue site could also be used . regardless of the active pulse mechanism , this modulated blood volume is radiated by a pulse oximeter sensor and the resulting signal is processed by the signal processing apparatus described below to yield sp v o 2 . fig6 illustrates the processing functions of the digital signal processor ( dsp ) 150 ( fig1 a ). each data channel input 152 , 154 , 158 ( fig1 a ) is operated on by one or more of the front - end processor 610 , saturation calculator 620 , plethysmograph feature extractor 630 and multiple parameter processor 640 functions of the dsp 150 . first , a digitized signal output from the adc 230 ( fig2 ) is input 602 to the front - end processor 610 , which demultiplexes , filters , normalizes and frequency transforms the signal , as described further below . a front - end output 612 provides a red signal spectrum and an ir signal spectrum for each data channel as inputs to the saturation calculator 620 . another front - end output 614 provides a demultiplexed , normalized ir plethysmograph for each data channel as an input to the feature extractor 630 . the saturation calculator output 622 provides arterial and venous saturation data for each data channel as input to the multiple parameter processor 640 . one feature extractor output 632 provides data on various plethysmograph shape parameters for each data channel as input into the multiple parameter processor 640 . another feature extractor output 634 , also coupled to multiple parameter processor 640 , provides an indication of plethysmograph quality and acts as a threshold for determining whether to ignore portions of the input signal 602 . the multiple parameter processor has a numerical output 642 that provides same - channel δsat parameters and cross - channel parameters , such as δsat xy or δpleth xy to a display 180 ( fig1 a ). the numeric output 642 may also provide saturation and plethysmograph parameters directly from the saturation calculator 620 or the feature extractor 630 without further processing other than data buffering . the multiple parameter processor also has a graphical output 644 that provides plethysmograph waveforms for each data channel in addition to graphics , depending on a particular application , the indicate the trend of the numerical parameters described above . fig7 is a functional block diagram of the front - end processor 610 for the stereo pulse oximeter . the digitized sensor output 118 ( fig2 ) is an input signal 602 to a demultiplexer 710 , which separates the input signal 602 into a red signal 712 and an infrared signal 714 . the separated red and infrared signals 712 , 714 are each input to a filter 720 to remove unwanted artifacts introduced by the demultiplexing operation . in one embodiment , the filter 720 is a finite - impulse - response , low - pass filter that also “ decimates ” or reduces the sample rate of the red and infrared signals 712 , 714 . the filtered signals 722 are then each normalized by a series combination of a log function 730 and bandpass filter 740 . the normalized signals , rd ( t ), ir ( t ) 742 are coupled to a fourier transform 750 , which provides red frequency spectrum and infrared frequency spectrum outputs , rd ( ω ), ir ( ω ) 612 . a demultiplexed infrared signal output 614 is also provided . fig8 shows a graph 800 illustrating idealized spectrums of rd ( t ) and ir ( t ) 752 ( fig7 ). the graph has an x - axis 810 that corresponds to the frequency of spectral components in these signals and a y - axis 820 that corresponds to the magnitude of the spectral components . the spectral components are the frequency content of rd ( t ) and ir ( t ), which are plethysmograph signals corresponding to the patient &# 39 ; s pulsatile blood flow , as described below . thus , the frequencies shown along the x - axis 810 , i . e . f 0 , f 1 , f 2 , are the fundamental and harmonics of the patient &# 39 ; s pulse rate . the spectrum of rd ( t ), denoted rd ( ω ) 612 ( fig7 ), is shown as a series of peaks , comprising a first peak 832 at a fundamental frequency , f 0 , a second peak 842 at a first harmonic , f 1 and a third peak 852 at a second harmonic , f 2 . similarly , the spectrum of ir ( t ), denoted ir ( ω ) 612 ( fig7 ), is shown as another series of peaks , comprising a first peak 834 at a fundamental frequency , f 0 , a second peak 844 at a first harmonic , f 1 and a third peak 854 at a second harmonic , f 2 . also shown in fig8 is the ratio of the spectral peaks of rd ( t ) and ir ( t ), denoted rd ( ω )/ ir ( ω ). this ratio is shown as a first ratio line 838 at the fundamental frequency f 0 , a second ratio line 848 at the first harmonic f 1 , and a third ratio line 858 at the second harmonic f 2 . the magnitude of these ratio lines rd ( ω )/ ir ( ω ) corresponds to the ratio rd / ir defined by equation ( 2 ), and , hence , can be used to determine sp a o 2 . this can be seen from parseval &# 39 ; s relation for a periodic signal , x ( t ), having a period t , where x k is the spectral component at the kth harmonic of x ( t ): equation ( 9 ) relates the energy in one period of the signal x ( t ) to the sum of the squared magnitudes of the spectral components . the term | x k | 2 can be interpreted as that part of the energy per period contributed by the kth harmonic . in an ideal measurement , the red and infrared signals are the same to within a constant scale factor , which corresponds to the arterial oxygen saturation . likewise , the red and infrared spectra are also the same to within a constant scale factor . thus , in an ideal measurement , all of the ratio lines 838 , 848 , 858 have substantially the same amplitude . any differences in the amplitude of the ratio lines is likely due to motion , scattering or other noise contaminations , as discussed further below . accordingly , any of the rd ( ω )/ ir ( ω ) ratio lines is equivalent to the ratio , rd / ir , of equation ( 2 ) and can be used to derive sp a o 2 . one skilled in the art will recognize that the representations in fig8 are idealized . in particular , in actual measured data , especially if contaminated by noise , the frequencies of the peaks of rd ( ω ) do not correspond exactly to the frequencies of the peaks of ir ( ω ). for example , the fundamental frequency , f 0 , found for rd ( ω ) will often be different from the fundamental frequency , f 0 ′, found for ir ( ω ) and similarly for the harmonics of f 0 . fig9 shows a graph 900 illustrating idealized spectrums rd ( ω ) and ir ( ω ) and associated ratio lines measured with an active pulse sensor . the graph 900 has an x - axis 910 that corresponds to the frequency of spectral components in these signals and a y - axis 920 that corresponds to the magnitude of the spectral components . the spectrum , rd ( ω ), is shown as two series of peaks . one series of peaks 930 occurs at a fundamental frequency , f h0 , and associated harmonics , f h1 and f h2 , of the patient &# 39 ; s pulse ( heart ) rate . another series of peaks 940 occurs at a fundamental frequency , f p0 , and associated harmonics , f p1 and f p2 , of the active pulse rate . similarly , the spectrum , ir ( ω ), is shown as two series of peaks . one series of peaks 950 occurs at a fundamental frequency , f h0 , and associated harmonics , f h1 and f h2 , of the patient &# 39 ; s pulse rate . another series of peaks 960 occurs at a fundamental frequency , f p0 , and associated harmonics , f p1 and f p2 , of the active pulse rate . accordingly , there are two series of rd / ir ratio lines . one series of ratio lines 970 are at the patient &# 39 ; s pulse rate and associated harmonics , and another series of ratio lines 980 are at the active pulser rate and associated harmonics . because only the arterial blood is pulsatile at the patient &# 39 ; s pulse rate , the ratio lines 970 are only a function of the arterial oxygen saturation . accordingly , sp a o 2 can be derived from the magnitude of these ratio lines 970 , as described above . further , a modulation level for the active pulse is selected which insignificantly perturbates the arterial blood while providing a measurable venous signal . this is possible because the arterial blood pressure is significantly larger than the venous pressure . the modulation level is regulated as described above with respect to fig2 , i . e . the dsp 150 , via a pulser drive control 291 , sets the magnitude of the pulser drive 280 to the pulse inducing mechanism 262 . assuming that the active pulse modulation of the arterial blood is insignificant , only the venous blood is pulsatile at the active pulser rate . hence , the ratio lines 980 are only a function of the venous oxygen saturation . accordingly , sp a o 2 can be derived from the magnitude of the pulse rate related ratio lines 980 in the same manner as sp a o 2 is derived from the magnitude of the pulse rate related ratio lines . propagation of optical radiation through tissue is affected by absorption and scattering processes . the operation of pulse oximeters was described qualitatively above using an analysis based on the beer - lambert law of absorption , equation ( 3 ). this approach , however , fails to account for the secondary effects of light scattering at pulse oximeter wavelengths . the primary light scatterer in blood is erythrocytes , i . e . red blood cells . a qualitative understanding of the effects of scattering on pulse oximetry is aided by a description of red blood cell properties within flowing blood . human blood is a suspension of cells in an aqueous solution . the cellular contents are essentially all red blood cells , with white cells making up less the 1 / 600 th of the total cellular volume and platelets less than 1 / 800 th of the total cellular volume . normally the hematocrit , which is the percentage of the total volume of blood occupied by cells , is about 50 % in large vessels and 25 % in small arterioles or venules . red blood cells are extremely deformable , taking on various shapes in response to the hydrodynamic stresses created by flowing blood . for example , assuming a laminar blood flow within a vessel , a parabolic velocity profile exists that is greatest in the vessel center and smallest along the vessel walls . nominally , red blood cells are shaped as biconcave disks with a diameter of 7 . 6 um and thickness of 2 . 8 um . exposed to this velocity profile , the red blood cells become parachute - shaped and aligned in the direction of the blood flow . thus , during systole , transmitted light is scattered by aligned , parachute - shaped cells . during diastole , the light is scattered by biconcave disks having a more or less random alignment . the time - varying shape and alignment of the red blood cells can have a significant effect on measured values of oxygen saturation if scattering is ignored . analogous to the analysis using the beer - lambert absorption law , scattering can be qualitatively understood as a function of the scattering coefficients of various tissues . specifically , the bulk scattering coefficient can be written as : where v b is the blood volume , − μ b is the scattering coefficient of blood , v t is the surrounding tissue volume and − μ t is the scattering coefficient of the surrounding tissue . the volume , v t , and scattering coefficient , − μ t , of the surrounding tissue are time invariant . the blood volume , v b , however , is pulsatile . the ratio of ratios computation , rd / ir , results in normalization of the time invariant or dc tissue absorption and cancellation of the time varying or ac pulsatile blood volume absorption to yield a number related to oxygen saturation . this computational approach is valid because the absorption coefficients of blood , ε hbo2 , λ , ε hb , λ given in equation ( 4 ) were assumed to change only slowly over time . the scattering coefficient of blood − μ b , however , is time variant . as described above , this variation is due to the time - varying alignment and shape of the red blood cells . this time variation in the detected intensity of light transmitted through a tissue site is not normalized or canceled by the rd / ir calculation . further , because the magnitude of the scattering coefficient variations is a function of blood flow , these variations become more pronounced with larger pulses in the blood supply . as a result , scattering produces frequency - dependent magnitude variations in the ratio lines rd ( ω )/ ir ( ω ). fig9 illustrates the effect of scattering on the spectra of the detected red and infrared intensity waveforms . when these waveforms are transformed into the frequency domain , the time varying component of scattering manifests itself as spreads 978 , 988 in the rd / ir ratio lines at each harmonic of the plethysmograph or active pulse rate . the magnitude of the ratio lines 970 at the fundamental and harmonics of the patient &# 39 ; s pulse rate varies between a minimum 972 and a maximum 974 , resulting in a magnitude spread 978 . similarly , the magnitude of the ratio lines 980 at the fundamental and harmonics of the active pulse rate varies between a minimum 982 and a maximum 984 , resulting in a magnitude spread 988 . normally , absent motion artifact or noise contamination , the spread 978 , 988 in the ratio lines is quiet small , but the magnitude of these spreads 978 , 988 , increases with larger blood flows or pulse magnitudes . scattering attributable to an active pulse can be regulated by adjusting the magnitude of the active pulse modulation based upon the amount of spread 978 , 988 of the ratio line magnitudes . thus , the active pulse magnitude can be increased to obtain a larger detected ac signal , but limited to below the point at which scattering becomes significant . fig1 depicts an embodiment of the signal processing for determining oxygen saturation from the ratio lines of rd ( ω )/ rd ( ω ). the red spectrum rd ( ω ) 612 and infrared spectrum ir ( ω ) 612 , computed as described above with respect to fig7 , are input to a peak detector 1010 . the peak detector 1010 separately calculates localized maximums for rd ( ω ) and ir ( ω ). the peak detector output 1012 is a series of frequencies corresponding to the patient pulse rate fundamental and harmonics . if an active pulse is used , the peak detector output 1012 is also a series of frequencies corresponding to the active pulse rate . although the active pulse rate is known , the detected peaks may have been shifted due to noise , motion artifact or other signal contamination . the peak detector output 1012 is coupled to a series combination of peak matcher 1020 and ratio line calculator 1030 . the ratio lines rd / ir are calculated by matching the frequency peaks of rd ( ω ) with the nearest frequency peaks of ir ( ω ). the ratio lines associated with the pulse rate harmonics 1032 are then separated into a different set from the ratio lines associated with the active pulse harmonics 1034 , assuming an active pulse is utilized . an average ratio line for each set 1032 , 1034 is calculated by averaging 1060 all ratio lines in a set . the magnitude of the average ratio line r 1062 for the pulse rate set 1032 is then fed to a look - up table ( lut ) 1090 , which provides an output 622 of the measured value of sp a o 2 . similarly , if an active pulse is used , the magnitude of the average ratio line μ 1064 for the active pulse rate set 1034 is then fed to a lut 1090 , which provides an output 622 of the measured value of sp v o 2 . a scattering detector 1080 computes the spread 988 ( fig9 ) in the set of ratio lines associated with the active pulse and provides this value 1082 to the dsp 150 ( fig2 ) so that the dsp can set the pulser drive control 291 ( fig2 ) to regulate the magnitude of the active pulse . alternatively , sp v o 2 may be measured from respiration - induced pulses in the venous blood , described above , without utilizing an active pulse sensor . specifically , a series of ratio lines 980 ( fig9 ) would occur at a fundamental frequency , f r0 , and associated harmonics , f r1 and f r2 , of the respiration rate , which is either known from the ventilator frequency or derived from a separate measurement of the natural respiration . as shown in fig1 , the ratio lines associated with the respiration rate harmonics 1034 are then separated into a different set from the ratio lines associated with the pulse rate harmonics 1032 . an average ratio line for the respiration rate set 1034 is calculated by averaging 1060 all ratio lines in that set . the magnitude of the average ratio line μ 1064 for the respiration rate set 1034 is then fed to a look - up table ( lut ) 1090 , which provides an output 622 of the measured value of sp v o 2 . fig1 illustrates the standard plethysmograph waveform 1100 , which can be derived from a pulse oximeter . the waveform 1100 is a visualization of blood volume change in the illuminated peripheral tissue caused by arterial blood flow , shown along the y - axis 1110 , over time , shown along the x - axis 1120 . the shape of the plethysmograph waveform 1100 is a function of heart stroke volume , pressure gradient , arterial elasticity and peripheral resistance . the ideal waveform 1100 displays a broad peripheral flow curve , with a short , steep inflow phase 1130 followed by a 3 to 4 times longer outflow phase 1140 . the inflow phase 1130 is the result of tissue distention by the rapid blood volume inflow during ventricular systole . during the outflow phase 1140 , blood flow continues into the vascular bed during diastole . the end diastolic baseline 1150 indicates the minimum basal tissue perfusion . during the outflow phase 1140 is a dicrotic notch 1160 , the nature of which is disputed . classically , the dicrotic notch 1160 is attributed to closure of the aortic valve at the end of ventricular systole . however , it may also be the result of reflection from the periphery of an initial , fast propagating , pressure pulse that occurs upon the opening of the aortic valve and that precedes the arterial flow wave . a double dicrotic notch can sometimes be observed , although its explanation is obscure , possibly the result of reflections reaching the sensor at different times . fig1 is a graph 1200 illustrating the absorption of light at a tissue site illuminated by a pulse oximetry sensor . the graph 1200 has a y - axis 1210 representing the total amount of light absorbed the tissue site , with time shown along an x - axis 1220 . the total absorption is represented by layers including the static absorption layers due to tissue 1230 , venous blood 1240 and a baseline of arterial blood 1250 . also shown is a variable absorption layer due to the pulse - added volume of arterial blood 1260 . the profile 1270 of the pulse - added arterial blood 1260 is seen as the plethysmograph waveform 1100 depicted in fig1 . fig1 illustrates the photoplethysmograph intensity signal 1300 detected by a pulse oximeter sensor . a pulse oximeter does not directly detect absorption , and hence does not directly measure the standard plethysmograph waveform 1100 ( fig1 ). however , the standard plethysmograph can be derived by observing that the detected intensity signal 1300 is merely an out of phase version of the absorption profile 1270 . that is , the peak detected intensity 1372 occurs at minimum absorption 1272 ( fig1 ), and minimum detected intensity 1374 occurs at maximum absorption 1274 ( fig1 ). further , a rapid rise in absorption 1276 ( fig1 ) during the inflow phase of the plethysmograph is reflected in a rapid decline 1376 in intensity , and the gradual decline 1278 ( fig1 ) in absorption during the outflow phase of the plethysmograph is reflected in a gradual increase 1378 in detected intensity . fig1 illustrates the digital signal processing for plethysmograph feature extraction 630 ( fig6 ). the input 614 is the ir signal output from the demultiplexer 710 ( fig7 ). this signal is shifted into a first - in , first - out ( fifo ) buffer , which allows fixed - length portions of the input signal 614 to be processed for feature extraction . the buffered output signal 1412 is coupled to a shape detector 1420 , slope calculator 1430 , feature width calculator 1440 and a notch locator 1450 , which perform the core feature extraction functions . the shape detector 1420 determines if a particular buffered signal portion 1412 contains specific gross features , such as a peak , a valley , an upward slope , a downward slope , a dicrotic notch or a multiple dicrotic notch . a detected shape output 1422 containing one or more flags indicating the gross feature content of the current signal portion 1412 is coupled to the other feature extraction functions 1430 , 1440 , 1450 and to the waveform quality determination functions 1460 , 1470 , 1480 . a slope calculator 1430 determines the amount of positive or negative slope in the signal portion 1412 if the shape detector output 1422 indicates a slope is present . the output slope value 1432 is coupled to the waveform quality functions 1460 , 1470 , 1480 in addition to the feature extraction output 632 . a feature calculator 1440 quantifies a feature in one or more signal portions 1412 specified by the shape detector 1420 , such as the magnitude , the area under , or the width of a peak or notch . the feature calculator output 1442 is a code indicating the feature and its value , which is coupled to the feature extraction output 632 . a feature locator 1450 quantifies the time of occurrence of one or more features of a signal portion 1412 as specified by the shape detector 1420 . the feature locator output 1452 , which is coupled to the feature extraction output 632 , is a code indicating a feature and an associated code indicating time of occurrence in reference to a particular epoch . the feature locator output 1452 allows a determination of the relative location of plethysmograph features in addition to a phase comparison of plethysmographs derived from two or more tissue sites . another feature extraction output 634 , which is coupled to the multiple parameter processor 640 ( fig6 ), provides an indication of waveform quality . input signals portions 1412 not having either a sharp downward edge 1460 , a symmetrical peak 1470 or a gradual decline 1480 are not processed further . fig1 illustrates the multiple parameter processing portion 640 ( fig6 ) of the signal processing . a differencing function 1510 has as inputs a first saturation value , sp 1 o 2 , and a second saturation value , sp 2 o 2 , 622 . the saturation input values 622 can be arterial and venous saturation values from a single data channel , arterial saturation values from two different data channels or venous saturation values from two different data channels . the differences of the saturation value inputs 622 are provided as an output 1514 , which is coupled to a saturation data memory 1520 . the saturation values 622 are also directly coupled to the saturation data memory 1520 . the memory 1520 stores a record of saturation values , spo 2 , for each channel , delta saturation values , δsat , for each channel and cross - channel delta saturation values , δsat xy , as required for a particular application . a flow calculator 1530 utilizes a plethysmograph input 614 or a bio - impedance probe input 1534 to provide a flow value 1538 , which is also coupled to the saturation data memory 1520 . for example , the flow value 1538 may be a perfusion index , pi , defined as follows : where ir max is the maximum value , ir min is the minimum value , and ir dc is the average value of the ir plethysmograph signal 614 ( fig7 ). the saturation data memory 1520 provides a buffered output 1522 that is coupled to a numerical display driver 1540 . the numerical display driver 1540 provides an output 642 to a standard display , such as led or lcd numerical display modules or a crt monitor . the memory output 1522 is also coupled to a saturation data analyzer 1530 , one function of which calculates a long - term trend of the values in memory 1520 . for example , the saturation data analyzer may average a saturation value over time , or provide samples of the saturation values taken at regular time intervals . the output 1532 can either be numerical , which is coupled to the numerical display driver 1540 , or graphical , which is coupled to the graphical display driver 1570 . the graphical display driver 1570 provides an output 644 to a standard graphical display device , such as led or lcd graphical display modules or a crt monitor . a pleth data memory 1550 has as inputs the ir plethysmograph signals 614 ( fig7 ) from each data channel and the associated extracted features 632 ( fig1 ). the memory 1550 also has an input indicating waveform quality 634 ( fig1 ). the pleth memory 1550 provides a buffered output 1558 that is coupled to the graphical display driver 1570 , allowing display of the plethysmograph waveforms for each data channel . the memory output 1558 is also coupled to a pleth data analyzer 1560 , one function of which calculates a long - term trend of the plethysmograph and shape parameters in pleth memory 1520 . for example , the pleth data analyzer 1560 may provide an average of particular shape parameters over time . as another example , the pleth data analyzer 1560 may provide a graphic showing an accumulation of many overlaid plethysmographs . the output 1562 can either be numerical , which is coupled to the numerical display driver 1540 , or graphical , which is coupled to the graphical display driver 1570 . another function of the saturation data analyzer 1530 and the pleth data analyzer 1560 is to compare oxygen status and plethysmograph parameters derived from multiple sites in order to isolate noise artifacts and to derive a more accurate estimate of these parameters . for example , it is unlikely that motion artifact will affect each peripheral site in the same manner . if the quality input 634 indicates a noisy plethysmograph for one channel during a particular time period , the pleth data analyzer 1560 can exchange this information 1565 with the saturation data analyzer 1530 . the saturation data analyzer 1530 can then ignore the saturation data for that channel for that time period in lieu of saturation data from another channel . in a similar fashion , noisy data from multiple channels can be averaged , correlated or otherwise processed to provide an estimate of sp a o 2 , sp v o 2 or pulse rate , or to provide a plethysmograph that is more accurate than can be derived from a single data channel . fig1 a illustrates detail of a single - site display screen 180 for the stereo pulse oximeter . the display has a numerical display portion 1610 controlled by the numerical display driver 1540 ( fig1 ) and a graphical display portion 1660 controlled by the graphical display driver 1570 ( fig1 ). the numerical display portion 1610 displays a value for sp a o 2 1620 , sp v o 2 1630 and pulse rate 1640 for a particular tissue site . the graphical display portion 1660 displays a plethysmograph 1662 for the corresponding tissue site , which can be displayed as a single waveform or an accumulated multiple of overlayed waveforms that may reveal a waveform trend . a push button or menu selection allows the user to switch to a display of data from any single one of the multiple tissue sites to which a sensor is attached . fig1 b illustrates detail of a multi - site display screen 180 for the stereo pulse oximeter . the numerical display portion 1610 displays a value for sp a o 2 1622 and sp v o 2 1632 for a first tissue site . also displayed is a value for sp a o 2 1624 and sp v o 2 1634 for a second tissue site . in addition , a value for pulse rate 1642 derived from either the first or second tissue site , or both , is displayed . the graphical display portion 1660 displays a first plethysmograph 1664 and a second plethysmograph 1666 corresponding to the first and second tissue sites , respectively . a push button , menu selection allows the user to manually switch between the single site display ( fig1 a ) and the multi - site display ( fig1 b ). also , a triggering event , such as an alarm based on multiple - site oxygen status parameters , causes the display to automatically switch from the single - site display to the multi - site display , enabling the user better view the conditions that caused the triggering event . one of ordinary skill will appreciate many display screens variations from those shown in fig1 a and 16b that are within the scope of this invention . for example , the stereo pulse oximeter could be configured to provide several push button or menu selectable display screens . one display screen might display more than two channels of oxygen status data . another display screen could display cross - channel parameters such as δsat xy or a comparison of plethysmograph shape parameters from two channels . one of ordinary skill will also appreciate many variations and modifications of layout and design for the graphical and numerical displays within the scope of this invention . oxygen is one of the most commonly used drugs in an intensive care unit and is an integral part of all respiratory support . the goal of oxygen therapy is to achieve adequate delivery of oxygen to the tissues without creating oxygen toxicity . too little oxygen results in organ damage and , in particular , brain damage . too much oxygen can result in , for example , pulmonary edema and , in neonates , retinopathy of prematurity ( rop ). infants receiving oxygen therapy , in particular , must have inspired oxygen concentration and blood oxygen levels monitored closely . oxygen titration in neonates is currently accomplished with either transcutaneous monitoring or monitoring with a conventional pulse oximeter . as mentioned above , transcutaneous monitoring involves the placement of a heated clark electrode against the skin surface . the electrode is secured to the skin surface with an airtight seal to eliminate contamination by room air gases . the skin surface beneath the electrode is then heated , which opens pre - capillary sphincters allowing localized arteriolar blood flow beneath the sensor . the so - called t c o 2 value that is measured correlates well with p a o 2 . however , there are several drawbacks to this approach . because the skin surface must be heated , a fifteen minute elapsed time after application is necessary before stable readings are acquired . further , the required temperature is 43 - 45 ° c . ( 110 ° f . ), with an associated risk of burns . in addition , titration is often accomplished by simply maintaining t c o 2 within acceptable limits for this parameter , e . g . an equivalent p a o 2 of 50 - 80 mm hg for neonates . however , p a o 2 alone does not provide an indication of balance between inspired oxygen and the rate of tissue oxygen consumption . if the patient is particularly anemic or hypovolemic , has an abnormal hemoglobin , or a small cardiac output , then oxygen delivery may be inadequate even in the presence of a normal p a o 2 . titration with a conventional pulse oximeter is similarly accomplished by maintaining sp a o 2 within acceptable limits , which also fails to consider tissue oxygen consumption . oxygen titration can be more adequately monitored with a continuous indication of oxygen consumption , which is equal to oxygen delivery according to fick &# 39 ; s algorithm , as noted above . further , continuous monitoring of oxygen consumption at a peripheral tissue site , although not necessarily indicative of overall oxygen consumption , may be indicative of an oxygen supply dependency . a measure of peripheral oxygen consumption can be expressed in terms of δsat = sp a o 2 − sp v o 2 and perfusion , which , as noted above , are parameters advantageously provided by the stereo pulse oximeter according to the present invention . oxygen consumption at a peripheral site is obtained by multiplying the difference between peripheral arterial and venous oxygen content by perfusion at the site . where oxygen content is measured in milliliters ( ml ) of o 2 per deciliters ( dl ) of blood and φ denotes perfusion in deciliters per minute . oxygen content , however , can be expressed in terms of the amount of oxygen bound to the hemoglobin plus the amount of oxygen dissolved in the plasma . the amount of bound oxygen is equal to the hemoglobin concentration , c hb , in grams per deciliter of blood , times the hemoglobin carrying capacity , which is 1 . 34 milliliters of o 2 per gram of hemoglobin times the hemoglobin oxygen saturation , so 2 . the amount of dissolved oxygen is simply the partial pressure of oxygen , po 2 , times the o 2 solubility coefficient in blood , which is 0 . 003 milliliters of o 2 per deciliter . the sum of these two terms yields : substituting equation ( 13 ) into equation ( 12 ) yields the following equation for tissue oxygen consumption : vpo 2 =[ 1 . 34c hb ( sp a o 2 − sp v o 2 )+ 0 . 003 ( p a o 2 − p v o 2 )] φ ( 14 ) except when the fractional inspired oxygen , fio 2 , is high , blood plasma plays a minimal role in oxygen delivery . thus , peripheral oxygen consumption is approximately : in order to illustrate a schema of oxygen titration , it is convenient to characterize the relationship between oxygen supplied at the airway to oxygen consumed at a peripheral tissue site . specifically , characterization of the relationship between δsat , φ and fio 2 is useful . assuming constant oxygen consumption at the tissue site , equation ( 15 ) is : equation ( 16 ) has a simple analog in electronic circuits , i . e . a variable resistor across a current or voltage source adjusted to maintain constant power . in this analog circuit , the current through the resistor , i , is equivalent to perfusion , the voltage across the resistor , v , is equivalent to δsat and the constant of equation ( 16 ) is equivalent to the constant power , p , consumed by the resistor . the equation representing this electrical analog is : fig1 a shows a graph 1701 that depicts a family of curves each corresponding to different values of p in equation ( 17 ). the graph 1701 has an x - axis 1710 indicating current , i , and a y - axis 1720 indicating voltage , v . a first curve 1730 shows v versus i for a constant power , p , of 0 . 5 watts ; a second curve 1740 shows v versus i for a constant p of 1 watt ; and a third curve 1750 shows v versus i for a constant p of 2 watts . using the analogy between equations ( 16 ) and equation ( 17 ), whenever φ ( current ) is small , the δsat ( voltage ) is large and vice - a - versa . also , a change in consumption ( power ) causes a shift in the curve along with a change in its curvature . that is , if the body suddenly changes its metabolic rate at the peripheral tissue site , the curve will accordingly shift up or shift down and will change its shape . equation ( 16 ) and the analogous constant consumption curves of fig1 a assume a supply independent condition , i . e . that peripheral oxygen consumption is satisfied by peripheral oxygen delivery . if the peripheral tissue site is starved for oxygen , then the locus of points for δsat versus φ is quite different from a hyperbola the amount of tissue oxygen extraction is at a maximum and is independent of φ . accordingly δsat is at a maximum and independent of φ . the above analysis provides insight into the relationship between δsat and φ . the relationship between δsat and fio 2 can also be characterized . fig1 b shows a graph 1702 of saturation along a y - axis 1760 and fractional inspired oxygen along an x - axis 1770 . a curve of sp a o 2 1780 and a curve of sp a o 2 1790 are depicted versus fio 2 . the difference between these curves 1780 , 1790 yields δsat 1785 versus fio 2 . when fio 2 is zero 1772 , oxygen saturation and , hence , both sp a o 2 1780 and sp v o 2 1790 are zero . as fio 2 is increased , sp a o 2 1780 also increases until virtually reaching 100 percent saturation 1762 . as fio 2 increases further , sp a o 2 1780 stays at virtually 100 percent saturation 1762 . as fio 2 is increased from zero 1772 , sp v o 2 1790 also increases . in this low fio 2 region 1774 , the peripheral tissue site is supply dependent and δsat 1785 also increases . at a certain point , the tissue site oxygen demand is met by supply . in this supply independent region 1776 , oxygen consumption is constant and equation ( 16 ) is valid . also , δsat 1785 is at a constant maximum , which is a function of the metabolism at the tissue site . as fio 2 increases further , eventually the partial pressure of oxygen becomes significant and the second term of equation ( 14 ) must be considered . in this high fio 2 region 1778 , δsat 1785 decreases because some of the tissue oxygen consumption is supplied by oxygen dissolved in the plasma . fig1 c shows a graph 1704 of saturation difference along a y - axis 1764 and fractional inspired oxygen along an x - axis 1770 . a curve of δsat 1786 is depicted versus fio 2 , corresponding to the region δsat 1785 depicted in fig1 b . the curve 1786 has a first deflection point 1766 occurring at the transition between the low fio 2 region 1774 ( fig1 b ) and the supply independent region 1776 ( fig1 b ). the curve 1786 also has a second deflection point 1768 occurring at the transition between the supply independent region 1776 ( fig1 b ) and the high fio 2 region 1778 ( fig1 b ). the curve 1786 illustrates how the trend for δsat , as measured by the stereo pulse oximeter , can be used to accurately titrate oxygen . the goal of oxygen titration is to supply sufficient oxygen to supply tissue demand and avoid unnecessarily high amounts of fio 2 . thus , the δsat parameter should be monitored so that fio 2 is adjusted between the two deflection points 1766 , 1768 . for neonates , fio 2 should be adjusted just beyond the first deflection point 1766 . for adults , fio 2 should be adjusted just before the second deflection point 1768 . fig1 illustrates a graph having a three - dimensional surface 1800 generally depicting the relationship between δsat , φ and fio 2 from the combined graphs of fig1 a and 17c . the graph has an x - axis 1810 showing fio 2 , a y - axis 1820 showing φ and a z - axis 1830 showing δsat . the surface 1800 has a supply dependent region 1840 , a perfusion - limited region 1850 , a constant consumption region 1860 and a plasma dependent region 1870 . the surface describes the oxygen status of a peripheral tissue site . the supply dependent region 1840 corresponds to the low fio 2 region 1774 ( fig1 b ) described above . that is , inspired oxygen into the lungs is so low that , at the tissue site , oxygen extraction by the tissues is limited by oxygen delivery , and δsat falls rapidly as fio 2 is reduced . the perfusion - limited region 1850 along the x - axis 1810 represents a low perfusion state where equation ( 16 ) is not valid . that is , perfusion at the tissue site is so low that oxygen extraction by the tissues is at a maximum , and , hence , δsat is at a maximum and is independent of fio 2 . a cross - section of the surface taken parallel to the y - axis 1820 yields a hyperbole - shaped constant consumption region 1860 , consistent with the constant metabolic rate curves illustrated above with respect to fig1 a . the plasma dependent region 1870 corresponds to the high fio 2 region 1778 ( fig1 b ) described above . that is , inspired oxygen into the lungs is so high that the tissue site is partially dependent on oxygen dissolved in the plasma the surface 1800 illustrates that perfusion should be monitored simultaneously with δsat to avoid the perfusion - limited region 1850 , where δsat is an unresponsive indicator of fio 2 , and to avoid misinterpreting hyperbolic changes in δsat that result from changes in perfusion . fig1 illustrates the heart / lung circulation of a hypertensive neonate . persistent pulmonary hypertension in neonates ( pphn ) is a neonatal condition with persistent elevation of pulmonary vascular resistance and pulmonary artery pressure . shown is a neonatal heart 1902 and a portion of a neonatal lung 1904 . the pulmonary artery 1910 that normally feeds oxygen depleted “ blue ” blood from the right ventricle 1920 to the lung 1904 is constricted . the back pressure from the constricted artery 1910 results in a right - to - left shunting of this oxygen depleted blood through the ductus arteriosus 1930 , causing it to mix with oxygen rich “ red ” blood flowing through the descending aorta 1940 . pphn treatment options include vasodilators , such as nitric oxide ( no ). inhaled exogenous no causes a dose - dependent decrease in pulmonary artery pressure and pulmonary vascular resistance , as well as a parallel increase in pulmonary blood flow , without affecting systemic arterial pressure . however , the response to no therapy is a function of the cause of the pphn as well as the time elapsed before initiation of therapy . potential toxic effects of no dictate the proper titration of no gas . too little no may not effectively relieve pulmonary hypertension , and too much no may cause cellular injury or toxicity . no therapy is currently monitored using intermittent ultrasound imaging and / or in vitro blood gas measurements . the drawbacks to these techniques are noncontinuous monitoring and disturbances to the neonate that can exacerbate or not reflect the hypertension in the non - disturbed state . the stereo pulse oximeter according to the present invention allows noninvasive , continuous monitoring of a neonate for detection and managed treatment of pphn that does not disturb the patient . a right hand sensor 130 ( fig1 ) provides arterial oxygen saturation and a plethysmograph for blood circulating from the left ventricle 1950 through the innominate artery 1960 , which supplies the right subclavian artery . because the innominate artery 1960 is upstream from the shunt at the ductus arteriosus 1930 , the oxygen saturation value and plethysmograph waveform obtained from the right hand are relatively unaffected by the shunt and serve as a baseline or reference for comparison with readings from other tissue sites . alternatively , a reference sensor can be placed on a facial site , such as an ear , the nose or the lips . these sites provide arterial oxygen saturation and a plethysmograph for blood circulating from the left ventricle 1950 to the innominate artery 1960 , which supplies the right common carotid artery ( not shown ), or to the left common carotid artery 1965 . a foot sensor 120 ( fig1 ) provides oxygen status for blood supplied from the descending aorta 1940 . the shunt 1930 affects both the oxygen saturation and the blood flow in the descending aorta 1940 . as stated above , the shunt 1930 causes oxygen - depleted blood to be mixed with oxygen - rich blood in the descending aorta 1940 . because the descending aorta 1940 supplies blood to the legs , the oxygen saturation readings at the foot will be lowered accordingly . the pphn condition , therefore , is manifested as a higher arterial oxygen saturation at the right hand reference site and a lower saturation at the foot site . the shunt also allows a transitory left to right flow during systole , which distends the main pulmonary artery 1980 as the result of the blood flow pressure at one end from the right ventricle and at the other end from the aortic arch 1990 . a left - to - right flow through the shunt 1930 into the distended artery 1980 alters the flow in the descending aorta 1940 and , as a result , the plethysmograph features measured at the foot . the pphn condition , therefore , also is manifested as a plethysmograph with a narrow peak and possibly a well - defined dicrotic notch at the left hand baseline site and a broadened peak and possibly no notch at the foot site . an optional left hand sensor 110 ( fig1 ) provides oxygen status for blood circulating from the left ventricle through the left subclavian artery 1970 that supplies the left arm . because the left subclavian artery 1970 is nearer the shunt 1930 than the further upstream innominate artery 1960 , it may experience some mixing of deoxygenated blood and an alteration in flow due to the shunt 1930 . the pphn condition , therefore , may also be manifested as a reduced saturation and an altered plethysmograph waveform at the left hand site as compared with the right hand baseline site , although to a lesser degree than with a foot site . thus , the pphn condition can be detected and its treatment monitored from δsat and plethysmograph morphology comparisons between a right hand baseline sensor site and one or more other sites , such as the left hand or foot . fig2 illustrates the fetal heart / lung circulation . shown is a fetal heart 2002 and a portion of a fetal lung 2004 . the lung 2004 is non - functional and fluid - filled . instead , oxygenated blood is supplied to the fetus from gas - exchange in the placenta with the mother &# 39 ; s blood supply . specifically , oxygenated blood flows from the placenta , through the umbilical vein 2006 and into the right atrium 2022 . there , it flows via the foramen 2024 into the left atrium 2052 , where it is pumped into the left ventricle 2050 and then into the aortic trunk 2092 . also , oxygenated blood is pumped from the right atrium 2022 into the right ventricle 2020 and directly into the descending aorta 2040 via the main pulmonary artery 2080 and the ductus arteriosus 2030 . normally , the ductus arteriosus 2030 is only open ( patent ) during fetal life and the first 12 to 24 hours of life in term infants . the purpose of the ductus arteriosus 2030 is to shunt blood pumped by the right ventricle 2020 past the constricted pulmonary circulation 2010 and into the aorta 2040 . fig2 illustrates a neonatal heart 2002 with a patent ductus arteriosus 2030 . the ductus arteriosus frequently fails to close in premature infants , allowing left - to - right shunting , i . e . oxygenated “ red ” blood flows from the aorta 2040 to the now unconstricted pulmonary artery 2010 and recirculates through the lungs 2004 . a persistent patent ductus arteriosus ( pda ) results in pulmonary hyperperfusion and an enlarged right ventricle 2020 , which leads to a variety of abnormal respiratory , cardiac and genitourinary symptoms . current pda diagnosis involves physical examination , chest x - ray , blood gas analysis , echocardiogram , or a combination of the above . for example , large pdas may be associated with a soft , long , low - frequency murmur detectable with a stethoscope . as another example , two - dimensional , color doppler echocardiography may show a retrograde flow from the ductus arteriosus 2030 into the main pulmonary artery 2080 . once a problematic pda is detected , closure can be effected medically with indomethacin or ibuprofen or surgically by ligation . multiple doses of indomethacin are commonplace but can still result in patency , demanding ligation . a drawback to current diagnostic techniques is that clinical symptoms of a pda can vary on an hourly basis , requiring extended and inherently intermittent testing . the stereo pulse oximeter according to the present invention allows for continuous evaluation of pda symptoms using non - invasive techniques . a right hand sensor 130 ( fig1 ) provides arterial oxygen saturation and a plethysmograph for blood circulating from the left ventricle 2050 through the innominate artery 2160 , which supplies the right subclavian artery leading to the right arm . because the innominate artery 2160 is upstream from the shunt at the ductus arteriosus 2030 , the oxygen saturation value and plethysmograph waveform obtained from the right hand are relatively unaffected by the shunt and serve as a baseline for comparison with readings from other tissue sites . a foot sensor 120 ( fig1 ) provides oxygen status for blood supplied from the descending aorta 2040 . unlike a pphn condition , the shunt 2030 does not affect oxygen saturation in the descending aorta 2040 , because the relatively low pressure in the pulmonary artery 2010 does not allow a mixing of deoxygenated blood into the relatively high pressure flow of oxygenated blood in the aorta 2040 . however , like a pphn condition , the shunt 2030 does affect the aortic flow . in particular , the shunt allows a transitory left - to - right flow during systole from the high pressure aorta 2040 to the low pressure pulmonary circulation 2010 . this left - to - right flow through the shunt 1930 alters the flow in the descending aorta 1940 and , as a result , the plethysmograph features measured at the foot . the pda condition , therefore , is manifested as a normal plethysmograph with a characteristically narrow peak and well - defined dicrotic notch at the right - hand baseline site compared with a damped plethysmograph with a broadened peak and reduced or missing notch at the foot site . further , the foot site waveform is phase shifted from the baseline waveform . these plethysmograph differences are accompanied by comparable arterial oxygen saturation values between the right - hand site and the foot site . an optional left hand sensor 110 ( fig1 ) provides oxygen status for blood circulating from the left ventricle through the left subclavian artery 2170 that supplies the left arm . because the left subclavian artery 2170 is nearer the shunt 2030 than the further upstream innominate artery 2160 , it may experience some alteration in flow due to the shunt 2030 . the pda condition , therefore , may also be manifested as an altered plethysmograph waveform at a left hand site as compared with the right hand baseline site , although to a lesser degree than with a foot site . thus , the pda condition can be detected and its treatment monitored from δsat xy ≈ 0 and plethysmograph morphology and phase comparisons between a right hand baseline sensor site and one or more other sites , such as the left hand or foot . one of ordinary skill will recognize that multiple site comparisons using the stereo pulse oximeter of the current invention may also be used to detect other cardiac abnormalities that cause mixing of oxygenated and deoxygenated blood , such as a ventricular hole or a patent foramen . further , abnormal mixing of oxygenated and deoxygenated blood may also be manifested in measurements provided by the stereo oximeters other than δsat xy and . δpleth xy as described above . for example , an inversion in δsat at a particular tissue site , i . e ., sp v o 2 being larger than sp a o 2 at that site , would indicate such an abnormal condition . coarctation of the aorta is a congenital cardiac anomaly in which obstruction or narrowing occurs in the distal aortic arch or proximal descending aorta . it occurs as either an isolated lesion or coexisting with a variety of other congenital cardiac anomalies , such as a pda . if the constriction is preductal , lower - trunk blood flow is supplied predominantly by the right ventricle via the ductus arteriosus , and cyanosis , i . e . poorly oxygenated blood , is present distal to the coarctation . this can be detected by the stereo pulse oximeter from a comparison of sp a o 2 between an upper body and a lower body site . if the constriction is postductal , blood supply to the lower trunk is supplied via the ascending aorta differential plethysmographs between the upper and lower extremities may not exist if the ductus is widely patent . if the ductus closes , however , this condition can be detected by the stereo pulse oximeter as a reduced amplitude and phase delay between the plethysmographs measured at a lower body site with respect to an upper body site . the stereo pulse oximeter has been disclosed in detail in connection with various embodiments of the present invention . these embodiments are disclosed by way of examples only and are not to limit the scope of the present invention , which is defined by the claims that follow . one of ordinary skill in the art will appreciate many variations and modifications within the scope of this invention .

a patient monitor has multiple sensors adapted to attach to tissue sites of a living subject . the sensors generate sensor signals that are responsive to at least two wavelengths of optical radiation after attenuation by pulsatile blood within the tissue sites .

referring to fig1 , and 3 , a laryngoscope 10 of the invention includes a handle 12 and a probe 14 having a proximal end 16 connected to the handle 12 and a distal end 18 projecting laterally therefrom . the probe is designed for its particular use , in this case for entering the throat area and deploying an et tube . in other applications for other body cavities the probe should be appropriately shaped and sized . an information gathering means 19 , including a camera means 20 is mounted on the laryngoscope 10 . the camera means 20 including lens 21 ( fig4 ) located in the vicinity and as close to the distal end 18 of the probe 14 as possible or along the probe 14 , or if necessary on the handle 12 for observing a visual field adjacent the distal end 18 of the probe 14 . a display means 24 is hinged about an axis 25 to be adjustably mounted on the handle 12 to allow adjustment for best viewing when manipulating the laryngoscope 10 . the display is operatively connected to the camera means 20 to receive the signal to display the visual field as observed by the camera means 20 . preferably , the camera means 20 is internally connected to the display means 24 via a digital to analog converter 24 a located within the compartment of the display means 24 . the information gathering means 19 also includes light emitters 27 ( fig4 ) in the vicinity of and as close to the distal end 18 of the probe 14 as possible or along the probe 14 , or if necessary on the handle 12 with the light conveyed to the distal end of the probe 18 via a fiberoptic light bundle , to illuminate the visual field in the area adjacent the distal end 18 of the probe 14 so that camera means 20 produces a usable image . the laryngoscope 10 is equipped with a grasping clamp means 30 ( see fig4 ) on the probe 14 in the vicinity of the distal end 18 for releasably holding an et tube . the clamp means 30 includes lips 31 and a control button 32 for manipulating and controlling the lips 31 . control button 32 , is accessible on the handle 12 . the handle 12 and probe 14 preferably have one or more internal channels or tubes to provide flow communication on demand between the handle 12 and proximal end 16 and the distal end 18 of the probe 14 for multiple purposes including delivery of oxygen containing gas . the channels originate at the handle with an infusion port 34 and suction port 36 which communicate respectively with an infusion port 35 and suction port 37 at the distal end 18 . purposes for the channels include introduction of oxygen 53 ( see fig5 ), medications , or irrigation fluids via infusion port 34 to the area adjacent to the distal end 18 , or for the suctioning of fluids and particles from the area adjacent to the distal end 18 from a vacuum source 52 ( see fig5 ) connected to suction port 36 and controlled by suction control means 54 and valve means 51 ( see fig5 ). other purposes for the channels include the introduction of endoscopic tools into the intake port 34 and channeled to the distal end 18 and out of infusion port 35 ( fig4 ), either to obtain biopsies , or to treat the operating field . the handle 12 also includes a suction control button 38 to provide means for turning on and off the suction and adjusting the strength of the suction along the suction channel via control means 54 utilizing valve means 51 ( see fig5 ). the handle 12 , has a compartment in which the following elements are provided ( see fig5 ): i . battery power supply means 39 for powering camera means 20 , light means 27 , control means 54 , d / a converter 24 a , display means 24 . ii . control means 54 , having both electrical and mechanical functions for controlling suction valve means 51 , light means 27 , distal probe tip 18 , d / a converter 24 a , display means 24 , grasping clamp means 30 . iii . mechanical controls to control the articulation 44 of the distal probe tip 18 and endotracheal tube grasping clamp control 32 to control the grasping clamp means 30 . the probe 14 also includes a controllable pivot point 42 . control of the pivot point 42 is provided by a flexion control wheel 44 with control lock 46 to provide a flexion control means to articulate the probe head 18 up and down to adjust the best visualization for the display means 24 . additional details include describing the optical scope as a lightweight , self contained , hand held scope made of plastics , rubber and electronics , weighing less than a pound , or ½ kilo . the display means 24 can be a small , removable lcd monitor . a removable , rechargeable , nickel - cadmium battery 39 can provide the power for the said laryngoscope 10 . a suitable infusion port 34 is provided by a threaded ( luer locked ) port , which will also accept the threaded nipple of a hypodermic syringe . this can allow , if dictated by the circumstances , the tracheal infusion of drugs in liquid form , such as lidocaine , narcan , atropine and epinephrine . biopsy brushes and other endoscopic tools can also be inserted at this port 34 for obtaining biopsies of the larynx or throat . the infusion port 35 can also infuse irrigation solutions , either to clean the lens 21 of the camera means 20 , or to wash away blood , mucus , gastric fluids or any other substances that the subject may have ingested . by attaching oxygen tubing connected to an oxygen source to the infusion port , 100 % concentration oxygen can be delivered continuously into the patient &# 39 ; s airway during intubation , thereby , reducing oxygen deprivation and hypoxia . the suction port 36 can be a cone shaped metal head that connects to plastic suction tubing from a suction source and thus provides suction to the suction port 37 at the distal end of the probe 18 . with use of the suction valve button 32 secretions , blood , or any other fluids that hinder the view of the camera lens 21 can be transported away from the site . this suction capability has the added benefit of being able to attach the scope surface against the surface of ( or “ suck up to ”) a foreign body for the purpose of extraction . if desired , the suction port 36 will accept standard oxygen tubing being mated to it . this way , the practitioner can use the control valve 39 to give the subject a burst of pure oxygen when needed during intubation , thereby , reducing oxygen deprivation and hypoxia . another variation of this system would be to manufacture the handle with a separate oxygen control valve to allow for a “ burst ” capability . the distal end of the probe 18 is ovoid in cross section . the ovoid probe is approximately 8 inches long , with a 90 - degree curve , and 1 inch wide and ⅜ inch thick in the adult model ( other options would be to create various sizes , adult , pediatric and a “ preemie ” pediatric model ). beneath the ovoid head there are a pair of pliable rubber grasping lips 31 about an inch long , to hold and guide the et tube for advancement into the larynx . there is an internal clamping assembly for the et tube clamping mechanism to force the grasping lips together to hold onto the et tube for placement . et tube deployment would be achieved when the et tube is pushed forward manually , with the practitioner using the et clamp control to open the rubber lips 31 of the et tube clamp assembly 30 , releasing the et tube and forming a channel , guiding the et tube to its proper position . it is not intended that this description be a limitation on this optical scope . this system is adaptable for medical or industrial endoscopic use , endoscopes , bronchoscopes , sigmoidoscopes , colonoscopes , laparoscopes , otoscopes and vaginal speculums . other versions of this device are possible , such as a disposable blade version . however , in a disposable blade version , the electronics and camera chip will be housed in the handle , with a socket to accept the disposable blades that would contain a fiber optic assembly and objective lens . by replacing the laryngoscope blade with an appropriate extension probe such as flexible fiberoptic colon , sigmoid , or bronchoscope tubes , otoscopic probe or a vaginal speculum blade , other uses are possible . with these and other objects in view , which will become apparent to one skilled in the art as the description proceeds , this invention resides in the novel construction , combination , and arrangement of parts substantially as hereinafter described , and more particularly defined by the appended claims , it being understood that changes in the precise embodiments of the herein disclosed invention are meant to be included as come within the scope of the claims . further objects and advantages of the regenerative system will become apparent from consideration of drawings and the ensuing description of the device . to use the laryngoscope 10 , the patient is prepared , placed in a supine position with the practitioner working from the head of the table . an assistant to the intubator oxygenates the subject ( using a bag - mask device delivering 100 % oxygen to the patient ) to help prevent hypoxia . the device 10 is turned on , with the monitor displaying 24 what the camera lens 21 “ sees ”. the scope 10 is then attached to suction and oxygen lines with the flow levels turned on . the insertion probe 14 is passed into the mouth to the back of the throat . oxygen flow is transmitted via the infusion port to the tip of the laryngoscope probe . the gas pressure of the oxygen flow pushes back the soft tissues of the throat and flows over the camera lens to obtain an unobstructed view of the operating field and to prevent secretions form accumulating on the lens . the oxygen will also diffuse into the patient &# 39 ; s respiratory tract , thus alleviating hypoxia . the infusion port accepts standard oxygen tubing and is also luer locked , that is , configured to accept medical syringes for the infusion of irrigants or medications into the operating field . any secretions , blood , or foreign bodies encountered by the probe can be suctioned , or removed on command via the suction control . the flexion control wheel is used to negotiate around the tongue and into the larynx and also to acquire visualization of the operating field in the presence of anatomical deformities in the patient . when the vocal cords are seen , the et tube is released by the handle mounted , et deployment clamp control switch . when this switch is depressed , it has a variable control capability and if pressed all the way down , will open the et clamps and deploy et tube . when the control switch is pressed gradually to loosen the clamping mechanism , the et clamps form a loose , guiding channel . this capability allows the professional intubator to use the video laryngoscope to hold the et tube tightly during insertion into the operating field and then to guide the tube in the right direction and direct final deployment of the et tube into the trachea with a push provided by the user &# 39 ; s other hand . the insertion probe is then pulled back and out of the patient &# 39 ; s mouth , and the patient has been intubated . the et tube is secured with tape or any other standard method of stabilizing an et tube . intubation with a video laryngoscope is accomplished without having to lift soft tissues out of the way for direct visualization , which results in less trauma and pain for the patient . intubation with a video laryngoscope infusing pure oxygen will help to alleviate hypoxia in the subject being intubated . by using the video laryngoscope , intubation is accomplished easily regardless of anatomical deformities , obstructions , or secretions , since the view is indirectly acquired by a variable position video probe that is controlled by the user . intubation by video laryngoscope gives visual proof of incubation , thereby reducing the need for chest x - rays and co 2 checking devices to prove proper placement of the et tube into the trachea .

a laryngoscope for use in intubating a patient &# 39 ; s trachea , in routine and emergency situations . the laryngoscope has a camera mounted in the vicinity of a distal end of its probe to observe the patient &# 39 ; s trachea opening and transmit a signal to a display on the handle . the distal end of the probe also includes ovoid , generally c - shaped gripping means , a pair of elongated grasping lips on the gripping means , and an internal clamping assembly for controlling the gripping means .

the aim of the present invention is to eradicate the foregoing problems through the provision of a therapeutically effective and immunologically - distinct , alternative and stable form of asparaginase , i . e ., p . furiosus asparaginase ( pfa ) or their mutants thereof . these asparaginases and their process for preparation are described in detail below , enable them to be used for treating patients suffering from diseases , such patients responding to asparagine deprivation as first line therapy or , alternatively , for treating patients who had previously developed hyper - sensitization to other microbial asparaginases , e . g ., that derived from e . coli , and / or modified forms of non - p . furiosus asparaginases , e . g ., e . coli or er . carotovora asparaginase that has been pegylated . the applicants have modeled the three - dimensional structure of an asparaginase from p . furiosus based on the published structure of a homologous enzyme from p . horikoshii . based on the modeled structure and sequence alignment analysis with that of e . coli , the inventors have identified amino acid residues of relevance for improving the properties of the asparaginase . the recombinant enzymes of the present invention , are stable in nature , as a result of which , they may also be used in the production of food products where it can be used to prevent the acrylamide synthesis . it is pertinent to mention that available enzymes had various drawbacks which ranged from instability to causing milder as well as severe side effects . it was also found that the side effects caused by the available enzymes were reportedly associated with glutaminase activity . in stark contrast , the l - asparaginases of the present invention have manifold advantages ; such enzymes being are devoid of any glutaminase activity . as a result , certain undesired side effects which were caused by existing and available enzymatic treatments are anticipated to be either greatly mitigated or non - existent on treatment with l - asparaginases of the present invention . therefore , the enzymes of the present invention provide the means of an alternative therapeutical method for the treatment of leukemia and likewise diseases where asparagine depletion or deprivation would be efficacious . other significant advantages of the present invention are that the aforesaid enzymes being stable enzymes which reduce the treatment cost through its long half life in serum ; resulting in reducing the need of multiple dose administration to the patients . further , an important aspect of the present invention is to reduce the production cost of the enzymes due to milder temperature requirements during production of l - asparaginases of the present invention . another important feature of the invention is that the l - asparaginase of the present invention does not require any sophisticated storage condition . the present invention also provides the stable enzymes for food industry as acrylamide synthesis inhibitor . a principal embodiment of the present invention is a novel mutant of l - asparaginase enzyme characterized in having high thermostability , ph stability and no glutaminase activity useful for therapeutics . yet another embodiment of the present invention is the mutant of l - asparaginase enzyme wherein high thermostability is in the temperature range of 37 - 90 ° c . yet another embodiment of the present invention is the mutant of l - asparaginase enzyme wherein the ph stability is in the range of 7 . 0 - 9 . 5 . yet another embodiment of the present invention is the mutant of l - asparaginase enzyme wherein the polypeptide sequence of the enzyme is selected from the group consisting of seq . id no . 6 , 8 , 10 . yet another embodiment of the present invention is the polypeptide sequence comprising at least one of the following substitutions k274e , t53q , and t53q / k274e . yet another embodiment of the present invention is the nucleic acid sequence corresponding to the polypeptide sequence is selected from the group consisting of seq id no 7 , 9 , 11 . yet another embodiment of the present invention is the primer sequence selected from the group consisting of seq id no . 14 , 15 , 16 , and 17 , useful for the amplification of mutant l - asparaginase gene . yet another embodiment of the present invention is an expression construct comprising any one of the modified nucleic acids . yet another embodiment of the present invention is a host cell comprising the expression construct . in yet another embodiment of the present invention a recombinant e . coli strain having the construct having international deposition no . mtcc 5579 , 5580 , 5581 and 5582 in the international depository “ microbial type culture collection ” at institute of microbial technology , chandigarh , india . further in another embodiment the invention provides a process of preparing the mutant l - asparaginase wherein it comprises the steps of : isolating pyrococcus furiosus asparaginase gene having seq id no . 2 ; amplifying the gene obtained in step a , using primers having seq id . no . 12 and 13 . cloning the gene obtained in step b , in an expression construct . mutagenizing the gene in the recombinant construct obtained in step c , using site directed mutagenesis , transforming the expression construct obtained in step d , into e . coli , purifying the mutant l - asparaginase enzyme . in yet another embodiment the present invention provides a pharmaceutical composition comprising the l - asparaginase mutant , optionally along with pharmaceutically acceptable excipient ( s ). in yet another embodiment the present invention provides a pharmaceutical composition for treating disease or disorder selected from the group consisting of leukemia and asparagine depletion related disorders . in yet another embodiment the present invention provides a pharmaceutical composition administered intramuscularly ( im ) and intravenously ( iv ). in yet another embodiment the present invention provides the use of mutant of l - asparaginase in acrylamide reduction in food products . in yet another embodiment the present invention provides a use of l - asparaginase as medicament in the treatment of a cancer . further in another embodiment the invention provides an isolated l - asparaginase enzyme of pyrococcus furiosus having seq id no . 4 . in yet another embodiment the invention provides the isolated polypeptide sequence of the l - asparaginase enzyme having sequence id no . 1 . in yet another embodiment the invention provides the isolated corresponding nucleic acid of the polypeptide sequence having seq . id 2 . in yet another embodiment the invention provides the method of isolating l - asparaginase enzyme of pyrococcus furiosus comprising the steps of : isolating pyrococcus furiosus asparaginase gene having seq id no . 2 ; amplifying the gene obtained in step a , using primers having seq id . no . 12 and 13 . cloning the gene obtained in step b , in an expression construct . transforming the expression construct obtained in step d , into e . coli , purifying the l - asparaginase enzyme having seq id no . 3 using ni - nta resins . removing his - tag by thrombin cleavage from the enzyme obtained in step e as herein described , purifying the l - asparaginase without his - tag obtained in step f having seq id no . 4 . in yet another embodiment the invention provides the modeled structure of the l - asparaginase enzyme of pyrococcus furiosus having seq id no . 3 . the following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention . the nucleotide sequence of 981 by coding region of p . furiosus asparaginase ( seq id : 2 ) is obtained from genebank accession number ( nc — 003413 . 1 ). from the sequence , the specific primers ( seq id : 12 , 13 ) for the pcr amplification of the gene coding p . furiosus asparaginase is synthesized . pcr amplification using these primers ( fig1 ) introduced an ndei and a bamhi restriction site to the 5 ′ and 3 ′ termini of the nucleotide sequences , respectively to facilitate directional cloning of this amplified genomic sequence into sequencing and / or expression vectors . the amplified p . furiosus asparaginase - specific amplified dna fragment is double digested with ndei and bamhi and cloned into the ndei and bamhi sites of the double digested pet 14b vector ( novagen , usa ) utilizing the specific conditions . the ligation reaction is incubated at 16 ° c . for 16 hr . and then 2 μl of this reaction is used to transform competent e . coli strain dh5α . transformants are then plated onto la plates containing 100 μg / ml ampicillin and incubated at 37 ° c ., for 14 hr . randomly 5 colonies are selected out from the la plate . these colonies are then grown in lb media containing 100 μg / ml ampicillin by incubating overnight at 37 ° c . on a shaker . from these cultures , plasmids are isolated using a standard dna “ mini - prep ” methodology . the concentration of plasmids was determined using spectrometric method at 260 nm . then the plasmids are single and double digested with ndei and bamhi restriction enzymes and run over the agarose gel along with a control plasmid without having insert as illustrated in fig3 . for the confirmation of the result , the p . furiosus asparaginase specific pcr primers are used to amplify the p . furiosus asparaginase - specific fragments isolated from the earlier mentioned clones ( fig4 ). these primers did not mediate amplification of non - insert containing bacterial dna . the final confirmation of the clone is done by dna sequencing . in the absence of the structure of pfa , a homology model of the same is constructed using modeller ( sali & amp ; blundell , 1993 ). the available crystal structure of p . horikoshii l - asparaginase ( pha ; pdb : 1 wls ) is used as template . the sequence alignment module in modeller is used to prepare the alignment files of the target and the template . these alignment files are further used to generate the 3d - structure model . ramachandran plots for the model and template l - asparaginases has been analyzed for verifying the quality of the model ( kleywegt & amp ; jones , 1996 ). site directed mutagenesis for creating different mutants of p . furiosus asparaginase two synthetic oligonucleotide primers ( complementary to each other ) containing the desired mutation is used to amplify ( pcr ) the entire vector containing an insert of interest . the product obtained is treated with dpni to digest the parental dna template ( semi - methylated ) and to select for mutation - containing synthesized dna ( non - methylated ). the nicked vector dna containing the desired mutations is then transformed into e . coli strain dh5α - competent cells ( fig7 a - 7 c ). mutation was confirmed by dna sequencing . for creating three different mutants , 2 set of primers ( seq id : 14 , 15 , 16 and 17 ) are used . the primers used for generating second site directed mutant t53q are used to make another site directed mutant ( a double mutant ) through pcr over k274e mutant plasmid as a template or vice - versa . the enzyme is expressed in e . coli strains , bl2icodon plus ( invitrogen ) and / or rosetta ( novagen ). to facilitate the purification of the enzyme , poly - his tag at n - terminal of the recombinant asparaginase is kept . nickel resin ( ni - nta [ nitilo - tri - acetic acid resin ]; qiagen ) is used to affinity purify the poly - his labeled recombinant asparaginase enzyme . the poly - his tag is cleaved by thrombin which leaves three extra amino acids ( gsh ) at the n - terminus of l - asparaginases . the enzyme is purified under denature conditions according to the following methodology . clone strains are grown to ˜ 0 . 6 od 600 nm , in the presence of chloramphenicol ( 17 μg / ml ) and ampicillin ( 100 μg / ml ) at 37 ° c . with shaking and then induced with iptg ( 1 mm ). then the cells are harvested by centrifugation and cell pellet obtained is lysed by sonication in lysis buffer [ 100 mm nah 2 po 4 , 10 mm tris - cl , 6 m guanidine chloride ( gdncl )/ 8 m urea ( ph 8 . 0 )]. following centrifugation , the supernatant is filtered with 0 . 45 μm filters . the filtrate is then incubated with ni - nta agarose resins , which is packed in a column for purification . after washing with wash buffer ( ph 6 . 3 ), protein is eluted in elution buffer ( ph 5 . 9 , 4 . 5 ). eluted fractions were collected in aliquots of 1 ml and analyzed on 12 % sds - page . after analysis , the fraction containing the protein of interest is pooled followed by dialysis against 50 mm tris - cl , 100 mm nacl , ph 8 . 0 . dialysed protein sample is then centrifuged to remove any precipitated protein fraction and then stored at 4 ° c . the enzymes is characterized in the terms of k m , v max , catalytic efficiency , enzyme kinetics ( table 1 ), substrate specificity , ph optimum , and temperature optimum . sds - page followed by coomassie blue staining of the gels , is used to observe enzyme homogeneity , evaluate subunit composition and determine enzyme molecular weight . gel filtration chromatography was carried out to determine its multimericity . enzymatic activity of l - asparaginase is quantitatively measured by the amount of ammonia released upon hydrolysis of l - asparagine using 50 mm buffer at ph 7 . 4 and 9 . 0 . in short , reaction mixture containing 50 mm tris - hcl ph 9 . 0 , or 50 mm na - phosphate , ph 7 . 4 , 10 mm l - asparagine ( merck ) and varying amount of enzyme solution in a final volume of 2 ml is incubated for 10 minutes at 80 ° c ., or 37 ° c . after incubation the reaction is stopped by adding 100 μl of 1 . 5 m trichloroacetic acid ( tca ). the solution is centrifuged followed by addition of 1 ml nessler &# 39 ; s reagent ( merck ) to 500 μl of the supernatant diluted with 7 ml water . od 480 nm of the resulting solution gave a measure of enzyme activity . a standard curve is prepared with ammonium sulphate . one international unit ( iu ) of l - asparaginase activity is defined as the amount of enzyme liberating 1 μmol nh 3 in one minute incubated at the above mentioned conditions . specific activity of l - asparaginase is defined as the units per milligram protein . enzyme stability is determined by incubating the enzyme with varying concentration of gdncl ( table 2 ), urea , increasing temperature and varying ph for various time intervals . the cell lines are grown in rpmi - 1640 medium containing 10 % fcs in the presence of 100 iu / ml penicillin and 100 μg / ml streptomycin , in 5 % co 2 incubator at 37 ° c . the control culture is treated with regular media only . mtt colorimetry is employed to investigate the proliferation of cells . cells ( k562 , hl - 60 and mcf7 ) at the logarithmic growth phase are suspended in solution to a cell density 2 . 5 × 10 4 / ml . this suspension ( 100 μl per well ) is then transferred to each well . the varying concentration ( 0 . 001 , 0 . 01 , 0 . 1 and 1 . 0 iu / ml ) of enzymes are added to the cell lines and the volume is made up to 200 μl with rpmi 1640 culture media . the plate is incubated in 5 % co 2 incubator at 37 ° c . for varying time ( 24 , 48 , 72 hr .) after each time periods , the 20 μl of 5 mg / ml mtt is added in each well and then further incubated for 2 hr . in the same incubator . cells are then isolated by centrifugation and cell pellets are suspended in 150 μl dmso followed by 30 min . incubation . absorbance is measured at 540nm after cells are completely dissolved . the enzyme disclosed in the present invention is devoid of any glutaminase activity thereby reducing undesired side effects caused by existing and available enzymatic treatments . the present invention provides a useful alternative therapeutic method for treatment of leukemia and likewise diseases where l - asparagines depletion or deprivation would be efficacious . the enzymes claimed in the invention are thermally stable and have long shelf - lives which reduce storage costs . being stable the enzymes of this invention have long half life in serum in treated patients resulting in reduction in dose requirement for treatment . the present invention provides an enzyme which is easy to produce and purify in quantities thereby reducing the cost of treatment . the present invention also provides stable enzymes that can be used in food industry for reduction of toxic acrylamide in fried and baked foods .

the present invention relates to a novel mutant of l - asparaginase enzyme characterized in having high thermostability , ph stability and no glutaminase activity useful for therapeutics and the process of preparing the same . the present invention specifically relates to mutant &# 39 ; s mtcc 5580 , mtcc 5581 and mtcc 5582 characterized in having higher stability , no glutaminase activity etc ., to allow their usage in the form of improved protein therapeutics . a thermostable l - asparaginase from p . furiosus was cloned and expressed in e . coli host . the enzyme was engineered at its active site to create three different mutants based on structural and sequence analysis with a e . coli — derived enzyme homologue . the mutants mtcc 5580 , mtcc 5581 and mtcc 5582 were tested for their stability , substrate affinity , optimum ph and temperature of activity and cytotoxicity . based on the studies , all the three enzymes were found thermostable and with no glutaminase activity as compared to other available enzyme eca ii . mtcc 5579 and the above said three mutants showed the cytotoxicity on the leukemic cell lines . the present study showed that these enzymes are promising candidates for the treatment of leukemia .

the tractor shown in fig1 comprises a frame 1 and is supported by front wheels 2 and rear wheels 3 and 4 arranged on both sides of the frame . the leading rear wheel 3 and the trailing rear wheel 4 on the same side of the tractor are journalled in a wheel carrier 5 which in operation is substantially horizontal and lies in the direction of forward travel a . the wheel carrier 5 and the wheels 3 and 4 carried by it are pivotable in operation about a pivotal axis 6 , which is horizontal and transverse of the direction a and is journalled in the frame 1 . the wheel axle 7 of the leading rear wheel 3 and the wheel axle 8 of the trailing rear wheel 4 are journalled at the front and rear ends respectively of the wheel carrier 5 . the pivotal axis 6 , about which the wheel carrier 5 is freely pivotable with respect to the frame 1 , is located approximately midway along the wheel carrier 5 . this construction is provided on both sides of the tractor and is such that each set of rear wheels 3 and 4 on each side of the tractor together with the associated wheel carrier 5 is pivotable with respect to the frame 1 independently of the set of wheels 3 and 4 and wheel carrier 5 on the other side of the tractor . a driving engine 9 is mounted on the frame 1 at generally the same position along the tractor as the wheels 3 and 4 . a driver &# 39 ; s cab 10 is provided in the region of the front wheels 2 and the interval between the wheels 2 and 3 . in the cab there is a driver &# 39 ; s seat 11 and a console 12 provided with a steering wheel 13 for controlling the steerable front wheels 2 and with other steering and control members of the tractor . the driver &# 39 ; s seat 11 and the console 12 together with the steering and control members can turn as a whole about a substantially vertical pivotal axis 14 located between the console 12 and the seat 11 , so that the assembly can be set in either of two positions offset from one another by 180 ° . in one of these positions the driver faces in the direction a and in the other position he faces in the opposite direction . at the front the tractor has a three - point hitching device 15 and at the rear it has a three - point hitching device 16 . in the example illustrated in fig1 a rotary harrow 17 is attached to the rear three - point hitching device 16 ; the tines 18 of the harrow 17 penetrate the soil to a given depth . the harrow 17 is driven through a power take - off shaft 19 near the hitching device 16 . near the front hitching device 15 there is another power take - off shaft . the rear wheels 3 and 4 on each side of the tractor can be driven by a driving shaft 20 ( fig2 ), which is coaxial with the pivotal axis 6 . the driving shaft 20 is rotated by the driving engine 9 through a torque converter ( not shown ) and a differential gear . each end of the driving shaft 20 is provided with a pinion located in the wheel carrier 5 concerned , this pinion being coupled via a gear train in the wheel carrier 5 with pinions coaxial with the wheel axles 7 and 8 . all of the pinions are located inside the wheel carrier concerned and can turn together with the wheel axles 7 and 8 and with the wheel carrier 5 about the pivotal axis 6 . the pairs of rear wheels 3 and 4 on the two sides of the tractor frame are , therefore , all drivable and are capable of turning freely about the pivotal axis 6 in pairs independently of the set located on the other side . near the driving shaft 20 , on the top of the carrier beam 5 , there is a coupling arm 21 which is inclined inwardly from bottom to top away from its wheel carrier 5 . each of the two coupling arms 21 is rigidly secured at one end to its wheel carrier 5 and is movably coupled at the other end with a rod 22 which is integral with or pivotally coupled with a spool of a control valve 23 , which is rigidly connected to the tractor frame near the wheel carrier 5 . an input duct 24 connects each control valve 23 with a hydraulic pump 25 , which draws hydraulic fluid through a duct 26 from a fluid reservoir 27 . the valve 23 also communicates directly with the reservoir 27 through a duct 28 . the control valve 23 also communicates through a duct 29 with a working chamber of a hydraulic cylinder 30 containing piston 31 which is coupled by a piston rod 32 with a bell - crank lever 33 . the lever 33 is connected by a lifting rod 34 to the lower arms 35 of the hitching device 16 . a set of the parts 21 , 22 , 23 , 24 , 28 , and 29 to 35 is provided on each side of the tractor . the two sets of parts are , however , fed by a common pump 25 . the parts 21 , 22 , 23 , 24 to 32 together with the wheels 3 , 4 and the wheel carrier 5 constitute a control means for the hitching device 16 . the hydraulic pump 25 is driven from the drive shaft 20 through a transmission ( not shown ) comprising , for example , a gear box having a fixed transmission ratio . the speed of the pump 25 is , therefore , proportional to the travelling speed of the tractor . thus , when the tractor is stationary , there is no pressure in the duct 24 . in this case the control valve 23 is fed by a second pump which is driven by the output shaft of the engine 9 . for this purpose the duct 24 includes a valve ( not shown ), which automatically connects the control valve 23 with the second pump when the pump 25 delivers no pressure . the construction described above operates as follows : if , for example , the leading rear wheel 3 on one side of the tractor runs into a depression of the ground surface , the set of the two rear wheels 3 and 4 on that side of the tractor turns in a counter - clockwise direction as seen in fig2 . the coupling arm 21 then draws the rod 22 outwardly of the housing of the control valve 23 into a position in which hydraulic fluid is conducted towards the reservoir 27 from the working chamber of the cylinder 30 ( fluid in this working chamber being pressurized by the weight of the machine ) through the duct 29 , the valve 23 and the duct 28 . as a result the lower lifting arms 35 turn downwardly so that the attached machine 17 can follow the depression of the ground surface . if the leading rear wheel 3 is raised by a bump in the ground or if the trailing rear wheel 4 runs through a depression in the ground , the set of these wheels together with the wheel carrier 5 turns in a clockwise direction so that the spool of the control valve 23 is moved inwardly of the control valve 23 into a position in which hydraulic fluid supplied by the pump 25 flows through the duct 24 , the control valve 23 and the duct 29 into the cylinder 30 so that the lower lifting arm 35 turns upwardly and the attached machine 17 is lifted . this combination of directions of movement is particularly important when the magnitude of unevennesses of the ground , in the direction a , are approximately equal to or less than the distance between the front wheels 2 and the wheels 4 . therefore , the wheels 3 and 4 constitute sensing members of the sensing device . this effect is obtained on each side of the tractor independently of the events on the other side of the tractor . between the occurrence of the upward and downward movements of the wheels 3 and 4 and the turning of the wheel carrier 5 , and the moment at which the machine will respond to these movements there should be a lapse of time depending upon the instantaneous travelling speed of the tractor and upon the distance between the wheel responding to the unevenness and the machine . since the output of the pump 25 depends upon the travelling speed , the rate of movement of the piston 31 with respect to the cylinder 20 also depends upon the travelling speed . the delay is adjusted as a function of the size of the machine 17 and the rate of flow is regulated by an adjustable throttle valve 36 in the duct 29 . this throttle valve 36 can be set through a duct 37 indicated by broken lines in dependence upon the pressure delivered by the pump 25 and hence upon the travelling speed . in an alternative construction , the slide of the control valve 23 is designed so that if , for example , the wheel 3 moves downwards the pump 25 feeds fluid into the duct 29 and into the cylinder 30 so that the lifting arm 35 turns upwardly . such a control is particularly advantageous when the magnitude of the unevennesses of the ground are approximately equal to or larger than the distance between the front wheels 2 and the wheels 4 . with the control arrangement described above , the hitching device is held at a predetermined height above the ground during operation so that the machine will follow unevennesses of the ground . in the embodiment of fig4 the tractor comprises rear wheels 38 which can be driven by a driving shaft 39 which is connected by a differential gear and a torque converter with a driving engine 40 . between the front wheels ( not shown in fig4 ) and the rear wheels 38 , and a short distance in front of the latter , there is a sensing member in the form of a sensing wheel 41 which is rotatable about a horizontal shaft 42 journalled in a carrier 43 , and extending transversely of the direction of forward travel a . the carrier 43 is pivotable with respect to the rest of the tractor about a pivotal shaft 44 journalled in the tractor frame . the pivotal shaft 44 is located close to the driving shaft 39 . the carrier 43 has an extension arm 45 on the side of the pivotal shaft 44 away from the wheel 41 , the free end of this arm 45 carrying a shaft portion 46 , which is upwardly movable in a slot 47 in a holder 48 . the holder 48 itself is slidable up and down with respect to the tractor frame in a guide 49 . a spring 50 acts between the top of the holder 48 and the tractor frame . the spring 50 tends to pull the holder 48 upwards . the bottom of the holder 48 is connected by a coupling piece 51 to a lower lifting arm 52 of a three - point hitching device 54 which also has a top lifting arm 53 . between the fastening point of the coupling piece 51 and the rear end of the lifting arm 52 there is a pivotal shaft 52a , about which the lifting arm 52 can turn with respect to the frame . inside the holder 48 there is a potentiometer with two end contacts 55 and 56 , which are fixed in position with respect to the holder 48 . the shaft portion 46 located in the slot 47 is provided with a wiper 57 , which is displaceable along the potentiometer and the holder dependent upon the position of the carrier 43 and the arm 45 . the end contacts 55 and 56 and the wiper 57 are connected to inputs 58 , 59 , 60 of a power amplifier 61 , which is connected by leads 62 and 63 to the battery 64 of the tractor . the current supply to the power amplifier 61 can be switched on and off by the driver from his seat by means of a switch 65 . the current amplifier has outputs 66 , 67 and 68 connected to the two end contacts and the central contact respectively of an electromagnetic two - way solenoid 69 . inside the solenoid there is a displaceable core to which a spool of a control valve 70 is connected . a hydraulic pump 71 is connected to the control valve 70 and a duct 72 connects the control valve with a fluid reservoir 73 . the pump 71 draws fluid from the reservoir 73 . the control valve 70 communicates through a duct 74 with a hydraulic cylinder 74 which contains a piston 76 connected with a piston rod 77 coupled with a bell - crank lever 78 , which is connected by a lifting rod 79 to the lower lifting arm 52 at a location between the pivotal shaft 52a and the rear free end of the lifting arm 52 . the spool of the control valve 70 can also be directly manually actuated by a lever 80 located near the driver . a machine is coupled with the hitching device 54 . the pump 71 is driven by the driving shaft 39 so that the fluid delivery is again dependent upon the travelling speed , while the same precautions are taken as in the previous embodiment for operation when the tractor is stationary . the parts 41 to 45 constitute a sensing member which forms the control means together with the parts 46 to 51 and 55 to 75 . if during operation the tractor travels over uneven ground and the sensing wheel 41 runs , for example , into a depression in the ground , the carrier 43 and the arm 45 rigidly secured to it will turn about the pivotal shaft 44 in a counter - clockwise direction ( fig4 ). the shaft portion 46 and the wiper 57 connected to it will move upwardly in the slot 47 with respect to the holder 48 so that the electrical resistance between the contacts 55 and 57 will decrease and the resistance of the other branch ( between the contacts 57 and 56 ) will increase . this resistance variation in the branches of the potentiometer is fed to the inputs 58 to 60 of the power amplifier 61 so that from the output terminals 66 to 68 of the amplifier 61 currents of different intensities flow through the two branches of the solenoid 69 . as a result of the magnetic field variations in the solenoid 69 the core will move axially in the solenoid 69 so that the spool of the control valve 70 is displaced . this displacement places the ducts 74 and 72 in communication with one another and the fluid in the cylinder 75 , pressurized by the weight of the machine attached to the hitching device 54 , flows back through the ducts 74 and 72 into the reservoir 73 . as a result , the machine will move downwardly with respect to the tractor to follow the depression of the ground . if the sensing wheel 41 moves upwardly to pass over a bump in the ground , different currents will flow from the amplifier 61 through the two branches of the solenoid 69 owing to the downward movement of the wiper 57 with respect to the potentiometer so that the spool will move in the opposite direction . in this case , the spool is set so that the pump 71 can introduce hydraulic fluid through the duct 74 into the cylinder 75 as a result of which the lower arms 52 of the hitching device and hence the attached machine are raised to follow the bump . as in the first embodiment , the duct 74 may include an adjustable throttle valve 36 , which is connected through a separate duct , analogous to the duct 37 , with the outlet of the pump 71 . thus , as in the first embodiment , a delay may be incorporated which varies with the travelling speed of the tractor . the control valve shown in fig4 may be used on both sides of the tractor , so that each control valve actuates one of the two lower lifting arms 52 . the pump 71 can feed both of the control valves 70 . the control valve shown in fig4 may also be employed in the case where the positions of the hitching device and of the attached machine vary with respect to the tractor , the position of the sensing wheel 41 remaining the same . if a lifting arm 52 moves downwards , for example , due to leakage of hydraulic fluid , the holder 48 is drawn upwards by the spring 50 past the shaft portion 46 and the wiper 57 . this relative movement of the wiper with respect to the holder 58 is the same as that which occurs when the sensing wheel 41 runs over a bump in the ground , and the control means causes the lower lifting arms 52 to move upwardly until the resistance of the two branches of the potentiometer are again the same . in both of the embodiments described above the control means described is designed so that when the wheel 3 or the sensing wheel 41 moves downwardly the hitching device and the attached machine also move downwardly , and vice versa . this control is appropriate when the length of the unevenness is generally smaller than the distance between the front wheels and the rear wheels . however , if the dimension of an unevenness is approximately equal to or larger than the distance between the front wheels and the rear wheels of the tractor , it may be advantageous to invert the control so that when the foremost rear wheel 3 or the sensing wheel 41 moves upwardly the control means , after a delay , causes the machine to move downwards , and vice versa . to achieve this change - over , the connection between the coupling piece 51 and the lifting arm 52 has to be moved to that it is located between the pivotal shaft 52a and the rear free end of the arm 52 . thus the tractor can be simply adapted to the nature of the ground to be covered . the driver can actuate the hitching device using a lever 80 independently of the sensing device . this precaution may also be taken in the other embodiments . a third embodiment of a control means for a machine attached to a tractor is illustrated in fig5 and 6 . the parts of the construction of fig5 and 6 correspond with parts shown in fig4 are designated by the same reference numerals . the lower lifting arms 52 are each provided with a pivotal shaft 81 , about which is pivotable an arm 82 which slopes downwardly from front to rear and carries at its end a skid 83 , which is held during operation in contact with the ground by its own weight and which slides along the ground surface . the arm 82 extends to the other side of the pivotal shaft 81 and is coupled at its free end , by a rod 84 , with the spool of the control valve 70 . the control valve 70 is rigidly secured to the lifting arm 52 . the hydraulic pump 71 is , as before , driven through a transmission mechanism having a fixed transmission ratio by the driving shaft 39 . when the tractor is stationary the same precaution as described for the first embodiment is taken . the skid 83 may be replaced by a ground wheel . the skid 83 ( or the ground wheel ) is arranged at a short distance behind the wheel 38 . the arm 82 is bent outwardly at a position in front of the end of the lower lifting arm 52 and then bent back to extend substantially parallel to the lifting arm 52 , so that the skid 83 or the ground wheel does not hinder the attachment of the machine to the hitching device . the skid 83 thus follows unevennesses of the ground at a position located close to the machine , yet is sensitive to unevennesses of the ground over which passes the adjacent rear wheel 38 . owing to the distance between the front and rear wheels of the tractor the position of the arm 82 is substantially insensitive to unevennesses of the ground followed by the front wheels . if the rear wheel 38 runs up a rise in the ground , the arm 82 will turn with respect to the lifting arm 52 about the pivotal shaft 81 in a clockwise direction . the rod 84 displaces the spool of the control valve 70 so that hydraulic fluid flows from the pump 71 through the duct 74 into the cylinder 75 to move the piston 76 outwardly , so raising lifting arm 52 . the adjusted delay is such that the machine is lifted as it reaches the rise . this delay may be obtained by the adjustable throttle valve 36 shown in fig2 the adjustment of which is performed through the duct 37 communicating with the pressure side of the pump 71 . at a higher travelling speed the pump pressure is higher so that the throttling effect of the valve 36 is decreased and the piston will respond more quickly than with a lower travelling speed . when the skid 83 arrives at the rise , a reverse control is performed which is transmitted with a time lag to the lifting arm 52 . if the rear wheel 38 runs through a depression in the ground , the arm 82 turns upwardly . this connects the duct 74 with the reservoir 73 so that the lifting arm 52 turns downwardly after a delay , under the action of the weight of the machine , to follow the depression of the ground . the spool of the control valve 70 may , as an alternative , be designed so that the movements of the lifting arm 52 as a result of the movements of the skid 83 are performed in the reverse senses . in this case , when a rear wheel 38 runs up a rise in the ground ( so that the arm 82 turns downwards with respect to the arm 52 ) the lifting arm 52 will also turn downwards . this structure of the control valve is appropriate when the length of the unevenness of the ground is of the same general order of magnitude as the distance between the front and rear wheels of the tractor , or is larger than that distance . with this setting the skid 83 will hold the hitching device during operation at a predetermined level above the ground . if the lower lifting arm 52 turns downwards unintentionally for some reason or other ( for example , due to leakage of fluid ), the skid 83 turns upwardly with respect to the lifting arm 52 after which the control valve 70 rigidly secured to the lifting arm 52 will cause the lifting arm to turn upwards again . as in the previous embodiments , the control valve may be a double device in which each lifting arm 52 is connected with one of the control means 36 , 37 , 70 to 75 , 82 to 84 . the pump 71 can again feed both control valves . the sensing wheels 41 and the other parts 46 to 51 , 55 to 75 of the control means shown in fig4 and arranged on both sides of the tractor or the skid 83 and the parts 36 , 37 , 70 to 75 shown in fig5 and also arranged on both sides of the tractor for controlling the lifting arms 52 separately may also be employed in the embodiment of the tractor shown in fig1 in conjunction with the hitching device 15 , when the tractor is travelling backwards , the wheel 41 being then in front of the wheel 2 or the skid 83 being behind the wheel 2 , with respect to this backwards travel direction . although various features of the tractors described and illustrated in the drawings , will be set forth in the following claims as inventive features , it is to be understood that the invention is not necessarily limited to these features and encompasses all novel features described both individually and in various combinations .

an agricultural tractor with a hitching or lifting device which carries a farm implement . a control mechanism is provided on the tractor for adjusting automatically the height of the hitching device to enable the implement to follow irregularities in the underlying ground . the control mechanism includes a sensing member which , in one embodiment , comprises two wheels which may pivot together about a common axis , such pivoting causing adjustment of the hitching device . in another embodiment , independently pivotable wheels or a further ground engaging member such as a skid may be located ahead of or behind the ground engaging wheels of a tractor which , by connection to the control mechanisms cause the hitching device to adjust to the height of the underlying ground .

this invention deals with novel tissue adhesive formulations based on combinations of a 2 - cyanoacrylate ester and one or more compliant , absorbable polyesters ( or similar chemical entities ), including slow - absorbing ones or a combination of both types of polyesters . more specifically , the cyanoacrylate fraction of these formulations comprises at least one 2 - cyanoacrylate ester of the general formula i . wherein r is selected from the group consisting of alkyl groups having from 1 to about 8 carbon atoms and , preferably , alkoxyalkyl groups having the formula r 1 — o — r 2 wherein r 1 is an alkyl group having from 1 to about 8 , preferably 2 to 3 carbon atoms and r 2 is an alkylene group having from 3 to about 6 , preferably 3 to 4 carbon atoms . the polyester component can be admixed with the cyanoacrylate component at a level of about 2 to 50 percent , preferably 2 to 25 percent and more preferably from about 5 to 10 percent . the polyester component comprise one or more of the following types of polyesters : ( 1 ) polyalkylene succinate , preferably polytrimethylene succinate ; ( 2 ) copolymers of a polyalkylene succinate and trimethylene carbonate ; ( 3 ) polyalkylene succinate grafted with one or more of the following monomers : trimethylene carbonate , lactide , glycolide , ε - caprolactone , 1 , 5 - dioxepan - 2 - one , and p - dioxanone ; ( 4 ) copolyesters of a polyalkylene oxalate and trimethylene carbonate ; ( 5 ) copolyester of oxalate polymer and trimethylene carbonate wherein the oxalate functionalities are linked to polyethylene polyglycol having a mn in excess of 200 da ; ( 6 ) copolyesters of polytrimethylene succinate and an alkylene oxalate ; ( 7 ) copolyesters of an oxalate polymer of trimethylene diol or polyethylene glycol and a polyalkylene succinate ; ( 8 ) a copolyester comprising a polyethylene glycol linked to succinate and oxalate units ; ( 9 ) an oxalate polymer of a polyethylene glycol having an average degree of polymerization of more than 4 ; ( 10 ) an oxalate copolymer of a polyethylene glycol having a degree of polymerization of more than 4 and an alkane - diol ; ( 11 ) a polytrimethylene carbonate ; ( 12 ) a copolymer of trimethylene carbonate and one or more cyclic ester such as glycolide , lactide , ε - caprolactone , morpholinedione , and p - dioxanones ; ( 13 ) a vinylacetate - based polymer ; ( 14 ) a block copolymer of polyethylene glycol and one or more cyclic monomers such as trimethylene carbonate , glycolide , lactide , ε - caprolactone , morpholinedione , and p - dioxanone ; ( 15 ) polytrimethylene dicarboxylate of acids such as succinic , glutaric , and adipic acids ; ( 16 ) a copolymer of a polyalkylene succinate and trimethylene carbonate ; ( 17 ) a polyalkylene dicarboxylate grafted with one or more cyclic monomer such as trimethylene carbonate , glycolide , lactide , p - dioxanone , ε - caprolactone , and 1 , 5 - dioxepan - 2 - one ; ( 18 ) a copolymer of a polyethylene glycol oxalate and trimethylene carbonate ; ( 19 ) a copolyester of trimethylene succinate and alkylene oxalate ; and ( 20 ) a low melting crystalline copolymer of ε - caprolactone , glycolide , and dl - lactide . another aspect of this invention deals with crystalline absorbable materials made of segmented or block copolymers , wherein the crystalline fraction is due to segments or blocks that melt below 70 ° c . and the entire system displays a t g below 50 ° c . more specifically , this invention deals with two types of crystalline copolymers , wherein the crystalline fraction is due to polyalkylene oxalate or caprolactone - based segment / blocks . a preferred composition of this invention is a copolymer made by end - grafting one or two cyclic monomers onto a crystalline copolymeric alkylene oxalate chain . in a more preferable embodiment , the alkylene oxalate chains are based on randomly placed units of hexamethylene and octamethylene oxalate end - grafted with dl - lactide or a mixture of dl - lactide and glycolide to produce a crystalline polyalkylene oxalate fraction and an amorphous poly - 2 - hydroxy acid fraction . in turn , this amorphous fraction can be made from dl - lactide and / or one or more monomer such as p - dioxanone , caprolactone , glycolide , and trimethylene carbonate . this invention also deals with crystalline copolymers with a crystalline fraction derived from an ε - caprolactone - based segment / block and a non - crystalline faction due to segments / blocks formed by subsequent copolymerization of the crystalline component with dl - lactide and / or one or a mixture of cyclic monomers such as p - dioxanone , ε - caprolactone , glycolide , and trimethylene carbonate . a preferred composition of this copolymer is made in two steps . in the first step 90 / 10 copolymeric chain of ε - caprolactone and glycolide is formed by ring opening polymerization . in the second step , the resulting crystalline product is then grafted with dl - lactide and glycolide in an approximately 65 / 52 ratio . these compositions can be converted to compliant films having a tensile modulus of less than 300 , 000 psi which can be used as a barrier or part of a composite system for use for post - surgical adhesion prevention . most important is the use of these copolymers as high molecular weight compositions ( having an inherent viscosity of more than 0 . 4 in hexafluoro isopropyl alcohol ) as a modifier to a fast - polymerizing cyanoacrylate tissue adhesive / sealant , such as those based on methoxypropyl cyanoacrylate ( mpc ) to form adhesive coherent materials which display higher compliance than systems devoid of the modifier subject of this invention . another aspect of this invention deals with a unique formulation comprising an absorbable 2 - cyanoacrylate and a polyester at a ratio between 95 / 5 and 50 / 50 wherein the polyester is one or more of those described above . in another aspect of this invention , the subject formulation can be used in repairing or sealing soft tissues including , but not limited to , those of the skin and all internal tissues such as those of the cardiovascular , digestive , ocular , urinogenital and respiratory systems , muscles , tendons , ligaments and articulating cartilaginous components . another aspect of this invention is the use of these formulations , with and without an inorganic or organic metallic additive , as hemostatic agents . preferably , such additives are inorganic and / or organic salts of iron , such as ferric chloride , ferric citrate , and ferric gluconate . another aspect of this invention is the use of the subject formulation in attaching natural or synthetic patches used in repairing defective walls , as in repairing the retina , abdominal wall and conduits of the respiratory , vascular , and urinogenital systems . another aspect of this invention is a formulation of an absorbable cyanoacrylate and polyester that can be used with or without an antimicrobial agent as a cover for open wounds , burns , and ulcers . another aspect of this invention deals with a hemostatic adhesive formulation comprising an absorbable crystalline microparticulate cation exchanger with or without an immobilized metal ion such as fe + 2 , fe + 3 , ca + 2 , mg + 2 , and zn + 2 . the microparticles can be dispersed in a absorbable liquid gel - former , a liquid copolyester , or polytrimethylene carbonate , which may also be mixed with a cyanoacrylate monomer such as mpc . another aspect of this invention deals with a hemostatic formulation comprising an absorbable cyanoacrylate such as an the alkoxyalkyl cyanoacrylate admixed with polymeric oxalates , as modifiers , which have been patented as hemostatic agents that form compliant films that undergo absorption in the biologic environment ( u . s . pat . no . 5 , 350 , 798 ). known absorbable and non - absorbable cyanoacrylates affect hemostasis through rapid conversion to a polymeric barrier which physically interrupts bleeding at the application site . occasionally , these barriers fail at sites experiencing pulsatile stresses as in the case of punctured blood vessels . this provided an incentive to explore new cyanoacrylate formulations that have the acknowledged attributes of the physical barriers but interact directly with the blood components to maximize the hemostatic effect without compromising the safety of the system . hence , this invention deals with cyanoacrylate formulations containing polymeric modifiers for controlling their viscosity and / or absorption , in addition to miscible iron salts that can themselves contribute to the hemostatic events . and this invention deals more specifically with an absorbable cyanoacrylate formulation containing at least one polymeric modifier for increasing the compliance or the absorption rate of the resulting polycyanoacrylate and a miscible iron salt for enhanced hemostatic effect . thus , one aspect of the invention deals with an absorbable formulation of an alkoxyalkyl cyanoacrylate with at least one absorbable modifier capable of increasing the polycyanoacrylate compliance and its absorption rate and a miscible iron salt for increasing the hemostatic efficiency , wherein the polymeric modifiers are ( 1 ) oxalate polymers of oligomeric ethylene glycol or polyethylene glycol ( peg ); ( 2 ) copolyesters of trimethylene carbonate / glycolide , a mixture of trimethylene carbonate , caprolactone and glycolide , or a mixture of lactide glycolide and ε - caprolactone ; and ( 3 ) acid tipped polyethylene glycol , copolyesters of “ 2 ” or their copolymers with peg . the iron salt can be a ferric chloride or iron salt of gluconic or citric acid . another aspect of this invention describes the use of a slow - absorbing cyanoacrylate formulation based on an alkyl cyanoacrylate and one or more polymeric modifiers capable of increasing the compliance of the polyalkyl cyanoacrylate , wherein said modifier comprises a copolyester having one or more of the chain repeat units : trimethylene succinate , trimethylene carbonate , and ε - caprolactone , which may be covalently attached to peg segments . similar low modulus , practically amorphous or liquid linear or branched polyesters or vinyl acetate - based polymers can be used as modifiers . typical vinyl acetate - based polymers are polyvinyl acetate and 5 / 95 or 25 / 75 ethylene vinyl acetate copolymers . another aspect of this invention is the use of a thin film or pledget comprising a chitosan or an acylated chitosan to aid the performance of the liquid formulation and accelerate the hemostatic effect . in another aspect of this invention , the polymeric modifier is an acylated chitosan . in another aspect of this invention , the polymeric modifier is liquid at room temperature . in another aspect of the invention , the polymeric modifier represents at least 1 - 50 % of the mass of the alkoxyalkyl cyanoacrylate - based formulation . in another aspect of this invention , the polymeric modifier is a polyester of polyethylene glycol and one or more of the following diacids , adipic acid , succinic , and glutaric acid . in another aspect of the invention , polymeric alkoxyalkyl cyanoacrylates having a molecular weight of at least 1000 dalton can be the modifier or part of a mixture of polymeric modifiers . in another aspect of the invention , the polymeric modifier is a mixture of two or more systems , one of which is a high molecular polymer of an alkoxyalkyl cyanoacrylate . in another aspect of this invention , the performance of the adhesive or hemostatic adhesive can be aided by using a chitosan - based pledget as an adjuvant that facilitates the positioning of said adhesive or hemostatic adhesive and accentuate the hemostatic effect of the latter . the pledget can be prepared by extruding a solution of chitosan ( made preferably by 70 - 90 % deacetylation of the acetamido groups of chitin ) acetate into an alkaline coagulating bath to produce thin films . these can be pressed and cut into proper sizes to produce the pledget subject of this invention . in yet another aspect of the invention , a pledget similar to the chitosan - based one comprising a partially or fully denatured protein film , which may also contain a multivalent metal ion such as fe + 3 , is used to accentuate the hemostatic effect of the liquid formulation . the protein may or may not be acylated with a cyclic anhydride such as glutaric anhydride . the protein can be albumin or a soy protein isolate . typical examples of the absorbable formulations and their performance are given below , which are comprised of methoxypropyl cyanoacrylate ( mpc ), a lactide / glycolide / ε - caprolactone copolymeric modifier ( l1 ) and polymethoxypropyl cyanoacrylate ( mpc ) that is formed by the free radical polymerization of mpc . specific examples for the preparation of representative adhesive formulations and their use as components in hemostatic / adhesive systems and their intermediates are also illustrated below . first , a prepolymer of 90 / 10 ε - caprolactone / glycolide copolymer was prepared using decyl alcohol as the initiator and stannous octoate as the catalyst , respectively . the polymerization was conducted at 170 ° c . the resulting polymer was cooled to 120 ° c . and a 65 / 52 mixture of glycolide and dl - lactide added . when the added monomers dissolved with stirring at about 120 ° c ., the second stage of the polymerization process was then completed at about 170 ° c . trace amounts of unreacted monomer were distilled under reduced pressure at about 110 ° c . the resulting product was shown by dsc to melt at about 48 ° c . and underwent a glass transition below 40 ° c . the polymer was shown to have an inherent viscosity of 0 . 35 in chloroform at 0 . 1 percent concentration . glycolide ( 0 . 08865 moles ) was mixed with ε - caprolactone ( 1 . 455 moles ) and a catalytic amount of stannous octoate ( 0 . 3 moles ) and tartaric acid ( 0 . 075 moles ). the system was heated at 150 ° c . and was stirred at this temperature for 6 hours . at the conclusion of the reaction , the unreacted monomer was removed by heating at 120 ° c . under reduced pressure for 30 minutes . the resulting polymer had a peak melting temperature of 49 . 1 ° c . as measured by dsc and an m w of 151 , 948 as measured by gpc . glycolide ( 0 . 21 moles ) was mixed with ε - caprolactone ( 4 . 0 moles ) and a catalytic amount of stannous octoate ( 0 . 8 mole ) and glycolic acid ( 0 . 40 moles ). the system was heated to 150 ° c . and was stirred at this temperature for 14 hours . at the conclusion of the reaction , the unreacted monomer was removed by heating at 120 ° c . under reduced pressure for 1 hour . the resulting polymer had a peak melting temperature of 54 . 3 ° c . as measured by dsc . glycolide ( 0 . 13 moles ) was mixed with ε - caprolactone ( 1 . 18 ) and a catalytic amount of stannous octoate ( 0 . 262 mole ) and 1 - decanol ( 3 . 275 mole ). the system was heated to 170 ° c . and was stirred at this temperature for 30 minutes . the reaction was then cooled to 120 ° c . glycolide ( 0 . 65 moles ) and dl - lactide ( 0 . 52 moles ) were added to the prepolymer . after melting the second charge , the system was heated to 170 ° c . and was stirred at this temperature for 6 . 5 hours . at the conclusion of the reaction , the unreacted monomer was removed by heating at 130 ° c . under reduced pressure for 1 . 5 hours . the resulting polymer was characterized by dsc ( for t m ), solution viscosity ( for molecular dimensions ), ir and nmr ( for chemical composition ). the adhesive formulations of examples 5 - 7 were prepared by dissolving 5 % ( by weight ) modifier in 95 % methoxy propyl cyanoacrylate ( mpc ). components were measured in a 15 ml polypropylene centrifuge tube . the modifier was dissolved at ambient temperature by shaking and vortexing over the course of several hours . after extended mixing periods , the modifier dissolved in the mpc and formed a one - phase solution . this adhesive formulation was prepared by dissolving the modifier of example 1 in mpc at a 10 / 90 weight ratio . components were mixed in a 15 ml polypropylene centrifuge tube . the plasticizer was dissolved at ambient temperature by shaking and vortexing over the course of several hours . after extended mixing periods , the plasticizer dissolved in the mpc and formed a one phase liquid solution . d and c violet # 2 was added to the formulations of example nos . 5 and 8 at a concentration of 0 . 05 % ( by weight ). the dye was measured into the already prepared formulations and was dissolved by shaking and vortexing at room temperature . the resulting material was a one phase liquid solution . in vitro bond strength evaluation of adhesive formulations using goat skin a layer of paraffin wax approximately 2 cm thick was molded into the bottom of 15 cm × 26 . 5 cm polypropylene containers . goat skin ( 7 . 5 cm × 20 . 5 cm ) was dissected from the subcutaneous tissue , stretched to its original dimensions , and pinned onto the wax . each skin sample was then submerged in a saline solution ( 0 . 9 % w / vol . nacl and 0 . 05 % w / vol . nan 3 ). samples were stored in a freezer at − 10 ° c . prior to use , each sample was removed from the freezer and thawed . saline was decanted from the container , and the skin was rinsed with cold water . all excess moisture was decanted , and the sample was blotted dry . two 19 cm incisions were cut along the length of the skin sample . the skin about the incision was approximated and 400 μl of an adhesive formulation was applied . after polymerization , each incision was cut into test strips approximately 2 cm wide . the samples were tested in tension on an mts 858 minibionix universal testing apparatus at a strain rate of 0 . 42 mm / sec . the wound strength was calculated as the force required to separate the adjoined ends of the incision divided by the cross sectional area of the sample . the average wound strength for each formulation and the corresponding standard deviation are presented in table ii . the tissue adhesive formulation of example no . 5 and , for comparative purposes , 100 % mpc , were tested using an in vivo model in sprague dawley rats that weighed approximately 225 g . anesthesia was induced via subcutaneous injection of 0 . 5 mg / kg acepromazine and 0 . 05 mg / kg buprenorphine ; rats were maintained under anesthesia via 1 . 5 - 2 . 5 % isofluorane inhalation . once anesthetized , rats were shaved and scrubbed with nolvasan scrub . four incisions were made on the back of each rat . two incisions were made 2 cm lateral to the dorsal midline on each side of the rat . each incision was approximately 4 cm long and 1 cm separated each incision on each side of the rat . several incisions were selected as controls and closed with four interrupted sutures ( vicryl size 3 - 0 braided suture , ethicon ). remaining incisions were approximated and 75 μl f - 65 was applied . rats were fitted with elizabethan collars to minimize interference with the incisions . at two weeks post - op , rats were euthanized in a co 2 precharged chamber . the skin from the back of each rat was dissected from the subcutaneous tissue . each incision was cut into two test strips approximately 1 cm wide . healed incision strength was measured in tension using an mts 858 minibionix at a strain rate of 0 . 42 mm / sec . the wound breaking strength was calculated as the force required to separate the wound divided by the cross sectional area of the sample . the average wound strength for each set and the corresponding standard deviation are presented in table iii . the breaking strength of the healed incisions was comparable to those augmented with sutures . each average and standard deviation in the table is based on at least eight separate repaired incisions . to enhance the hemostatic properties of the adhesive formulation of example 5 , it was mixed with 5 % ( by weight ) of ferric chloride to form a uniform solution . in addition , both ferric chloride and ferrous gluconate were mixed with the adhesive formulation of example 8 at amounts ranging from 0 . 1 % to 10 % ( by weight ). the ferric chloride and ferrous gluconate were dissolved by shaking and vortexing at room temperature . a low hydrophilicity copolymer of polyethylene glycol 400 ( peg - 400 ) with trimethylene carbonate ( tmc ) and glycolide was prepared by grafting 15 parts of peg - 400 with 85 parts of tmc following the general procedure of u . s . pat . no . 5 , 612 , 052 . methoxypropyl cyanoacrylate was mixed with the desired modifier ( which has been sterilized at 120 ° c . for 1 hour ) in a laminar flow hood and then agitated to produce a visually one - phase system . the formulations are given below in table iv . heparinized blood samples were collected from a new zealand white rabbit . the clotting potential of adhesive formulations was tested by adding 100 μl of blood and 10 μl of the adhesive formulation to a well in a 96 well microtiter plate . ten such samples were tested per formulation . the samples were visually inspected over the course of 30 min . and observations were recorded . the formulations were rated as poor , moderate , or good blood clotters as shown in table v . in vivo evaluation of formulations using the liver incision test for blood clotting efficiency twelve - week - old new zealand white rabbits were anesthetized via 2 % isofluorane inhalation . the rabbits were shaved and scrubbed , then incised to expose the liver . an incision was cut into the liver measuring 2 cm in length . several microliters of adhesives outlined in examples 22 - 25 were applied to the wound , and the hemostatic properties of each formulation was observed as recorded in table vi . in vivo evaluation of formulation using the vena cava puncture test for blood clotting efficiency after the liver incision tests detailed in examples 29 - 32 were completed , the vena cava was exposed and a small puncture wound was created perpendicular to the length of the vessel . adhesive formulations made in accordance with example nos . 22 and 26 were applied to the wound , finger pressure was applied to the site , and the bleeding ceased immediately . a new zealand white rabbit was anesthetized and a midline incision was made starting at the xiphoid process and extending 12 cm to a point caudal to the umbilicus . the peritoneum was entered and the liver was isolated . a 2 cm long incision was made on the liver and either 100 ul of a hemostatic formulation or the hemostatic formulation soaked into a chitosan pledget was applied to the wound . in addition , a piece of chitosan pledget ( thin film made by casting a base - coagulated chitosan acetate solution ) was tested alone as a control . the formulation of example 23 was applied using sterile tips and a micropipette . observations on the hemostatic properties of the material were recorded along with the time to stop bleeding ( where possible ). the formulation of example 23 was also tested on a vena cava puncture wound . in addition , a piece of chitosan pledget was tested alone as a control . the vena cava was exposed and punctured with an 18 gauge needle . the hemostatic formulation (˜ 100 μl ) was applied to the chitosan pledget , placed on the wound , and then general observations on the hemostatic property were recorded . the present liquid copolyester was made by ring - opening a mixture of 95 / 5 trimethylene carbonate / glycolide with ethylene glycol as an initiator and stannous octoate as a catalyst at 160 ° c . for 1 . 5 hours . typically , the liquid polymer , which is hydroxy - terminated , is treated with an equivalent amount of glutaric anhydride to esterify the end - groups and form carboxylic groups at both ends of the chain . the reaction is carried out by heating the mixture at about 100 ° c . for 30 min ., 110 ° c . for 40 min , then at 120 ° c . for 40 min . the product is then heated under reduced pressure ( about 0 . 1 mm hg ) at 120 ° c . to remove traces of unreacted anhydride . for specific examples , the presence of carboxylic end - groups was confirmed by titration in conjunction with ir spectroscopy and gpc ( for determining molecular weight and molecular weight distribution ). a 90 / 10 mixture of mpc and a carboxy - terminated copolyester made in accordance with example 35 , with and without 1 % chopped ( 1 mm length ) polyglycolide yarn , was prepared and the adhesive properties of the formulation with and without the yarn were evaluated in vitro . results indicate the carboxylation as well as the chopped fibers contribute significantly to ease of application and eventual bond strength , respectively . the chopped fibers accelerated blood clotting . as part of the animal protocol , anesthesia was induced via subcutaneous injection of 0 . 5 mg / kg acepromazine and 0 . 05 mg / kg buprenorphine . rats were maintained under anesthesia via 1 . 5 - 2 . 5 % isofluorane inhalation . once anesthetized , rats were shaved and scrubbed with nolvasan scrub . four incisions were made on the back of each rat . two incisions were made 2 cm lateral to the dorsal midline on each side of the rat . each incision was approximately 4 cm long and 1 cm separated each incision on each side of the rat . the incisions on the left side were used as controls ; these were closed with either four surgical staples or four interrupted sutures . the incisions on the right side were closed with an adhesive formulation ; a limited number of these also received two surgical staples to insure wound closure . at two weeks post - operative , rats were euthanized in a co 2 precharged chamber . the back skin from the rats was dissected from the subcutaneous tissue . each incision was cut into two test strips approximately 1 cm wide . healed incision strength was measured in tension using an mts 858 minibionix at a strain rate of 0 . 42 mm / sec . the wound strength was calculated as the force required to separate the wound divided by the cross sectional area of the sample . the average wound strength for each set and the corresponding standard deviation are presented in table vii . each average and standard deviation in the table is a result of at least eight separate incisions . the foregoing description of preferred embodiments of the invention has been presented for illustration , and is not intended to be exhaustive . modifications are possible in light of the above teachings or may be acquired from practice of the invention .

the present invention is directed to bioabsorbable adhesive / hemostatic formulations of a 2 - alkoxyalkylcyanoacrylate and liquid or solid polymeric modifiers and adjuvant . the present adhesive formulations are useful as tissue adhesive / sealants , hemostatic agents , and as a means for patching or anastomic coupling of damaged organs .

the spinal implant 10 is inserted in the intervertebral space to replace damaged , missing or excised disk material ( fig1 ). the implant 10 is formed from an upper plate 11 having a first inwardly facing surface 14 with a shaped body 16 and a lower plate 12 having a second inwardly facing surface 20 with a shaped body 22 . the facing sides of the plates support a donut shaped cushioning coupler 24 to replicate the displaced disc material ( fig2 - 4 ). the cushioning coupler 24 is a compressible elastic hollow body formed as a toroidal ring secured between the plates . an annular cavity of the hollow body can be filled with an incompressible fluid such as physiological sodium chloride or a silicon oil . alternatively a highly elastic polymer , for example polyurethane , can be used . with a fluid medium which is incompressible under the occurring loads , the elastic compressible hollow body maintains a constant volume . under “ decentralized ” loads , the liquid content in the cavity of the hollow body shifts within the annular cavity and leads to an expansion of the body in that region . thus , tensile stresses are reduced or even avoided . in addition , stabilizing links 27 are positioned along four corners of the implant for use in securing the plate 11 and 12 together , but also to prevent over compression of the shaped cushioning coupler 24 in a bending moment ( fig2 , 3 ). the stabilizing links 27 are also made of an elastic or compressible polymer . the links or bushings are comprised of a resilient material with a fiberous laminate skeleton which provides both compression and tension resistance . excessive bending of the implant can result in the expansion of the body in a radial direction under compressive stress which can be limited if the radial limit of the body is reinforced by a stabilizing links 27 reinforcing means . compression along one edge results in expansion along an opposite edge , the stabilizing links accommodating this reaction . plates 11 and 12 include adjustable mounting brackets or depth stops 30 and 31 . the upper plate 11 includes a mounting bracket or depth stop 30 having a base or elongated planar body 42 that is slidable within the recesses , groves or receptacle 40 . locking screws 43 maintain the base to the receptacle at a position selected by the surgeon . teeth or sharp protuberances 45 engage the bone and prevent movement upon placement . similarly , lower plate 12 includes a mounting bracket 31 having a base or planar body 32 that is slidable within receptacle 41 . locking screws 36 , maintain the base or planar body 32 to the receptacle 41 at a position selected by the surgeon . as illustrated in fig1 , 2 and 3 , the mounting brackets can be positioned at different positions to accommodate the individual situation . with the above description providing certain details , embodiments of the device ( s ) are provided . in preferred embodiments a spinal implant comprises an upper endplate 11 , a lower endplate 12 , a cushioning coupler 24 , a stabilizing linker 27 , an adjustable mounting bracket or depth stop 30 , 31 , a bone screw 80 or combinations thereof ( fig3 ). in preferred embodiments , the upper 11 and lower endplates 12 comprise a planar surface 60 , pointed , rounded or curved 61 edges . in preferred embodiments , the upper 11 and lower 12 end plates comprise an outward facing surface 15 and 17 respectively , for receiving the depth stop 30 , 31 and engaging a vertebra ; an inward facing surface 14 , 20 for engaging the cushioning coupler 24 . the outward facing surfaces of the upper and lower plates comprise one or more receptacles , recesses or grooves 40 for receipt of the depth stop 30 , 31 . in other preferred embodiment , the inward facing surface comprises a shaped body 16 , 22 , the shaped body comprising a convex dome , a concave dome , a shaped protuberance , or a recess , and , one or more slots or recesses 70 for receiving one or more stabilizing linkers 27 , the stabilizing linkers 27 being detachably fastened to the upper and lower plates by a pin 81 ( fig3 , 4 , 5 ). the stabilizing linkers comprising one or more holes 83 , aligned with the holes 82 of the upper and lower endplates ( fig3 and 5 ). in preferred embodiments , the stabilizing linkers further serve the purpose of a spinal ligament allowing for a degree of movement and stability . in preferred embodiments , the pins 81 are inserted into one or more holes 82 , tunneled horizontally through each plate through to the slot 70 , and aligned with a pin receiving aperture 83 in the stabilizing linker 27 . in preferred embodiments , the stabilizing linkers 27 are blocked shaped having planar , curved , concave or a convex surface . however , it is to be understood that these linkers can have any shape or size and can be placed at varying distances and positions from each other , depending on the position of the slots or recesses in the upper and lower plates . in a preferred embodiment , the cushioning coupler 24 is removable , and is shaped and dimensioned for disposition between the upper 11 and lower 12 endplates , within the confines of the stabilizing linker 27 disposed on the periphery or edges 61 of the upper and lower endplates ( fig4 ). in preferred embodiments , the cushioning coupler 24 comprises a doughnut or toroid shape , square shape , spherical shape , oval or elliptical shaped . preferably , the cushioning coupler 24 is toroid shaped . the shaped body 16 , 22 , can thus be shaped , dimensioned or patterned to accommodate the cushioning coupler 24 . the cushioning coupler is optionally fillable with volumetric fluids comprising : saline , gels , latex , polymers , polyethylenes , silicones , polyurethanes , collagen , or hydrogels . in preferred embodiments , the cushioning coupler 24 is a compressible elastic body . in another preferred embodiment , the retractable bracket or depth stop 30 comprises an elongated planar body 42 with at least one sharp protuberance 45 disposed on the surface of the planar body 42 , the planar surface having a first end 46 for sliding into the recesses or grooves 40 of the outward facing surfaces 15 , 17 of the upper 11 and lower 12 endplates , a second end 47 which is perpendicular to the planar body , comprising an aperture 48 for receipt of a bone screw 80 ( fig3 ). similarly , the retractable bracket or depth stop 31 comprises an elongated planar body 32 with at least one sharp protuberance 45 disposed on the surface of the planar body 32 , the planar surface having a first end 37 for sliding into the recesses or grooves 40 of the outward facing surfaces 15 , 17 of the upper 11 and lower 12 endplates , a second end 33 which is perpendicular to the planar body , comprising an aperture 34 for receipt of a bone screw 80 . the sharp protuberances 45 engage the bone and prevent movement upon placement of the retractable brackets or depth stops 30 , 31 ( fig3 ). in yet another preferred embodiment , the planar body 42 , 32 comprises one or more apertures 49 , 35 for receipt of a set screw 43 , 36 for securing the depth stop or mounting bracket 30 , 31 to the upper and lower plates and to fix the position of the depth stop . in preferred embodiments , the bone screw 80 attaches the device to the intervertebral space . in other preferred embodiments , the device and components thereof are formed from biocompatible materials , such as titanium , or any conventional material used for surgical implants , such as stainless steel and its many different alloys , titanium alloys , metallic alloys , polymeric materials , plastics , plastic composites , elastic materials , shape memory alloys ( e . g . nitinol ), shape memory polymers , stainless steel and alloys thereof , thermoplastics , thermoplastic composites , organic polymer thermoplastics , plastics , plastic composites , ceramic or combinations thereof and any other metal or material with the requisite strength and biologically inert properties . unless otherwise defined , all terms ( including technical and scientific terms ) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . it will be further understood that terms , such as those defined in commonly used dictionaries , should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein . as used herein , the singular forms “ a ”, “ an ” and “ the ” are intended to include the plural forms as well , unless the context clearly indicates otherwise . furthermore , to the extent that the terms “ including ”, “ includes ”, “ having ”, “ has ”, “ with ”, or variants thereof are used in either the detailed description and / or the claims , such terms are intended to be inclusive in a manner similar to the term “ comprising .” it is to be understood that while a certain form of the invention is illustrated , it is not to be limited to the specific form or arrangement herein described and shown . it will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification and any drawings / figures included herein . one skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned , as well as those inherent therein . the embodiments , methods , procedures and techniques described herein are presently representative of the preferred embodiments , are intended to be exemplary and are not intended as limitations on the scope . changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention and are defined by the scope of the appended claims . although the invention has been described in connection with specific preferred 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 which are obvious to those skilled in the art are intended to be within the scope of the following claims .

a spinal implant for insertion between adjacent vertebrae to function as a disc prosthesis . the prosthesis is formed from two plates fastened to adjacent vertebrae facing each other . the facing sides of the plates have a donut shaped cushioning coupler to replicate the displaced disc material . stabilizing links are positioned along the edge of the plates to prevent over compression of the shaped cushioning coupler in a bending moment . adjustable mounting brackets are used to secure the implant to the spine .

it should be noted that like elements are represented using like numerals in all the figures and the description . one embodiment is described with reference to the trima accel ® automated collection system ( manufactured and sold by terumo bct , inc ., lakewood , colo ., usa ) but it should be noted that any apheresis system , such as , but not limited to the cobe ® spectra system , spectra optia ® system and the trima ® automatic collection system all also manufactured and sold by terumo bct , inc . may be used without departing from the spirit and scope of the invention . the embodiments described herein may also may be used with the apheresis systems of other manufacturers such as the autopheresis c system manufactured by fenwal , inc . lake zurich , ill ., u . s . a . or the pcs system as manufactured by haemonetics corp . of bainbridge , mass . the embodiments may also use an endogenous photosensitizer , though other photosensitizers could be used . a “ photosensitizer ” is defined as any compound which absorbs radiation of one or more defined wavelengths and subsequently utilizes the absorbed energy to carry out a chemical process . examples of such photosensitizers include porphyrins , psoralens , dyes such as neutral red , methylene blue , acridine , toluidines , flavine ( acriflavine hydrochloride ) and phenothiazine derivatives , coumarins , quinolones , quinones , and anthroquinones . also , endogenous photosensitizers may be used . the term “ endogenous ” means naturally found in a human or mammalian body , either as a result of synthesis by the body or because of ingestion as an essential foodstuff ( e . g . vitamins ) or formation of metabolites and / or byproducts in vivo . examples of such endogenous photosensitizers are alloxazines such as 7 , 8 - dimethyl - 10 - ribityl isoalloxazine ( riboflavin ), 7 , 8 , 10 - trimethylisoalloxazine ( lumiflavin ), 7 , 8 - dimethylalloxazine ( lumichrome ), isoalloxazine - adenine dinucleotide ( flavine adenine dinucleotide [ fad ]), alloxazine mononucleotide ( also known as flavine mononucleotide [ fmn ] and riboflavine - 5 - phosphate ), vitamin ks , vitamin l , their metabolites and precursors , and napththoquinones , naphthalenes , naphthols and their derivatives having planar molecular conformations . the term “ alloxazine ” includes isoalloxazines . the fluid containing the photosensitizer is exposed to photoradiation of the appropriate wavelength to activate the photosensitizer , using an amount of photoradiation sufficient to activate the photosensitizer , but less than that which would cause non - specific damage to the biological components or substantially interfere with biological activity of other proteins present in the fluid . the wavelength used will depend on the photosensitizer selected . the activated photosensitizer inactivates any microorganisms contained in the fluid . as used herein , the term “ inactivation of a microorganism ” means totally or partially preventing the microorganism from replicating , either by killing the microorganism or otherwise interfering with its ability to reproduce . one embodiment further includes an optional prion filter . the p - capt ® filter manufactured by macopharma of mouvaux , france removes prions from at least one blood component . this filter uses ligand technology attached to resin with filter media . prion proteins attach to the ligands for removal from a blood component product . a blood apheresis system 2 is illustrated in fig1 and allows for a continuous blood component separation process . generally , in a continuous system or an on - line system , whole blood is withdrawn from a donor / patient 4 and provided to a blood component separation device 6 where the blood is separated into the individual blood components with at least one of these blood components being removed from the device 6 with the other components being returned to the donor . the continuous system 2 also provides for further separation or concentration of plasma into plasma proteins and the addition of photosensitizer to the plasma proteins for collection . also , the continuous system may provide for filtration for removal of prions . in the blood apheresis system 2 , blood is withdrawn from the donor / patient 4 and directed through a pre - connected disposable set 8 ( the disposable set embodiment of fig2 is shown in fig1 ) which includes an extracorporeal tubing circuit 10 , a blood processing or separation vessel 352 and a plasma separator or concentrator 205 which defines a completely closed and sterile system . the disposable set 8 is mounted on the blood component separation device 6 which includes a pump / valve / sensor assembly 1000 for interfacing with the extracorporeal tubing circuit 10 , and a channel assembly 200 for interfacing with the disposable blood processing vessel 352 . the channel assembly 200 includes a channel housing 204 which is rotatably interconnected with a rotatable centrifuge rotor assembly 568 which provides the centrifugal forces required to separate blood into its various blood component types by centrifugation . the blood processing vessel 352 is inter - fitted into the channel housing 204 to fit with a groove or channel in the channel housing . blood thus flows from the donor / patient 4 , through the extracorporeal tubing circuit 10 , and into the rotating blood processing vessel 352 . the blood within the blood processing vessel 352 is separated into various blood component types and at least one of these blood component types ( e . g ., plasma ) is continually removed from the blood processing vessel 352 . the plasma component may then be further concentrated or separated into plasma proteins to which photosensitizer is added as part of the continuous on - line system . blood components which are not being retained for collection or for use in therapeutic treatments are also removed from the blood processing vessel 352 and returned to the donor / patient 4 via the extracorporeal tubing circuit 10 . the blood processing vessel 352 may optionally be used for a platelet collection although such collection will not be described . operation of the blood component separation device 6 is controlled by one or more processors , not shown . in order to assist the operator of the apheresis system 2 with various aspects of its operation , the blood component separation device 6 includes a graphical interface 660 with a touch screen input / output device 664 connected to the processor . the apheresis system below will be described with respect to a red blood cell collection and a plasma protein collection . although an additional red blood cell collection is described it is further understood that other blood components , such as , but not limited to , platelets could alternatively , or , in addition , be collected . it is understood , however , that a plasma collection only may also occur if desired . if plasma collection only is desired , with subsequent separation and collection of plasma proteins , and addition of photosensitizer , the system described below can be simplified . for example , the red blood cell collection assembly 950 could be deleted . also the replacement fluid assembly 960 can be optional . collecting plasma proteins only with no red blood cell collection can provide a simplified closed system . the apheresis system will also be disclosed with respect to pathogen reduction treatment of the desired plasma proteins to be collected and optional prion filtration . as illustrated in fig2 , and alternate embodiments fig3 , 11 and 12 , blood - primable pre - connected extracorporeal tubing circuit 10 comprises a cassette assembly 110 and a number of tubing assemblies 20 , 50 , 60 , 950 , 90 , 100 and optionally 960 interconnected therewith . generally , blood removal / return tubing assembly 20 provides a single needle interface between a donor / patient 4 and cassette assembly 110 , and blood inlet / blood component tubing subassembly 60 provides the interface between cassette assembly 110 and blood processing vessel 352 . an anticoagulant tubing assembly 50 , plasma or plasma protein collection tubing assembly 90 , red blood cell collection assembly 950 and vent bag tubing subassembly 100 are also interconnected with cassette assembly 110 . optionally , a replacement fluid sub - assembly 960 may be included . the extracorporeal tubing circuit 10 including the assemblies or sub - assemblies above and blood processing vessel 352 are interconnected to yield a closed disposable system or pre - connected disposable for a single use . cassette assembly 110 includes front and back molded plastic plates ( not shown ) that are hot - welded together to define a rectangular cassette member 115 having integral fluid passageways . the cassette assembly 110 further includes a number of outwardly extending tubing loops , described below , interconnecting various integral passageways . the integral passageways are also interconnected to the various tubing assemblies . the blood removal / return tubing assembly 20 includes a needle subassembly 30 interconnected with blood removal tubing 22 , blood return tubing 24 and anticoagulant tubing 26 via a common manifold 28 . the needle subassembly 30 includes a needle 32 having a protective needle sleeve 34 and needle cap 36 , and interconnect tubing 38 between needle 32 and manifold 28 . needle subassembly 30 further includes a d sleeve 40 and tubing clamp 42 positioned about the interconnect tubing 38 . blood removal tubing 22 may be provided with a y - connector 44 interconnected with a blood sampling subassembly 46 . as shown in fig4 the blood removal / return assembly includes first integral passageway 190 a connected to the bottom of reservoir 150 , tubing loop 192 and second integral fluid passageway 190 b interconnected with tubing loop 192 and blood return tubing 24 . as seen in fig4 , cassette assembly 110 of fig2 , 3 , 11 and 12 includes a first integral anticoagulant passageway 120 a interconnected with the anticoagulant tubing 26 of the blood removal / return tubing assembly 20 . the cassette assembly 110 further includes a second integral anticoagulant passageway 120 b and a pump - engaging , anticoagulant tubing loop 122 between the first and second integral anticoagulant passageways 120 a , 120 b . the second integral anticoagulant passageway 120 b is interconnected with anticoagulant tubing 54 . the anticoagulant tubing assembly 50 includes a spike drip chamber 52 , ( fig2 , 3 , 11 and 12 ) connectable to an anticoagulant source , anticoagulant feed tubing 54 and a sterile barrier filter 56 . during use , the anticoagulant tubing assembly 50 supplies anticoagulant to the blood removed from a donor / patient 4 to reduce or prevent any clotting in the extracorporeal tubing circuit 10 . cassette assembly 110 also includes a first integral blood inlet passageway 130 a interconnected with blood removal tubing 22 of the blood removal / return tubing assembly 20 . the cassette assembly 110 further includes a second integral blood inlet passageway 130 b and a pump - engaging , blood inlet tubing loop 132 between the first and second integral blood inlet passageways 130 a , 130 b . the first integral blood inlet passageway 130 a includes a first pressure - sensing module 134 and inlet filter 136 , and the second integral blood inlet passageway 130 b includes a second pressure - sensing module 138 . the second integral blood inlet passageway 130 b is interconnected with blood inlet tubing 62 of the blood inlet / blood component tubing assembly 60 . blood inlet tubing 62 is also interconnected with input port 392 of blood processing vessel 352 to provide whole blood thereto for processing . to return separated blood components to cassette assembly 110 , the blood inlet / blood component tubing assembly 60 further includes a red blood cell ( rbc ) outlet tubing 64 with outlet port 520 and plasma outlet tubing 68 with outlet port 456 . alternatively the outlet tubing and outlet ports could be for other blood components such as platelets . a control port for controlling the interface is shown at 61 . the blood inlet tubing 62 , rbc outlet tubing 64 , and plasma outlet tubing 68 all pass through first and second strain relief members 72 and 74 and a braided bearing member 76 there between . this advantageously allows for a sealess interconnection , as taught in u . s . pat . no . 4 , 425 , 112 incorporated by reference herein . as shown , multi - lumen connectors 78 can be employed in the various tubing lines . an optional replacement fluid tubing assembly 960 may be provided for delivery of replacement fluid such as sterile saline solution ( s ) ( or replacement / exchange rbcs or plasma , e . g .) to the donor / patient 4 . as shown , the replacement fluid assembly 960 includes at least a replacement fluid inlet tubing line 962 attached to the cassette 110 in fluid communication with an internal replacement fluid passageway 140 a which is in turn connected to a replacement fluid tubing loop 142 which is connected back to the cassette 110 and an internal replacement fluid passageway 140 b . further internal passageways or spurs 144 a and 144 b and a tubing loop 146 are also shown . internal passageway 144 b is blocked off to disallow any fluid flow therein or therethrough . no outlet tubing line is preferably connected thereto and passageway 144 b may also be omitted . the replacement fluid assembly 960 further preferably includes one or more spike assemblies 964 a - 964 b with optional associated sterile barrier devices 966 a - 966 b and tubing connection lines 968 a - 968 b which may be connected to tubing line 962 via a y - connector 969 as shown . one or more slide clamp ( s ) 970 may also be included . as the plasma proteins may be frozen before use the sterile barrier devices 966 a - 966 b are optional . although the replacement fluid assembly is shown as introducing such fluid through 140 a and tubing loop 142 such is only exemplary . in other words the fluid could be introduced through other tubing loops for return such as tubing loop 162 or such fluid could even be aspirated through tubing into the system . the plasma outlet tubing 68 of blood inlet / blood component tubing assembly 60 interconnects with a first integral plasma passageway 160 a of cassette assembly 110 . cassette assembly 110 further includes a pump - engaging , plasma tubing loop 162 interconnecting the first integral plasma passageway 160 a and a second integral plasma passageway 160 b . the second integral plasma passageway 160 b includes first and second spurs 164 a and 164 b . the first spur 164 a is interconnected to the plasma collection tubing assembly 90 . the plasma collection tubing assembly 90 may be employed to collect plasma proteins during use and includes plasma collector tubing 92 , plasma separator or plasma separator unit 205 , plasma collector tubing 93 and one or more plasma collection bags , containers or reservoirs 94 . a slide clamp 96 may be provided on plasma collector tubing 93 . the plasma collection tubing assembly 90 may also be employed for further separation of the plasma component as will be described in more detail below . the second spur 164 b of the second integral plasma passageway 160 b is interconnected to a plasma return tubing loop 166 to return plasma to donor / patient 4 . for such purpose , the plasma return tubing loop 166 is interconnected to the top of the blood return reservoir 150 of the cassette assembly 110 . the plasma return assembly also returns plasma after separation or concentration . the post separation return includes tubing 963 which connects to tubing 962 , spurs 140 a and 140 b as well as pumps engaging plasma tubing loop 142 . spur 144 a is connected to plasma return loop or tubing 146 to deliver plasma to cassette reservoir 150 for ultimate delivery to the donor / patient 4 . spur 140 b is not used in the configuration shown and is closed off . similarly this sub - assembly can be used to provide replacement fluid through 962 , 140 a , tubing loop 142 , 140 b and 146 to return reservoir 150 . if no replacement fluid is required the portion of tubing 962 related to the replacement fluid sub - assembly above the connection with tubing 963 may be omitted . although the plasma return assembly is shown returning plasma through tubing loop 142 , the plasma could also be returned through another pump loop arrangement such as 162 . the plasma collection tubing assembly further includes a plasma separation sub - assembly shown in fig2 , 3 , 5 , 6 , 11 and 12 including hollow fiber membrane separator or concentrator 205 . the hollow fiber membrane separator is the plasma separator or plasma separator unit . tubing 92 is interconnected to the inlet 203 of the separator 205 . tubing 93 is interconnected to the outlet 206 of the membrane separator 205 . plasma collection tubing assembly 90 also includes tubing 963 , interconnected to second outlet 208 for returning plasma or proteins that are not to be collected . the plasma return assembly including return tubing 963 connects to tubing 962 and spur 140 a as described above . the plasma protein membrane concentrator or plasma membrane separator 205 includes inlet 203 in first end cap 214 and outlet 206 in the opposite end cap 216 . hollow fiber membranes are arranged between the two end caps 214 and 216 . such hollow fiber membranes include inter - capillary space ( ic ) within the hollow fibers and an extra - capillary space ( ec ) outside the hollow fibers . the pore size of the membrane forming the hollow fibers may be selected so that components such as plasma or optionally , protein of selected molecular weight may pass between the ic and ec spaces . thus , if plasma separated from whole blood enters through tubing 92 and inlet 203 into the ic space , plasma and any proteins able to pass through the membrane pores to the ec space will pass through outlet 208 and tubing 963 . table 1 below shows various protein factions and their molecular weight in kilodalton . the pore size of the membrane can be chosen to have a cut off value to pass through the membrane all but the desired protein fractions such as those given in the table . for example , the pore size could be such to pass all below 50 kilodaltons or the pore size could be selected to pass through the membrane those in a range in which the cut off value is selected between 50 kda and 1300 kda . the pore size could be selected to have a cut off value even lower than 50 kilodaltons such that only plasma liquid and sodium chloride pass through the membrane with all plasma proteins being collected . for example , a membrane having a pore size such that only constituents with a molecular weight of less than 50 kda will pass , all proteins in table 1 will be collected through outlet 206 with only plasma less proteins being returned through outlet 208 . for another example , a membrane having a pore size such that only constituents having a molecular weight of less than 150 kda will be returned , only a portion of the proteins with a molecular weight greater than 150 kda will be collected . plasma and other plasma proteins of less than 150 kda molecular weight will pass through the membrane to outlet 208 . in the embodiment of fig2 and 5 , plasma proteins to be collect are mixed with photosensitizer in bag or container 94 . outlet 206 of the membrane separator 205 is fluidly connected to the collection container or bag 94 . photosensitizer for pathogen reduction may be included in plasma collection bags , containers or reservoirs 94 as part of the tubing assembly and the plasma collection assembly . the pathogen reduction process will be more fully described below . the photosensitizer may be in liquid form in bag 94 or it , alternatively could be in dry form for mixing with the plasma proteins . the photosensitizer may be present in plasma collection bag 94 at any desired concentration from about 1 μm up to the solubility of the photosensitizer in the plasma proteins . for 7 , 8 - dimethyl - 10 - ribityl isoalloxazine a concentration range between about 1 μm and about 160 μm may be used . the amount of photosensitizer to be mixed with the plasma proteins will be an amount sufficient to adequately inactivate microorganisms therein , but less than a toxic , ( to humans or other mammals ), or insoluble amount . if the bag , container or reservoir 94 is the container used for illumination , it should be photo - permeable . blood bag or photo - permeable container 94 may be prepackaged to contain the photosensitizer in the either dry or aqueous form as shown in fig2 and 5 . the dry form may be in a dry powder form , a pill , capsule , tablet form or in various combinations therefore . the term dry solid or dry form envisions the components being in a loose powered state or in a solid state such as a pill , capsule , tablet capable of dissolving in fluid or any equivalent thereof known to one skilled in the art . in the alternative embodiment of fig3 and 6 , the photosensitizer is in dry form in cartridge 98 which is also part of the tubing assembly and the plasma collection assembly . the plasma proteins pass through cartridge 98 , mixing with the dry photosensitizer , on the way to bag or container 94 . the cartridge 98 could be another bag , a flask , a reservoir , a small cylinder or any similar container known in the art . also the tubing 93 itself could contain certain forms of prepackaged photosensitizer . cartridge 98 is located in plasma collector tubing 93 as shown in fig3 and 6 . as described above the dry form may be in a dry powder form , a pill , capsule , tablet form or in various combinations therefore . the plasma collection assembly 90 may also include an optional prion filter . such a filter may be a media filter as shown or , alternatively could be a membrane filter . as shown in fig7 the filter 95 may be located in tubing 93 between the outlet 206 of the membrane separator 205 and the collection bag 94 . if the cartridge 98 is used to introduce dry form photosensitzer into the system and into bag 94 , the filter 95 ( shown in solid lines in fig8 ), may be alternatively between the outlet 206 of the membrane separator and the dry cartridge 98 in tubing 93 . alternatively the filter may be between the cartridge 98 and the collection bag 94 in tubing 93 as shown in dashed lines in fig8 . as shown in fig2 , 3 , and 4 the rbc outlet tubing 64 of the blood inlet / blood component tubing assembly 60 is interconnected with integral rbc passageway 170 of cassette assembly 110 ( fig4 ). the integral rbc passageway 170 includes first and second spurs 170 a and 170 b , respectively . the first spur 170 a is interconnected with rbc return tubing loop 172 to return separated rbc to a donor / patient 4 . for such purpose , the rbc return tubing loop 172 is interconnected to the top of blood return reservoir 150 of the cassette assembly 110 . the second spur 170 b may be closed off if red blood cells are not to be collected or may be connected with an rbc collection tubing assembly 950 . rbc collection tubing assembly 950 includes rbc collector tubing 952 , at least one rbc collection reservoir , container , or bag 954 , and sterile barrier filter / drip spike assembly 956 . one or a larger practical number ( not shown ) of rbc bag ( s ) 954 may be connected to the collector tubing 952 . moreover , although not shown here one or more white blood cell ( wbc ) filtration devices and / or rbc storage solution connections and / or bags may also be pre - connected to and / or be included as component parts of the rbc collection tubing assembly 950 . vent bag tubing assembly 100 is also interconnected to the top of blood return reservoir 150 of cassette assembly 110 . the vent bag tubing assembly 100 includes vent tubing 102 and a vent bag 104 . during use , sterile air present since packaging within cassette assembly 110 , and particularly within blood return reservoir 150 , cyclically passes into and back out of vent tubing 102 and vent bag 104 , as will be further described . as illustrated in fig4 , pump - engaging tubing loops 122 , 132 , 142 , 162 and 192 extend from cassette member 115 to yield an asymmetric arrangement thereby facilitating proper mounting of cassette assembly 110 on blood component separation device 6 for use . in normal operation , whole blood will pass through needle assembly 30 , blood removal tubing 22 , cassette assembly 110 and blood inlet tubing 62 to processing vessel 352 . the whole blood will then be separated into blood components in vessel 352 . during product collection , plasma , and optionally rbcs will be passed out of vessel 352 through corresponding ports 520 and 456 for collection or further separation . the plasma to be further separated will pass into the plasma separator 205 with photosensitizer being added to any collected plasma proteins . in the cassette assembly the reservoir 150 having upper and lower ultrasonic sensors ( not shown ) is provided such that , during the blood processing mode , return blood will be removed from reservoir 150 during each blood return / replacement delivery sub - mode and accumulated during each blood removal sub - mode . when uncollected platelets and plasma ( and potentially white blood cells ) or red blood cells not collected and / or replacement fluid ( s ) have accumulated in reservoir 150 up to upper ultrasonic level sensor ( not shown ), operation of the pump 1090 associated with pump loop 192 will be initiated to remove the blood or replacement components from reservoir 150 through 190 a , 192 , and 190 b and transfer the same back to the donor / patient 4 via the return / delivery tubing 24 and needle assembly 20 . when the fluid level in the reservoir 150 drops down to the level of the lower ultrasonic level sensor , the return / delivery peristaltic pump 1090 will automatically turn off reinitiating blood removal sub - mode . the cycle between blood removal and blood return / replacement delivery sub - modes will then continue until a predetermined amount of plasma , and rbcs or other collected blood components have been harvested or collected . pump 1040 is associated with tubing pump loop 142 , pump 1066 is associated with tubing loop 162 , pump 1030 is associated with tubing loop 132 , pump 1020 is associated with tubing loop 122 , and pump 1090 is associated with tubing loop 192 when the cassette 110 is mounted on pump / valve / sensor assembly 1000 . the channel assembly 200 includes a channel housing 204 which is disposed on the rotatable centrifuge rotor assembly 568 ( fig1 ) and which receives a disposable blood processing vessel 352 . the channel housing 204 provides a mounting for the blood processing vessel 352 such that the blood may be separated into the blood component types in a desired manner . in this regard , the channel housing 204 includes a generally concave channel ( not shown ) in which the blood processing vessel 352 is positioned . the blood processing channel vessel 352 is disposed within the channel housing 204 such that blood can be provided to the blood processing vessel 352 during rotation of the channel housing 204 , to be separated into its various blood component types by centrifugation , and to have various blood component types removed from the blood processing vessel 352 during rotation of the channel housing 204 . in addition , the channel allows for a blood priming of the blood processing vessel 352 ( i . e ., using blood as the first liquid which is provided to the blood processing vessel 352 in an apheresis procedure ). the blood processing vessel 352 is disposed within the channel of the channel housing 204 for directly interfacing with and receiving a flow of blood in an apheresis procedure . further details of the blood processing vessel and parts of the apheresis system are described in u . s . pat . no . 6 , 514 , 189b1 . as shown in fig2 , 3 , 11 and 12 , blood is introduced into the interior of the blood processing vessel 352 through a blood inlet port 392 from inlet tubing 62 . the blood inlet port 392 extends into an interior portion of the blood processing vessel 352 . blood which is provided to the blood processing vessel 352 by the blood inlet port 392 is separated into at least plasma and optionally rbcs under centrifugal forces upon rotation of centrifuge rotor assembly 568 at an rpm for separation . separated plasma exits the blood processing vessel through port 456 and tubing 68 . separated red blood cells exit the blood through port 520 and tubing 64 . the apheresis system includes various valve assemblies shown schematically at 1120 , 1110 , and 1100 in fig4 . these valves are part of the pump / valve / sensor assembly 1000 . the apheresis system described herein provides for continuous separation of plasma and optionally red blood cells ( rbcs ) and / or plasma with continuous plasma separation and photosensitizer mixing . both the plasma separation and photosensitizer mixing occurs on - line when the blood removal / return assembly is on the rotor assembly 568 with respect to the apheresis system step . prion filtration may also occur on - line . for example , continuous separation may be provided with contemporaneous collection of plasma proteins with photosensitizer and / or with collection of rbcs . it is anticipated that four to eight tranfusable dosage double plasma protein products may be collected in a single apheresis procedure from a single donor . the plasma proteins to be treated may be illuminated in container and / or bag 94 or transferred to a photo - permeable container . the container to be illuminated is optionally agitated and exposed to photoradiation for a time sufficient to substantially inactivate the microorganisms . the photo - permeable container is made of transparent or semitransparent plastic , and the agitating device is preferably a shaker table . fig1 illustrates a bag or container 94 under illumination . the illuminator is shown at 400 . bag 94 rests on support platform 406 which could be a shaker table . the radiation sources are shown at 403 and 404 . the radiation emitting elements 401 and 402 may be visible or ultraviolet light or a combination thereof . the control unit 407 for the illuminator 400 controls the radiation sources as well as any shaker table . replacement fluid ( s ) are also optionally administrable within the procedures of the present embodiments . sterile saline solution ( s ) is one of the optional replacement fluids considered for use herein . thus , if / when large fluid amounts of plasma and / or rbcs are taken from a donor / patient , replacement fluid ( s ) may be delivered in return to leave the donor / patient adequately hydrated . the initiation of blood processing provides for the collection of plasma product or plasma protein product in one or more reservoir ( s ) 94 containing photosensitizer optionally with collection of red blood cells in one or more reservoir ( s ) 954 . alternatively , either rbc collection in reservoir ( s ) 954 or plasma collection in reservoir ( s ) 94 may also be selectively completed in separate procedures . during either collection procedure , blood component separation device 6 preferably controls the initiation and termination of successive blood removal and blood return . additionally , blood component separation device 6 will control the plasma and rbc collection processes according to predetermined protocols , preferably including control over the valve assemblies 1100 , 1110 and 1120 of the pump / valve / sensor assembly 1000 , and / or the appropriate pumps 1020 , 1030 , 1040 , 1066 and / or 1090 . initially , blood priming is carried out to prime the disposable system 10 . during blood priming , it may be desirable that the component separation begins even during the priming stage , and that some plasma enters plasma protein collection tubing assembly 90 . thus plasma may flow out through the outlet port 456 to tubing 68 . following and / or contemporaneously with the blood priming phase , blood separation control device 6 provides control signals to pump / valve / sensor assembly 1000 so that the optional replacement fluid lines may also be primed . in particular , replacement fluid valve assembly 1100 is opened and replacement fluid inlet pump 1040 is switched on to provide for the pumping of saline solution ( or other replacement fluid ( s )) through replacement fluid inlet tubing 962 and the replacement fluid tubing loop 142 into replacement fluid introduction tubing line 146 for initial collection in cassette reservoir 150 , though this initial priming collection will likely and preferably does constitute a small amount of replacement fluid ( s ). after priming is completed , yet still during the set - up phase , blood component separation device 6 may provide appropriate control signals to the pump / valve / sensor assembly 1000 such that all separated blood components flowing out of processing vessel 352 will first pass to return / delivery reservoir 150 . optionally , one or more cycles of separation and return of all blood components back to the donor may be performed before collection . also , blood component separation device 6 may continue operation of blood inlet pump assembly 1030 associated with pump loop 132 during one or more these initial blood component return sub - modes . to establish the desired ac ratio , blood component separation device 6 provides appropriate control signals to anticoagulant peristaltic pump 1020 so as to introduce anticoagulant into the blood inlet flow at a predetermined rate . the inlet flow rate of anti - coagulated blood to blood processing vessel 352 may be limited by a predetermined , maximum acceptable anticoagulant infusion rate ( acir ) to the donor / patient 4 . when collection begins , blood component separation device 6 may provide control signals so that plasma divert valve assembly 1110 switches to divert the flow of separated plasma pumped from vessel 352 through plasma outlet tubing 68 and plasma tubing loop 162 into plasma collector tubing 92 and into inlet 203 of membrane separator 205 . see also fig5 and 6 which show simplified views of the apheresis system . additionally , if plasma is to be collected alone , red blood cells will continue to flow from vessel 352 through outlet tubing 64 through return tubing loop 172 and into blood return reservoir 150 . however , if rbcs are to be collected , contemporaneously with plasma , then red blood cell valve 1120 switches to divert the flow of separated rbcs flowing from tubing 64 to and through spur 170 b ( of cassette 110 ) and into and through tubing line 952 to the one or more rbc collection reservoir ( s ) 954 . during any of the collection processes , one or more replacement fluid ( s ) may also be delivered to the donor / patient 4 . thus , whenever the separation device 6 is in a collection rather than the return mode , the replacement fluid inlet valve assembly 1100 may also be opened and the replacement fluid pump 1040 starts to flow replacement fluids from the fluid source ( not shown ) through tubing line 962 , cassette passageways 140 a and 140 b , and tubing loops 142 and 146 into the reservoir 150 . during separation and collection , channel housing 204 can be typically driven at a rotational velocity of about 3000 rpms to achieve the desired hematocrit during the both the setup and component collection phases . correspondingly , the blood inlet flow rate to vessel 352 may be established at below about 64 . 7 ml / min . the desired hematocrit can be reliably stabilized by passing about two whole blood volumes of vessel 352 through vessel 352 before the rbc and / or plasma collection phases are initiated . with respect to plasma collection , which may occur separate from or continuously with red blood cell collection , the separated plasma is pumped via pump 1066 through the plasma collect line 92 through filter separator or concentrator 205 to plasma component collection bag 94 through line 93 . the pore size of the filter 205 determines whether all proteins are collected in container 94 or only those proteins of sufficiently high molecular weight . the separated plasma is pumped out of rotor 352 through port 456 , line 68 , passageway 160 a , tubing 162 , passageway 160 b , by pump 1066 around which tubing 162 extends and flows via plasma collect line 92 into filter or separator 205 . the fraction of plasma proteins that do not pass through the filter membrane from the ic to the ec side enter tubing 93 and flow into storage bag 94 . in the embodiments of fig2 and 5 , photosensitizer contained in plasma component collection bag 94 mixes in the bag 94 with the collected plasma component or plasma proteins . this photosensitizer may be in liquid form for ease of mixing though dry form may be used . in the embodiment of fig3 and 6 , the photosensitizer , in dry form , is dissolved and mixed with the plasma component or plasma proteins as they pass through cartridge 98 in tubing 93 on their way to bag or container 94 . thus , the bag or container 94 will contain plasma proteins mixed with photosensitizer . if a prion filter is included in tubing 93 as shown in fig7 , 8 and 9 additional filtration of the desired plasma proteins will occur to remove the specific prion proteins . as the plasma proteins are pushed through the filter 95 , ( or optionally 97 ) by the continuous process the filter media or filter ligands will capture and remove the prion proteins prior to collection of the desired plasma proteins in bag 94 . the remainder of the plasma and / or proteins that pass to the ec side flow out of the filter 205 through outlet 208 , tubing 963 , 962 , passageway 140 a , tubing loop 142 , passageway 140 b , tubing 146 , to reservoir 150 and back to the donor 4 . an enriched plasma product , which may contain several times the normal amount or an increased concentration of the desired protein , could be produced by simply processing more plasma through the filter , concentrator or separator 205 . following collection of the desired quantity of red blood cells , ( if any ), the separation and collection of plasma proteins , and after blood separation device 6 has provided control signals to divert assemblies 1110 and 1120 so as to divert the respective separated plasma and separated rbc flows to reservoir 150 , if further blood processing is not desired , rinse back procedures may then be completed . the plasma pump 1066 is set at the full plasma rate equal to rate of the return / delivery pump 1090 for rinse back . at the end of the procedures , the plasma bag ( s ) 94 and the red blood cell reservoir ( s ), if any , 954 may be disconnected from the extracorporeal tubing circuit 10 . after disconnection of the plasma bag ( s ) 94 , such bags may be placed in an illuminator 400 to activate the photosensitizer to inactivate any pathogens contained therein as shown in fig1 . alternatively , the plasma proteins could be transferred to a photopermeable bag for illumination . radiation sources 403 , 404 illuminate bag 94 ( or a subsequent bag containing the contents of bag 94 ) with optional agitation of such bag . fig9 indicates another option for photoradiation . in this embodiment the plasma proteins with photosensitizer are exposed to the required radiation to activate the photosensitizer on - line . as shown in fig9 , the photosensitizer is added to the plasma proteins to be collected when such proteins pass through the cartridge 98 , ( as described for the embodiment of fig3 and 6 ). however tubing 93 is made of sufficiently photo - transmissive material such that the needed radiation for photosensitizer activation can occur in the tubing 93 . radiation source 99 adds the required radiation . this embodiment illustrates a flow - through system which permits radiation while the fluid or plasma proteins flows by the source illuminator . fig1 illustrates an alternative plasma collection assembly . in this embodiment the separated plasma from the blood processing vessel 352 is filtered and mixed with photosensitizer prior to further plasma separation . as shown in fig1 , prion filter 195 is in tubing 92 to filter separated plasma from the blood processing vessel 352 . after filtration , the filtered plasma mixes with photosensitizer as it passes through cartridge 198 containing dry form photosensitizer . this variation is particularly advantageous when both separated fractions of the plasma are collected as described below with respect to fig1 . alternatively only the prion filter 195 or the cartridge 198 could be in tubing 92 with the other being in tubing 93 . cartridge 198 could also be omitted if the photosensitizer is in the plasma collection bag 94 . fig1 illustrates an alternative embodiment wherein both separated fractions of plasma are collected . in this embodiment replacement fluid would typically be provided to the donor . as shown in fig1 the cartridge 198 may provide the photosensitizer to be mixed with the plasma . the plasma , after separation in plasma separator 205 , is provided to collection bags 94 and 294 . as described previously plasma proteins that do not pass through the membrane of the membrane separator 205 may be collected in container or collection bag 94 . plasma liquid or ultrafiltrate as well as any proteins with molecular weights sufficiently low to pass through the membrane separator will pass through tubing 293 and open slide clamp 296 to second collection bag 294 . if the cartridge 198 is not used , liquid or dry form photosensitizer may be in containers 94 and 294 for subsequent mixing with the plasma and proteins for collection . the embodiment of fig1 illustrates a further separation tubing set wherein the separated plasma enters the ec side of the plasma separator 205 through inlet port 1203 . thus plasma proteins that do not pass through the membrane , in this variation may be collected by exiting the ec side passing through tubing 193 to plasma collection container 94 . although this embodiment shows plasma and plasma proteins that pass through the filter being returned to the donor from the ic side through tubing 1963 and 962 such low molecular weight elements could alternatively be collected in another collection container . the simplified fig5 and 6 also indicate another option . as shown in fig5 and 6 , the plasma entering the plasma separator 205 is pumped on the inlet side 203 by pump 1066 and also the outlet ( ec ) side 208 by pump 1040 . however the locations of the pumps can be varied . for example , as shown in fig5 and 6 there also may be a pump on the ic exit side , ( illustrated in phantom lines as 1040 a ). this pump may be used with the inlet pump 1066 alone , ( no pumping through 1040 on the ec side ) or it may be used with pump 1040 alone , ( no pumping through 1066 into the inlet or ic side . thus two pumps are utilized but the exact locations of such pumps may be varied . having pump 1040 a pump on the ic side from 206 provides flow through the membrane by positive pressure on the ic side thus avoiding any degassing of the fluid as may occur using pumps 1066 and 1040 which exerts negative pressure on the ec side . if the membrane becomes blocked when pump 1040 a is used the compression force of the rollers of pump 1040 a could be such that they will lift sufficiently and provide less occlusion for the over volume or pressure . thus it can function as a pressure relief valve . this continuous apheresis procedure permits desirable proteins to be collected , with on - line preparation for subsequent pathogen treatment , and removed from a donor with the remainder of the plasma proteins being returned to the donor . this enables maximum collection and concentration of the desired proteins , instead of the smaller amount of desired protein contained within a single donation . using this procedure , plasma protein fractions with photosensitizer may be collected at the same time as other cellular components . specifically , desired plasma proteins may be collected from a donor , while the undesired components may be returned to the donor . this would enable greater amounts of desired plasma proteins to be collected from a single donor , without increasing the risk to the donor as the amount of fluid volume removed from a donor would not be detrimental . more plasma can be processed resulting in the collection of increased amounts of plasma protein . however , from the donor perspective the increased collection of proteins can be collected with the same volume removal as a typical plasma collection . the final concentration of the protein - enriched product could be adjusted by adjusting the ratio of the plasma flow into the filter and the plasma flow out of the filter . this can be done by adjusting pump speed of pump 1066 , 1040 or 1040 a . for example , if the membrane excluded all proteins and the flow rate through the filter was half that of the plasma flow into the filter , the resultant concentration of the proteins would be double that of normal donor plasma . if it is desired to collect high molecular weight proteins , the filter / column 205 could separate on a continuous basis the albumin and other low molecular weight proteins and return them to the donor , while collecting higher molecular weight fractions such as fibrinogen , igg , von willebrand factor and factor viii . alternatively , if lower molecular weight proteins are desired for collection , the higher molecular weight proteins could be returned to the donor , while the lower molecular weight proteins are collected by changing the tubing so that those that pass through the membrane are collected in a reservoir containing photosensitizer rather than returned . in this configuration outlet 208 would be connected to tubing 93 with outlet 206 being connected to tubing 963 for return to the donor . the separation specificity can be accomplished by selecting membranes which have pore sizes which correspond to the molecular weight of the desired protein . the high concentration protein collected could be used to enrich the plasma of a patient for therapeutic purposes . the high - concentration product may also be used for additional fractionation as described below where its yield of proteins would be much higher compared to normal plasma and thus produce an increased amount of protein concentrate products . fig1 illustrates , in block diagram form , the process of taking whole blood from a donor 11 ( whole blood ) and using apheresis apparatus 12 as described above to collect a concentrated protein fraction . the on - line process includes the addition of photosensitizer 13 . the collected plasma proteins 14 are illuminated 15 to inactivate the photosensitizer . the collected plasma proteins from the apheresis process may optionally be provided to plasma fractionation center 16 , and optionally pooled with other collections which have been treated for pathogen inactivation , for further fractionation or concentration of such product utilizing a known plasma fractionation process such as cold alcohol fractionation 18 ( also known as cohn fractionation ) or chromatography 17 . other known fractionation processes could be used . this process could be used to provide a highly concentrated plasma protein infusion product 19 such as ivig or clotting factor that has been treated for pathogen inactivation . it will be apparent to those skilled in the art that various modifications and variations to the methods and structure of the present invention without departing from its scope . thus it should be understood that the invention is not be limited to the specific examples given . rather , the invention is intended to cover modifications and variations provided they come within the scope of the following claims and their equivalents .

method and apparatus for separating plasma from blood in a separation vessel , separating the separated plasma into desired plasma proteins in a plasma separator fluidly connected to the separation vessel to receive the separated plasma , and adding photosensitizer to the desired plasma proteins for viral inactivation treatment of such proteins .

in the following description , reference is made to an illustrative embodiment for carrying out the invention . it is understood that other embodiments may be utilized without departing from the scope of the invention . for example , the invention is disclosed in the context of a vvi modality pacer for treating bradycardia . it should be appreciated that the technique for evoked response detection could also be applied to a dual chamber device where capture detection is used to control the energy of the pacing stimuli delivered to the atria . in a similar fashion the ability to detect the evoked response will find utility in tachyarrhythmia pacers where direct evidence that capture has occurred can be used as feedback to control the delivery of tachyarrhythmia therapies . the present invention will now be more fully described with reference to various figures of the drawings , fig1 showing generally how a pacemaker 10 in accordance with the present invention may be implanted in patient 12 . a pacemaker lead 14 is electrically coupled to pacemaker 10 and extends into the patient &# 39 ; s heart 16 via a vein 18 . the distal end of the lead 14 includes one or more exposed conductive electrodes for receiving electrical cardiac signals and for delivering electrical pacing stimuli to the patient &# 39 ; s heart 16 . in accordance with the invention to be hereinafter described , the distal end of the pacing lead 14 also incorporates an oxygen transducer ( not shown in fig1 due to the small scale of that figure ) for producing electrical signals representative of the oxygen saturation of the blood contained within the right ventricle of the heart 16 . turning to fig2 a block diagram of pacemaker 10 from fig1 is shown . although the present invention is described in conjunction with the pacemaker 10 having a microprocessor - based architecture , it will be understood that it could be implemented in any logic - based , custom integrated circuit architecture , if desired . it will also be understood that the present invention may be utilized in conjunction with other implantable medical devices , such as cardioverters , defibrillators , diagnostic monitoring devices , cardiac assist systems , and the like . in the embodiment shown in fig1 pacemaker 10 includes an activity sensor 20 , which may be , for example , a piezoelectric element bonded to the inside of the pacemaker &# 39 ; s housing . sensor 20 provides a sensor output which varies as a function of a measured parameter that relates to the metabolic requirements of patient 12 . in addition , pacemaker 10 includes an oxygen saturation sensor 22 disposed at the distal end of lead 14 , as previously noted , which may be similarly used to ascertain the metabolic requirements and / or cardiac output of patient 12 . the construction of the lead is not critical to the invention , various suitable lead arrangements being known to those skilled in the art . see for example , u . s . pat . no . 4 , 750 , 495 to moore , et al . which employs a two wavelength reflectance oximeter located in the right ventricle and uses measured oxygen saturation to control pacing rate . the &# 39 ; 495 patent is incorporated herein by reference . pacemaker 10 is schematically shown in fig2 to be electrically coupled by a pacing lead 14 to a patient &# 39 ; s heart 16 . lead 14 includes an intracardiac electrode 24 and oxygen saturation sensor 22 located near its distal end and positioned within the right ventricular chamber heart 16 . lead 14 can carry either unipolar or bipolar electrodes as is well known in the art . in the presently disclosed embodiment , lead 14 which couples pacemaker 10 to the ventricular endocardium can comprise a steroid - tipped , unipolar lead with an integral oxygen saturation transducer of the type describe in the aforementioned reference . electrode 24 is coupled by a suitable lead conductor 14a through input capacitor 26 to node 28 and to input / output terminals of an input / output circuit 30 . output from the first sensor 20 is coupled to input / output circuit 30 . output from oxygen sensor 22 is also coupled to input / output circuit 30 by a suitable lead conductor 14b . input / output circuit 30 contains the analog circuits for interface to the heart 16 , first sensor 20 , oxygen sensor 22 , and antenna 52 , as well as for the application of stimulating pulses to heart 16 to control its rate as a function thereof under control of the software - implemented algorithms in a microcomputer circuit 32 . microcomputer circuit 32 comprises an on - board circuit 34 and an off - board circuit 36 . on - board circuit 34 includes a microprocessor 38 , a system clock circuit 40 , and on - board ram 42 and rom 44 . off - board circuit 36 includes an off - board ram / rom unit 46 . microcomputer circuit 32 is coupled by data communication bus 48 to a digital controller / timer circuit 50 . microcomputer circuit 32 may be fabricated of custom integrated circuit devices augmented by standard ram / rom components . it will be understood that the electrical components represented by fig2 are powered by an appropriate implantable battery power source , not shown , in accordance with common practice in the art . an antenna 52 is connected to input / output circuit 30 for purposes of uplink / downlink telemetry through rf transmitter / receiver ( rf tx / rx ) unit 54 . telemetering both analog and digital data between antenna 52 and an external device , such as an external programmer ( not shown ), is accomplished in the presently disclosed embodiment by means of data first being digitally encoded and then pulse position modulate on a damped rf carrier , as substantially described in co - pending u . s . patent application ser . no . 07 / 468 , 407 , filed on jan . 22 , 1990 , entitled &# 34 ; improved telemetry format ,&# 34 ; which is assigned to the assignee of the present invention and which is incorporated herein by reference . a crystal oscillator circuit 56 , typically a 32 , 768 hz crystal - controlled oscillator , provides main timing clock signals to digital controller / timer circuit 50 . a vref / bias circuit 58 generates a stable voltage reference and bias currents for the analog circuits of input / output circuit 30 . an analog to digital converter / multiplexor ( adc / mux ) unit 60 digitizes analog signals and voltages to provide &# 34 ; real time &# 34 ; telemetry of oxygen saturation and intracardiac signals and battery end - of - life ( eol ) replacement function . a power - on reset ( por ) circuit 62 functions as a means to reset circuitry and related functions to a default condition upon detection of a low battery condition , which will occur upon initial device power - up or will transiently occur in the presence of electromagnetic interference , for example . the operating commands for controlling the timing of pacemaker 10 are coupled by bus 48 to digital controller / timer circuit 50 wherein digital timers and counters are employed to establish the overall escape interval of the pacemaker , as well as various refractory , blanking , and other timing windows for controlling the operation of the peripheral components within input / output circuit 30 . digital controller / timer circuit 50 is coupled to a sense amplifier 64 and an electrogram amplifier 66 for receiving amplified and processed signals picked up from electrode 24 through lead conductor 14a and capacitor 26 representative of the electrical activity of the patient &# 39 ; s heart 16 . sense amplifier 64 amplifies sensed electrical cardiac signals and provides this amplified signal to peak sense and threshold measurement circuitry 65 , which provides an indication of peak sense voltages and the measured sense amplifier threshold voltage on multiple conductor signal path 67 to digital controller / timer circuit 50 . the amplified sense amplifier signal is also provided to a comparator 69 . the electrogram signal developed by egm amplifier 66 is used on those occasions when the implanted device is being interrogated by an external programmer ( not shown ) in order to transmit by uplink telemetry a representation of the analog electrogram of the patient &# 39 ; s electrical heart activity as described in u . s . pat . no . 4 , 556 , 063 , issued to thompson et al ., assigned to the assignee of the present invention and incorporated herein by reference . input / output circuit 30 further includes sensitivity control circuitry 75 coupled between digital controller / timer circuit 50 and sense amplifier circuit 64 . sensitivity control circuit 75 controls the sense amplifier gain and thus the sensing threshold of sense amplifier 64 as instructed by digital controller / timer 50 . an output pulse generator 68 provides the pacing stimulus to the patient &# 39 ; s heart 16 through coupling capacitor 74 in response to a pacing trigger signal developed by digital controller / timer circuit 50 each time the escape interval times out , or an externally transmitted pacing command has been received , or in response to other stored commands as is well known in the pacing art . digital controller / timer circuit 50 is coupled to an activity circuit 70 for receiving , processing , and amplifying signals received from activity sensor 20 . activity circuit 70 produces an activity signal which is representative of the patient &# 39 ; s metabolic requirements . similarly , the digital controller / timer circuit 50 is coupled to an oxygen saturation circuit 72 for receiving , amplifying and processing sensor output from oxygen sensor 22 . in the presently disclosed embodiment of the invention , oxygen saturation circuit 72 produces an amplified , filtered analog oxygen signal which is received by digital controller / timer circuit 50 . the design of the oxygen saturation sensing circuitry is not critical to the invention herein described , various suitable designs being known to those skilled in the art . see for example , the &# 39 ; 495 patent to moore et al . in conjunction with adc / mux 60 , digital controller / timer circuit 50 samples and digitizes the oxygen saturation signal from the oxygen saturation circuit 72 to obtain the digital representation of the peak - to - peak value of the intracardiac blood oxygen saturation during each cardiac cycle . this value is provided to microprocessor 34 , which maintains a running average over a previous number of cardiac cycles of the intracardiac pulse temperature . dynamic oxygen sensor 22 is disposed in the right ventricle ( rv ) of the patient &# 39 ; s heart to sense oxygen saturation therein ( rv oxy ), and to provide a sensor output ( output oxy ) related to changes in the fluid oxygen saturation associated with the heart &# 39 ; s mechanical activity , contractility and blood flow . processing by pacemaker 10 of output oxy yields a signal which is proportional to the magnitude of such rv oxygen saturation changes . each sensed or paced rv event will yield a dynamically varying signal . in the preferred embodiment , the last sixteen valid pulse values ( both paced and sensed events ) are used to determine an average oxygen saturation pulse peak value , referred to as the oxygen pulse peak average or &# 34 ; oxy . avg &# 34 ; pacemaker 10 tests for validity of each peak oxygen value on a sample - by - sample basis , based upon the requirement that a sampled oxygen pulse peak value must be within a predetermined range defined by the oxy . avg value . in the preferred embodiment , this validity range is defined as oxygen pulse peak values between 25 % to 400 % of oxy . avg . values outside this validity range are considered artifacts and are ignored . once determined , oxy . avg is used to verify capture on a beat - by - beat basis . a programmable ( 25 % to 75 %, in 12 . 5 % steps ) threshold of oxy . avg value ( a continuous running average of 16 pulse oxygen saturation values ) during a window of time ( t2 ) subsequent to a stimulating pulse will be used to generate a capture detect signal in response to a successful capture due to the stimulating pulse . the capture detect signal is generated when the oxygen saturation circuitry 72 in conjunction with the microcomputer circuit 32 generates a detect signal during the capture detect window t2 . this capture detect signal may be used in a variety of ways , and is illustrated herein in the context of an auto - threshold - type pacer . in this instance , the capture detect signal is communicated to auto threshold logic 61 . auto threshold logic 61 controls the energy content of the pacing pulses delivered by the output circuit 68 to the lead system via capacitor 74 . in the event that a pacing pulse is delivered and no capture detect signal follows , auto threshold logic 61 will generate a control signal allowing input / output circuit 30 to increment the amplitude of the pacing pulses provided by output circuit 68 . auto threshold logic 61 may also decrement the amplitude of the pacing pulses in response to an extended period in which all pacing pulses successfully capture the heart to enable a determination of the minimum energy required to reliably pace the heart . auto threshold logic 1 may also respond to the failure of a pacing pulse to capture the heart by quickly triggering an additional pacing pulse at an increased amplitude . appropriate mechanisms for adjusting the energy content of the pacing pulses generated by output circuit 68 are disclosed in u . s . pat . no . 4 , 858 , 610 issued to callaghan et al ., u . s . pat . no . 4 , 878 , 497 issued to callaghan et al ., and u . s . pat . no . 4 , 729 , 376 issued to decote , all of which are incorporated herein by reference in their entireties . alternative pacing functions which may be modified in response to the detection or nondetection of cardiac depolarizations during the capture detect window are described in u . s . pat . no . 4 , 795 , 366 issued to callaghan et al ., and in the above cited u . s . pat . no . 4 , 305 , 396 issued to whittkampf , both of which are incorporated herein by reference in their entireties . the operation of the invention is illustrated in fig3 . this figure shows simulated tracings of cardiac waveforms and associated oxygen saturation tracing illustrating the theory underlying the present invention . pacing pulses were delivered unipolarly between the tip electrode and electrode corresponding to pacemaker 10 housing ( fig1 ). tracing 1 was taken with the sense amplifier 64 coupled to tip and can electrodes , and corresponds to the signals seen on the pacing lead 14 . tracing 2 corresponds to the signal seen by the oxygen saturation circuit 72 from the sensor 22 . tracing 3 reflects the logic level output of the peak oxygen saturation detect circuitry . tracing 4 corresponds to the capture detect window signal . high logic level signals in tracing 4 correspond to the duration of the capture detect window t2 . tracing 5 corresponds to the logic level output of the evoked response detection circuitry and indicates the occurrence of a sensed ventricular depolarization during the t2 time window . tracing 6 corresponds to the output of the output circuit 68 ( fig2 ). the amplitude of the pacing pulses are reflected by the height of the pulse markers . the occurrence of pacing pulses is also reflected by the artifacts 112 , 114 , 116 , 118 and 120 ( tracing 1 ). the first cardiac waveform 110 results from a normal sinus depolarization of the heart . the sensed detect signal 122 on tracing 3 reflects the normal detection of this event . in the context of the pacer of fig2 this detected depolarization resets the escape interval timer contained within digital controller timer circuit 50 . at the conclusion of the escape interval , timer 50 generates a v pace signal which triggers a ventricular pacing pulse from output circuit 68 . artifact 112 and pacing pulse marker 142 on tracing 6 indicate the delivery of a pacing pulse . a capture detect window is defined thereafter as indicated at 128 , on tracing 4 . no depolarization results , as the pacing pulse is of insufficient amplitude to capture the heart . this lack of capture is evidenced by the fact that no v sense detect signal follows the delivery of the pacing pulse at 112 . in this instance , the auto threshold logic 61 ( fig2 ) generates another ventricular pacing pulse at a programmed upper rate limit interval as indicated by artifact 114 . the amplitude of this pacing pulse is increased , as indicated by pacing pulse marker 144 in tracing 6 . in this instance the second pacing pulse captures the heart as evidenced by the depolarization waveform 115 on tracing 1 . this ventricular depolarization was detected within the capture detect window 130 following the delivery of pacing pulse at 114 , as evidenced by v sense detect signal 124 in tracing 3 and capture detect signal 138 in tracing 5 . the tracings associated with depolarization waveform 121 illustrates a sequence of three pacing pulses delivered at 116 , 118 and 120 . the first two pacing pulses ( 116 and 118 ) fail to capture the heart , as indicated by the absence of v sense detect signals and capture detect signals during capture detect window 132 and 134 . pacing pulse amplitude is increased with each pulse , as indicated by pacing pulse markers 146 , 148 and 150 ( all at the programmable upper rate limit interval ). the third pulse delivered at 120 is successful in capturing the heart as indicated by v sense detect signal 126 and capture detect signal 140 during capture detect window 136 . in fig3 the t1 period extends from the conclusion of ventricular pace signal depicted in the figure by pacing artifacts 112 , 114 , 116 , 118 and 120 . the duration of the t1 period should be short with an expected duration of 10 - 50 milliseconds . the duration of period t2 should be long enough to allow a detection of any pacemaker triggered cardiac response . the inventor believes that 100 to 300 milliseconds is an appropriate duration for t2 . fig4 shows a hardware flow diagram setting forth a state machine description of the detection procedure performed by the circuitry of fig2 . in state a ( 200 ) shown in the flow diagram , both the t1 and t2 timing functions of the capture detection timer in digital controller timer circuit 50 are disabled . this state corresponds to the pacer &# 39 ; s operation during sinus rhythm which inhibits the pacemaker . the state is reentered upon the occurrence of a v sense detect signal as at 122 in tracing 3 . the occurrence of a v paced signal at decision block 202 forces a state transition to state b ( 204 ) where the t1 timing function is enabled . as the period t1 times out the machine moves from state b ( 204 ) to state c ( 208 ) where the t2 window is being timed . the v sense detect signal occurs during t2 and is taken as the indication of an evoked response and a capture detect is declared in block 208 . the expiration of the t2 time period , tested at decision block 210 , triggers adjustment of the pacing pulse amplitude at 212 and the return to state a ( 200 ).

a pacemaker system which includes an oxygen saturation sensor located near the distal end of a transvenous pacing lead generates a cycle - by - cycle variation of oxygen saturation indicative of the mechanical pumping action of the heart . a timer is used to define a detection window after the generation of a pacing pulse . the occurrence of a detected depolarization within the detection window indicates that the pacing pulses capture the heart .